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1
Sato, Shigeto, and Nobutaka Hattori. "Genetic Mutations and Mitochondrial Toxins Shed New Light on the Pathogenesis of Parkinson's Disease." Parkinson's Disease 2011 (2011): 1–7. http://dx.doi.org/10.4061/2011/979231.
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The cellular abnormalities in Parkinson's disease (PD) include mitochondrial dysfunction and oxidative damage, which are probably induced by both genetic predisposition and environmental factors. Mitochondrial dysfunction has long been implicated in the pathogenesis of PD. The recent discovery of genes associated with the etiology of familial PD has emphasized the role of mitochondrial dysfunction in PD. The discovery and increasing knowledge of the function of PINK1 and parkin, which are associated with the mitochondria, have also enhanced the understanding of cellular functions. The PINK1-parkin pathway is associated with quality control of the mitochondria, as determined in cultured cells treated with the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), which causes mitochondrial depolarization. To date, the use of mitochondrial toxins, for example, 1-methyl-4-phynyl-tetrahydropyridine (MPTP) and CCCP, has contributed to our understanding of PD. We review how these toxins and familial PD gene products are associated with and have enhanced our understanding of the role of mitochondrial dysfunction in PD.
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Candelise, Niccolò, Illari Salvatori, Silvia Scaricamazza, Valentina Nesci, Henri Zenuni, Alberto Ferri, and Cristiana Valle. "Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship." Metabolites 12, no. 3 (March 9, 2022): 233. http://dx.doi.org/10.3390/metabo12030233.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. Despite the increasing effort in understanding the etiopathology of ALS, it still remains an obscure disease, and no therapies are currently available to halt its progression. Following the discovery of the first gene associated with familial forms of ALS, Cu–Zn superoxide dismutase, it appeared evident that mitochondria were key elements in the onset of the pathology. However, as more and more ALS-related genes were discovered, the attention shifted from mitochondria impairment to other biological functions such as protein aggregation and RNA metabolism. In recent years, mitochondria have again earned central, mechanistic roles in the pathology, due to accumulating evidence of their derangement in ALS animal models and patients, often resulting in the dysregulation of the energetic metabolism. In this review, we first provide an update of the last lustrum on the molecular mechanisms by which the most well-known ALS-related proteins affect mitochondrial functions and cellular bioenergetics. Next, we focus on evidence gathered from human specimens and advance the concept of a cellular-specific mitochondrial “metabolic threshold”, which may appear pivotal in ALS pathogenesis.
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McBride, Heidi M. "Parkin mitochondria in the autophagosome." Journal of Cell Biology 183, no. 5 (November 24, 2008): 757–59. http://dx.doi.org/10.1083/jcb.200810184.
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Narendra et al. (see p. 795 of this issue) have made an exciting new discovery that links the fields of mitochondrial quality control and the genetics of Parkinson's disease (PD). Through an elegant series of high-resolution imaging experiments, they are the first to provide evidence that the PARK2 gene product Parkin is selectively recruited to damaged or uncoupled mitochondria. This recruitment leads to the clearance of the organelles through the autophagosome, demonstrating a primary function for Parkin in the regulation of mitochondrial turnover. This work significantly increases our understanding of PD and provides a new framework for the development of therapeutic interventions.
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Napier, Ian, Prem Ponka, and Des R. Richardson. "Iron trafficking in the mitochondrion: novel pathways revealed by disease." Blood 105, no. 5 (March 1, 2005): 1867–74. http://dx.doi.org/10.1182/blood-2004-10-3856.
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AbstractIt is well known that iron (Fe) is transported to the mitochondrion for heme synthesis. However, only recently has the importance of this organelle for many other facets of Fe metabolism become widely appreciated. Indeed, this was stimulated by the description of human disease states that implicate mitochondrial Fe metabolism. In particular, studies assessing various diseases leading to mitochondrial Fe loading have produced intriguing findings. For instance, the disease X-linked sideroblastic anemia with ataxia (XLSA/A) is due to a mutation in the ATP-binding cassette protein B7 (ABCB7) transporter that is thought to transfer [Fe-S] clusters from the mitochondrion to the cytoplasm. This and numerous other findings suggest the mitochondrion is a dynamo of Fe metabolism, being vital not only for heme synthesis but also for playing a critical role in the genesis of [Fe-S] clusters. Studies examining the disease Friedreich ataxia have suggested that a mutation in the gene encoding frataxin leads to mitochondrial Fe loading. Apart from these findings, the recently discovered mitochondrial ferritin that may store Fe in ring sideroblasts could also regulate the level of Fe needed for heme and [Fe-S] cluster synthesis. In this review, we suggest a model of mitochondrial Fe processing that may account for the pathology observed in these disease states.
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Kalvala, Anil Kumar, Islauddin Khan, Chayanika Gundu, and Ashutosh Kumar. "An Overview on ATP Dependent and Independent Proteases Including an Anterograde to Retrograde Control on Mitochondrial Function; Focus on Diabetes and Diabetic Complications." Current Pharmaceutical Design 25, no. 23 (September 30, 2019): 2584–94. http://dx.doi.org/10.2174/1381612825666190718153901.
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Mitochondria are the central power stations of the cell involved with a myriad of cell signalling pathways that contribute for whole health status of the cell. It is a well known fact that not only mitochondrial genome encodes for mitochondrial proteins but there are several other mitochondrial specific proteins encoded by nuclear genome which regulate plethora of cell catabolic and anabolic process. Anterograde pathways include nuclear gene encoded proteins and their specific transport into the mitochondria and regulation of mitochondrial homeostasis. The retrograde pathways include crosstalk between the mitochondria and cytoplasmic proteins. Indeed, ATP dependent and independent proteases are identified to be very critical in balancing anterograde to retrograde signalling and vice versa to maintain the cell viability or cell death. Different experimental studies conducted on silencing the genes of these proteases have shown embryonic lethality, cancer cells death, increased hepatic glucose output, insulin tolerance, increased protein exclusion bodies, mitochondrial dysfunction, and defect in mitochondrial biogenesis, increased inflammation, Apoptosis etc. These experimental studies included from eubacteria to eukaryotes. Hence, many lines of theories proposed these proteases are conservative from eubacteria to eukaryotes. However, the regulation of these proteases at gene level is not clearly understood and still research is warranted. In this review, we articulated the origin and regulation of these proteases and the cross talk between the nucleus and mitochondria vice versa, and highlighted the role of these proteases in diabetes and diabetic complications in human diseases.
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Insolera, Ryan, Péter Lőrincz, Alec J. Wishnie, Gábor Juhász, and Catherine A. Collins. "Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons." PLOS Genetics 17, no. 8 (August 12, 2021): e1009731. http://dx.doi.org/10.1371/journal.pgen.1009731.
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A healthy population of mitochondria, maintained by proper fission, fusion, and degradation, is critical for the long-term survival and function of neurons. Here, our discovery of mitophagy intermediates in fission-impaired Drosophila neurons brings new perspective into the relationship between mitochondrial fission and mitophagy. Neurons lacking either the ataxia disease gene Vps13D or the dynamin related protein Drp1 contain enlarged mitochondria that are engaged with autophagy machinery and also lack matrix components. Reporter assays combined with genetic studies imply that mitophagy both initiates and is completed in Drp1 impaired neurons, but fails to complete in Vps13D impaired neurons, which accumulate compromised mitochondria within stalled mito-phagophores. Our findings imply that in fission-defective neurons, mitophagy becomes induced, and that the lipid channel containing protein Vps13D has separable functions in mitochondrial fission and phagophore elongation.
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Meyrick, Jonathan, Renae J. Stefanetti, Linda Errington, Robert McFarland, Gráinne S. Gorman, and Nichola Z. Lax. "Model systems informing mechanisms and drug discovery: a systematic review of POLG-related disease models." Wellcome Open Research 8 (January 20, 2023): 33. http://dx.doi.org/10.12688/wellcomeopenres.18637.1.
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Introduction Pathogenic variants in the gene encoding the catalytic subunit of DNA polymerase gamma (POLG), comprise an important single-gene cause of inherited mitochondrial disorders. Clinical manifestations are now recognised as an array of overlapping clinical features rather than discrete syndromes as originally conceptualised. Animal and cellular models have been used to address numerous scientific questions, from basic science to the development and assessment of novel therapies. Here, we sought to perform a systematic review of the existing models used in mitochondrial research and their effectiveness in recapitulating POLG-related disease. Methods Four databases were searched from inception to May 31, 2022: MEDLINE, Scopus, Web of Science, and Cochrane Review. Original articles available in English, reporting the use of a model system designed to recapitulate POLG-related disease, or related pathogenicity, were eligible for inclusion. Risk of bias and the methodological quality of articles were assessed by an adapted version of the Cochrane Risk of Bias Tool, with the quality of evidence synthesized across each model. Results A total of 55 articles, including seven model organisms (Human, yeast [Saccharomyces cerevisiae and Schizosaccharomyces pombe], Drosophila, Mouse, Nematoda, and Zebrafish) with 258 distinct variants were included. Of these, 66% (N=38) of articles recapitulated mitochondrial DNA (mtDNA) depletion and 42% (N=23) recapitulated POLG-related disease. Thirty-three percent of articles (N=18/55) utilised tissue-specific models of POLG-related dysfunction, while 13% (N=7) investigated the effect of potential therapeutics in POLG-related mitochondrial disorders. Discussion The available evidence supporting the ability of models for POLG-related disease to recapitulate molecular mechanisms and phenotype is limited, inconsistent and of poor methodologic quality. Further success in examining and translating novel therapies into effective treatments will be enhanced by the availability of more robust models that better recapitulate the entire spectrum of POLG-related disease. PROSPERO registration: CRD42021234883
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DiMauro, Salvatore. "A Brief History of Mitochondrial Pathologies." International Journal of Molecular Sciences 20, no. 22 (November 12, 2019): 5643. http://dx.doi.org/10.3390/ijms20225643.
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The history of “mitochondrial pathologies”, namely genetic pathologies affecting mitochondrial metabolism because of mutations in nuclear DNA-encoded genes for proteins active inside mitochondria or mutations in mitochondrial DNA-encoded genes, began in 1988. In that year, two different groups of researchers discovered, respectively, large-scale single deletions of mitochondrial DNA (mtDNA) in muscle biopsies from patients with “mitochondrial myopathies” and a point mutation in the mtDNA gene for subunit 4 of NADH dehydrogenase (MTND4), associated with maternally inherited Leber’s hereditary optic neuropathy (LHON). Henceforth, a novel conceptual “mitochondrial genetics”, separate from mendelian genetics, arose, based on three features of mtDNA: (1) polyplasmy; (2) maternal inheritance; and (3) mitotic segregation. Diagnosis of mtDNA-related diseases became possible through genetic analysis and experimental approaches involving histochemical staining of muscle or brain sections, single-fiber polymerase chain reaction (PCR) of mtDNA, and the creation of patient-derived “cybrid” (cytoplasmic hybrid) immortal fibroblast cell lines. The availability of the above-mentioned techniques along with the novel sensitivity of clinicians to such disorders led to the characterization of a constantly growing number of pathologies. Here is traced a brief historical perspective on the discovery of autonomous pathogenic mtDNA mutations and on the related mendelian pathology altering mtDNA integrity.
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Vizziello, Maria, Linda Borellini, Giulia Franco, and Gianluca Ardolino. "Disruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson’s Disease." Cells 10, no. 11 (November 4, 2021): 3022. http://dx.doi.org/10.3390/cells10113022.
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The progressive reduction of the dopaminergic neurons of the substantia nigra is the fundamental process underlying Parkinson’s disease (PD), while the mechanism of susceptibility of this specific neuronal population is largely unclear. Disturbances in mitochondrial function have been recognized as one of the main pathways in sporadic PD since the finding of respiratory chain impairment in animal models of PD. Studies on genetic forms of PD have provided new insight on the role of mitochondrial bioenergetics, homeostasis, and autophagy. PINK1 (PTEN-induced putative kinase 1) gene mutations, although rare, are the second most common cause of recessively inherited early-onset PD, after Parkin gene mutations. Our knowledge of PINK1 and Parkin function has increased dramatically in the last years, with the discovery that a process called mitophagy, which plays a key role in the maintenance of mitochondrial health, is mediated by the PINK1/Parkin pathway. In vitro and in vivo models have been developed, supporting the role of PINK1 in synaptic transmission, particularly affecting dopaminergic neurons. It is of paramount importance to further define the role of PINK1 in mitophagy and mitochondrial homeostasis in PD pathogenesis in order to delineate novel therapeutic targets.
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Maier, Dieter, Carol L. Farr, Burkhard Poeck, Anuradha Alahari, Marion Vogel, Susanne Fischer, Laurie S. Kaguni, and Stephan Schneuwly. "Mitochondrial Single-stranded DNA-binding Protein Is Required for Mitochondrial DNA Replication and Development in Drosophila melanogaster." Molecular Biology of the Cell 12, no. 4 (April 2001): 821–30. http://dx.doi.org/10.1091/mbc.12.4.821.
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The discovery that several inherited human diseases are caused by mtDNA depletion has led to an increased interest in the replication and maintenance of mtDNA. We have isolated a new mutant in thelopo (low power) gene fromDrosophila melanogaster affecting the mitochondrial single-stranded DNA-binding protein (mtSSB), which is one of the key components in mtDNA replication and maintenance.lopo 1 mutants die late in the third instar before completion of metamorphosis because of a failure in cell proliferation. Molecular, histochemical, and physiological experiments show a drastic decrease in mtDNA content that is coupled with the loss of respiration in these mutants. However, the number and morphology of mitochondria are not greatly affected. Immunocytochemical analysis shows that mtSSB is expressed in all tissues but is highly enriched in proliferating tissues and in the developing oocyte.lopo 1 is the first mtSSB mutant in higher eukaryotes, and its analysis demonstrates the essential function of this gene in development, providing an excellent model to study mitochondrial biogenesis in animals.
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Tanaka, Masaru, Ágnes Szabó, Eleonóra Spekker, Helga Polyák, Fanni Tóth, and László Vécsei. "Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan–Kynurenine Metabolic System." Cells 11, no. 16 (August 21, 2022): 2607. http://dx.doi.org/10.3390/cells11162607.
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Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, a number of mutations in mtDNA were identified as a cause of severe inheritable metabolic diseases with neurological manifestation, and the impairment of mitochondrial functions has been probed in the pathogenesis of a wide range of illnesses including neurodegenerative diseases. Recently, a growing number of preclinical studies have revealed that animal behaviors are influenced by the impairment of mitochondrial functions and possibly by the loss of mitochondrial stress resilience. Indeed, as high as 54% of patients with one of the most common primary mitochondrial diseases, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, present psychiatric symptoms including cognitive impairment, mood disorder, anxiety, and psychosis. Mitochondria are multifunctional organelles which produce cellular energy and play a major role in other cellular functions including homeostasis, cellular signaling, and gene expression, among others. Mitochondrial functions are observed to be compromised and to become less resilient under continuous stress. Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)–kynurenine (KYN) metabolic system, which observably contributes to the development of pathological conditions including neurological and psychiatric disorders. This review discusses the functions of mitochondria and the Trp-KYN system, the interaction of the Trp-KYN system with mitochondria, and the current understanding of the involvement of mitochondria and the Trp-KYN system in preclinical and clinical studies of major neurological and psychiatric diseases.
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Li, Xinlu (Crystal). "Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS): a once obscure neurodegenerative disease with increasing significance for neurological research." McGill Science Undergraduate Research Journal 8, no. 1 (March 31, 2013): 69–74. http://dx.doi.org/10.26443/msurj.v8i1.114.
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Background: Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare cerebellar ataxia occurring in the Charlevoix-Saguenay population in Quebec with high incidence as a result of founder effects. Following the discovery of the gene responsible for the disease, many other patient groups have been identified worldwide and the characterization of the gene product, sacsin, has unveiled similarities between the pathogenic mechanism of ARSACS and those of other major neurodegenerative disease.
Summary: The core symptoms of ARSACS consist of a triad of early-onset cerebellar ataxia, peripheral neuropathy and spasticity, which is accounted by degeneration of Purkinje neurons. The gene responsible for the disease is located on chromosome 13q11 and encodes for the chaperone sacsin. Drp-1, a GTPase crucial for regulating mitochondrial fission/fusion dynamics, has been identified as a potential substrate of sacsin, suggesting a link between the pathogenic mechanisms of ARSACS and prevalent neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases.
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Kiechle, Frederick L., and Xinbo Zhang. "The Postgenomic Era." Archives of Pathology & Laboratory Medicine 126, no. 3 (March 1, 2002): 255–62. http://dx.doi.org/10.5858/2002-126-0255-tpe.
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Abstract Objectives.—To review the advances in clinically useful molecular biological techniques and to identify their applications in clinical practice, as presented at the Tenth Annual William Beaumont Hospital DNA Symposium. Data Sources.—The 11 manuscripts submitted were reviewed and their major findings were compared with literature on the same topic. Study Selection.—Manuscripts address creative thinking techniques applied to DNA discovery, extraction of DNA from clotted blood, the relationship of mitochondrial dysfunction in neurodegenerative disorders, and molecular methods to identify human lymphocyte antigen class I and class II loci. Two other manuscripts review current issues in molecular microbiology, including detection of hepatitis C virus and biological warfare. The last 5 manuscripts describe current issues in molecular cardiovascular disease, including assessing thrombotic risk, genomic analysis, gene therapy, and a device for aiding in cardiac angiogenesis. Data Synthesis.—Novel problem-solving techniques have been used in the past and will be required in the future in DNA discovery. The extraction of DNA from clotted blood demonstrates a potential cost-effective strategy. Cybrids created from mitochondrial DNA-depleted cells and mitochondrial DNA from a platelet donor have been useful in defining the role mitochondria play in neurodegeneration. Mitochondrial depletion has been reported as a genetically inherited disorder or after human immunodeficiency virus therapy. Hepatitis C viral detection by qualitative, quantitative, or genotyping techniques is useful clinically. Preparedness for potential biological warfare is a responsibility of all clinical laboratorians. Thrombotic risk in cardiovascular disorders may be assessed by coagulation screening assays and further defined by mutation analysis for specific genes for prothrombin and factor V Leiden. Gene therapy for reducing arteriosclerotic risk has been hindered primarily by complications introduced by the vectors used to introduce the therapeutic genes. Neovascularization in cardiac muscle with occluded vessels represents a promising method for recovery of viable tissue following ischemia. Conclusions.—The sequence of the human genome was reported by 2 groups in February 2001. The postgenomic era will emphasize the use of microarrays and database software for genomic and proteomic screening in the search for useful clinical assays. The number of molecular pathologic techniques and assays will expand as additional disease-associated mutations are defined. Gene therapy and tissue engineering will represent successful therapeutic adjuncts.
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Havalová, Henrieta, Gabriela Ondrovičová, Barbora Keresztesová, Jacob A. Bauer, Vladimír Pevala, Eva Kutejová, and Nina Kunová. "Mitochondrial HSP70 Chaperone System—The Influence of Post-Translational Modifications and Involvement in Human Diseases." International Journal of Molecular Sciences 22, no. 15 (July 28, 2021): 8077. http://dx.doi.org/10.3390/ijms22158077.
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Since their discovery, heat shock proteins (HSPs) have been identified in all domains of life, which demonstrates their importance and conserved functional role in maintaining protein homeostasis. Mitochondria possess several members of the major HSP sub-families that perform essential tasks for keeping the organelle in a fully functional and healthy state. In humans, the mitochondrial HSP70 chaperone system comprises a central molecular chaperone, mtHSP70 or mortalin (HSPA9), which is actively involved in stabilizing and importing nuclear gene products and in refolding mitochondrial precursor proteins, and three co-chaperones (HSP70-escort protein 1—HEP1, tumorous imaginal disc protein 1—TID-1, and Gro-P like protein E—GRPE), which regulate and accelerate its protein folding functions. In this review, we summarize the roles of mitochondrial molecular chaperones with particular focus on the human mtHsp70 and its co-chaperones, whose deregulated expression, mutations, and post-translational modifications are often considered to be the main cause of neurological disorders, genetic diseases, and malignant growth.
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Kim, Donghwan, Ji-Hye Kim, Young-Ho Kang, Je Seong Kim, Sung-Cheol Yun, Sang-Wook Kang, and Youngsup Song. "Suppression of Brown Adipocyte Autophagy Improves Energy Metabolism by Regulating Mitochondrial Turnover." International Journal of Molecular Sciences 20, no. 14 (July 18, 2019): 3520. http://dx.doi.org/10.3390/ijms20143520.
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The high abundance of mitochondria and the expression of mitochondrial uncoupling protein 1 (UCP1) confer upon brown adipose tissue (BAT) the unique capacity to convert chemical energy into heat at the expense of ATP synthesis. It was long believed that BAT is present only in infants, and so, it was not considered as a potential therapeutic target for metabolic syndrome; however, the discovery of metabolically active BAT in adult humans has re-stimulated interest in the contributions of BAT metabolic regulation and dysfunction to health and disease. Here we demonstrate that brown adipocyte autophagy plays a critical role in the regulation BAT activity and systemic energy metabolism. Mice deficient in brown adipocyte autophagy due to BAT-specific deletion of Atg7—a gene essential for autophagosome generation—maintained higher mitochondrial content due to suppression of mitochondrial clearance and exhibited improved insulin sensitivity and energy metabolism. Autophagy was upregulated in BAT of older mice compared to younger mice, suggesting its involvement in the age-dependent decline of BAT activity and metabolic rate. These findings suggest that brown adipocyte autophagy plays a crucial role in metabolism and that targeting this pathway may be a potential therapeutic strategy for metabolic syndrome.
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Kim, Hyunjin, Jinsung Yang, Min Ju Kim, Sekyu Choi, Ju-Ryung Chung, Jong-Min Kim, Young Hyun Yoo, Jongkyeong Chung, and Hyongjong Koh. "Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1) Mutation and TRAP1 Inhibitor Gamitrinib-triphenylphosphonium (G-TPP) Induce a Forkhead Box O (FOXO)-dependent Cell Protective Signal from Mitochondria." Journal of Biological Chemistry 291, no. 4 (December 2, 2015): 1841–53. http://dx.doi.org/10.1074/jbc.m115.656934.
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TRAP1 (tumor necrosis factor receptor-associated protein 1), a mitochondrial Hsp90 family chaperone, has been identified as a critical regulator of cell survival and bioenergetics in tumor cells. To discover novel signaling networks regulated by TRAP1, we generated Drosophila TRAP1 mutants. The mutants successfully developed into adults and produced fertile progeny, showing that TRAP1 is dispensable in development and reproduction. Surprisingly, mutation or knockdown of TRAP1 markedly enhanced Drosophila survival under oxidative stress. Moreover, TRAP1 mutation ameliorated mitochondrial dysfunction and dopaminergic (DA) neuron loss induced by deletion of a familial Parkinson disease gene PINK1 (Pten-induced kinase 1) in Drosophila. Gamitrinib-triphenylphosphonium, a mitochondria-targeted Hsp90 inhibitor that increases cell death in HeLa and MCF7 cells, consistently inhibited cell death induced by oxidative stress and mitochondrial dysfunction induced by PINK1 mutation in mouse embryonic fibroblast cells and DA cell models such as SH-SY5Y and SN4741 cells. Additionally, gamitrinib-triphenylphosphonium also suppressed the defective locomotive activity and DA neuron loss in Drosophila PINK1 null mutants. In further genetic analyses, we showed enhanced expression of Thor, a downstream target gene of transcription factor FOXO, in TRAP1 mutants. Furthermore, deletion of FOXO almost nullified the protective roles of TRAP1 mutation against oxidative stress and PINK1 mutation. These results strongly suggest that inhibition of the mitochondrial chaperone TRAP1 generates a retrograde cell protective signal from mitochondria to the nucleus in a FOXO-dependent manner.
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Kulkarni, Sakil, Jiansheng Huang, Eric Tycksen, Paul F. Cliften, and David A. Rudnick. "Diet Modifies Pioglitazone’s Influence on Hepatic PPARγ-Regulated Mitochondrial Gene Expression." PPAR Research 2020 (September 10, 2020): 1–20. http://dx.doi.org/10.1155/2020/3817573.
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Pioglitazone (Pio) is a thiazolidinedione (TZD) insulin-sensitizing drug whose effects result predominantly from its modulation of the transcriptional activity of peroxisome proliferator-activated-receptor-gamma (PPARγ). Pio is used to treat human insulin-resistant diabetes and also frequently considered for treatment of nonalcoholic steatohepatitis (NASH). In both settings, Pio’s beneficial effects are believed to result primarily from its actions on adipose PPARγ activity, which improves insulin sensitivity and reduces the delivery of fatty acids to the liver. Nevertheless, a recent clinical trial showed variable efficacy of Pio in human NASH. Hepatocytes also express PPARγ, and such expression increases with insulin resistance and in nonalcoholic fatty liver disease (NAFLD). Furthermore, mice that overexpress hepatocellular PPARγ and Pio-treated mice with extrahepatic PPARγ gene disruption develop features of NAFLD. Thus, Pio’s direct impact on hepatocellular gene expression might also be a determinant of this drug’s ultimate influence on insulin resistance and NAFLD. Previous studies have characterized Pio’s PPARγ-dependent effects on hepatic expression of specific adipogenic, lipogenic, and other metabolic genes. However, such transcriptional regulation has not been comprehensively assessed. The studies reported here address that consideration by genome-wide comparisons of Pio’s hepatic transcriptional effects in wildtype (WT) and liver-specific PPARγ-knockout (KO) mice given either control or high-fat (HFD) diets. The results identify a large set of hepatic genes for which Pio’s liver PPARγ-dependent transcriptional effects are concordant with its effects on RXR-DNA binding in WT mice. These data also show that HFD modifies Pio’s influence on a subset of such transcriptional regulation. Finally, our findings reveal a broader influence of Pio on PPARγ-dependent hepatic expression of nuclear genes encoding mitochondrial proteins than previously recognized. Taken together, these studies provide new insights about the tissue-specific mechanisms by which Pio affects hepatic gene expression and the broad scope of this drug’s influence on such regulation.
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Ji, Yanchun, Juanjuan Zhang, Yuanyuan Lu, Qiuzi Yi, Mengquan Chen, Shipeng Xie, Xiaoting Mao, et al. "Complex I mutations synergize to worsen the phenotypic expression of Leber's hereditary optic neuropathy." Journal of Biological Chemistry 295, no. 38 (July 28, 2020): 13224–38. http://dx.doi.org/10.1074/jbc.ra120.014603.
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Leber's hereditary optic neuropathy (LHON) is a maternal inheritance of eye disease because of the mitochondrial DNA (mtDNA) mutations. We previously discovered a 3866T>C mutation within the gene for the ND1 subunit of complex I as possibly amplifying disease progression for patients bearing the disease-causing 11778G>A mutation within the gene for the ND4 subunit of complex I. However, whether and how the ND1 mutation exacerbates the ND4 mutation were unknown. In this report, we showed that four Chinese families bearing both m.3866T>C and m.11778G>A mutations exhibited higher penetrances of LHON than 6 Chinese pedigrees carrying only the m.3866T>C mutation or families harboring only the m.11778G>A mutation. The protein structure analysis revealed that the m.3866T>C (I187T) and m.11778G>A (R340H) mutations destabilized the specific interactions with other residues of ND1 and ND4, thereby altering the structure and function of complex I. Cellular data obtained using cybrids, constructed by transferring mitochondria from the Chinese families into mtDNA-less (ρ°) cells, demonstrated that the mutations perturbed the stability, assembly, and activity of complex I, leading to changes in mitochondrial ATP levels and membrane potential and increasing the production of reactive oxygen species. These mitochondrial dysfunctions promoted the apoptotic sensitivity of cells and decreased mitophagy. Cybrids bearing only the m.3866T>C mutation displayed mild mitochondrial dysfunctions, whereas those harboring both m.3866T>C and m.11778G>A mutations exhibited greater mitochondrial dysfunctions. These suggested that the m.3866T>C mutation acted in synergy with the m.11778G>A mutation, aggravating mitochondrial dysfunctions and contributing to higher penetrance of LHON in these families carrying both mtDNA mutations.
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Rabinovich-Ernst, Orna, Jing Sun, BIN LIN, and Iain D. Fraser. "An arrayed genome-wide RNAi screen for the discovery of novel inflammasome regulators." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 64.6. http://dx.doi.org/10.4049/jimmunol.198.supp.64.6.
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Abstract Bacterial lipopolysaccharide (LPS) is a prominent PAMP implicated as the primary causative agent of septic shock in a wide range of bacterial infections. LPS is known to activate two receptors: the plasma membrane receptor, TLR4, and the cytosolic receptor, Caspase 11. We have conducted a genome-wide siRNA screen to identify novel gene products involved in the non-canonical inflammasome response to cytosolic LPS. A ‘prime-trigger’ assay was established in which macrophages were primed with Pam3CSK4, triggered by transfection of the active component of LPS, Lipid A, and IL-1α secretion measured by a screening-optimized HTRF assay, and pyroptosis was evaluated using an LDH assay. The screen was designed to identify and distinguish regulators at multiple stages of the non-canonical inflammasome activation process, from TLR priming, to cytosolic LPS detection, pyroptosis and IL-1α release. Initial analysis of the primary screen data identified a high canonical pathway hit rate in both the TLR priming step and the response to cytosolic LPS, with Irak4, Irak2, Casp4, Gsdmd and Gsdmc among the strongest gene hits. Among the genes not previously linked to regulation of the non-canonical inflammasome, we observed an enrichment for mitochondrial proteins. In order to further validate this finding, we have created a CRISPR/Cas9 knock-out macrophage cell line and knock-out mouse for one of the mitochondrial screen hits, confirming the effect of this novel hit on IL-1α release in response to cytosolic LPS. Our results suggest a critical role for mitochondria in regulation of the non-canonical inflammasome response. This work was generously supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases.
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Walne, Amanda J., Tom Vulliamy, Findlay Bewicke-Copley, Jun Wang, Jenna Alnajar, Maria G. Bridger, Bernard Ma, Hemanth Tummala, and Inderjeet Dokal. "Genome-wide whole-blood transcriptome profiling across inherited bone marrow failure subtypes." Blood Advances 5, no. 23 (December 9, 2021): 5360–71. http://dx.doi.org/10.1182/bloodadvances.2021005360.
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Abstract Gene expression profiling has long been used in understanding the contribution of genes and related pathways in disease pathogenesis and susceptibility. We have performed whole-blood transcriptomic profiling in a subset of patients with inherited bone marrow failure (IBMF) whose diseases are clinically and genetically characterized as Fanconi anemia (FA), Shwachman-Diamond syndrome (SDS), and dyskeratosis congenita (DC). We hypothesized that annotating whole-blood transcripts genome wide will aid in understanding the complexity of gene regulation across these IBMF subtypes. Initial analysis of these blood-derived transcriptomes revealed significant skewing toward upregulated genes in patients with FA when compared with controls. Patients with SDS or DC also showed similar skewing profiles in their transcriptional status revealing a common pattern across these different IBMF subtypes. Gene set enrichment analysis revealed shared pathways involved in protein translation and elongation (ribosome constituents), RNA metabolism (nonsense-mediated decay), and mitochondrial function (electron transport chain). We further identified a discovery set of 26 upregulated genes at stringent cutoff (false discovery rate < 0.05) that appeared as a unified signature across the IBMF subtypes. Subsequent transcriptomic analysis on genetically uncharacterized patients with BMF revealed a striking overlap of genes, including 22 from the discovery set, which indicates a unified transcriptional drive across the classic (FA, SDS, and DC) and uncharacterized BMF subtypes. This study has relevance in disease pathogenesis, for example, in explaining the features (including the BMF) common to all patients with IBMF and suggests harnessing this transcriptional signature for patient benefit.
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Al-Kafaji, Ghada, Halla F. Bakheit, Faisal AlAli, Mina Fattah, Saad Alhajeri, Maram A. Alharbi, Abdulqader Daif, Manahel Mahmood Alsabbagh, Materah Salem Alwehaidah, and Moiz Bakhiet. "Next-generation sequencing of the whole mitochondrial genome identifies functionally deleterious mutations in patients with multiple sclerosis." PLOS ONE 17, no. 2 (February 7, 2022): e0263606. http://dx.doi.org/10.1371/journal.pone.0263606.
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Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system with genetics and environmental determinants. Studies focused on the neurogenetics of MS showed that mitochondrial DNA (mtDNA) mutations that can ultimately lead to mitochondrial dysfunction, alter brain energy metabolism and cause neurodegeneration. We analyzed the whole mitochondrial genome using next-generation sequencing (NGS) from 47 Saudi individuals, 23 patients with relapsing-remitting MS and 24 healthy controls to identify mtDNA disease-related mutations/variants. A large number of variants were detected in the D-loop and coding genes of mtDNA. While distinct unique variants were only present in patients or only occur in controls, a number of common variants were shared among the two groups. The prevalence of some common variants differed significantly between patients and controls, thus could be implicated in susceptibility to MS. Of the unique variants only present in the patients, 34 were missense mutations, located in different mtDNA-encoded genes. Seven of these mutations were not previously reported in MS, and predicted to be deleterious with considerable impacts on the functions and structures of encoded-proteins and may play a role in the pathogenesis of MS. These include two heteroplasmic mutations namely 10237T>C in MT-ND3 gene and 15884G>C in MT-CYB gene; and three homoplasmic mutations namely 9288A>G in MT-CO3 gene, 14484T>C in MT-ND6 gene, 15431G>A in MT-CYB gene, 8490T>C in MT-ATP8 gene and 5437C>T in MT-ND2 gene. Notably some patients harboured multiple mutations while other patients carried the same mutations. This study is the first to sequence the entire mitochondrial genome in MS patients in an Arab population. Our results expanded the mutational spectrum of mtDNA variants in MS and highlighted the efficiency of NGS in population-specific mtDNA variant discovery. Further investigations in a larger cohort are warranted to confirm the role of mtDNA MS.
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Van Haute, Lindsey, Song-Yi Lee, Beverly J. McCann, Christopher A. Powell, Dhiru Bansal, Lina Vasiliauskaitė, Caterina Garone, et al. "NSUN2 introduces 5-methylcytosines in mammalian mitochondrial tRNAs." Nucleic Acids Research 47, no. 16 (July 5, 2019): 8720–33. http://dx.doi.org/10.1093/nar/gkz559.
Full textAbstract:
Abstract Expression of human mitochondrial DNA is indispensable for proper function of the oxidative phosphorylation machinery. The mitochondrial genome encodes 22 tRNAs, 2 rRNAs and 11 mRNAs and their post-transcriptional modification constitutes one of the key regulatory steps during mitochondrial gene expression. Cytosine-5 methylation (m5C) has been detected in mitochondrial transcriptome, however its biogenesis has not been investigated in details. Mammalian NOP2/Sun RNA Methyltransferase Family Member 2 (NSUN2) has been characterized as an RNA methyltransferase introducing m5C in nuclear-encoded tRNAs, mRNAs and microRNAs and associated with cell proliferation and differentiation, with pathogenic variants in NSUN2 being linked to neurodevelopmental disorders. Here we employ spatially restricted proximity labelling and immunodetection to demonstrate that NSUN2 is imported into the matrix of mammalian mitochondria. Using three genetic models for NSUN2 inactivation—knockout mice, patient-derived fibroblasts and CRISPR/Cas9 knockout in human cells—we show that NSUN2 is necessary for the generation of m5C at positions 48, 49 and 50 of several mammalian mitochondrial tRNAs. Finally, we show that inactivation of NSUN2 does not have a profound effect on mitochondrial tRNA stability and oxidative phosphorylation in differentiated cells. We discuss the importance of the newly discovered function of NSUN2 in the context of human disease.
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Gay, Emma, Adam Santanasto, Ryan Cvejkus, Mary Wojczynski, Mary Feitosa, and Nancy W. Glynn. "ENERGY METABOLISM RELATED CANDIDATE GENE ASSOCIATION STUDY OF PERCEIVED PHYSICAL FATIGABILITY." Innovation in Aging 6, Supplement_1 (November 1, 2022): 369. http://dx.doi.org/10.1093/geroni/igac059.1458.
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Abstract Mitochondrial energy production decreases while fatigability increases with age. Genes associated with energy metabolism may contribute to fatigability. Using Long Life Family Study (LLFS), we initially assessed variants (SNPs) in 272 candidate autosomal genes involved in energy metabolism (previously associated with mitochondrial dysfunction disease) with perceived physical fatigability. Two generations of LLFS enrollees (N=2342, mean age=73.7, range 60-108 years) completed the Pittsburgh Fatigability Scale (PFS, 0-50, higher=greater fatigability) at Visit 2 (2014-2017). Physical fatigability prevalence was 42.1% (PFS≥15). Generalized linear mixed models assessed the association of each SNP with continuous PFS (GENESIS R package) adjusted for age, sex, field center, and family relatedness. We found no associations with perceived physical fatigability, all p>2.5E-7 (Bonferroni multiple comparison corrected p-value). Next steps will examine variants in the mitochondrial genome and BTBD3, another promising candidate gene recently discovered. Genetic biomarker(s) may identify individuals susceptible to greater fatigability to target for early intervention.
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Annesley, Sarah Jane, Claire Yvonne Allan, Oana Sanislav, Andrew Evans, and Paul Robert Fisher. "Dysregulated Gene Expression in Lymphoblasts from Parkinson’s Disease." Proteomes 10, no. 2 (June 1, 2022): 20. http://dx.doi.org/10.3390/proteomes10020020.
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Parkinson’s disease is the second largest neurodegenerative disease worldwide and is caused by a combination of genetics and environment. It is characterized by the death of neurons in the substantia nigra of the brain but is not solely a disease of the brain, as it affects multiple tissues and organs. Studying Parkinson’s disease in accessible tissues such as skin and blood has increased our understanding of the disease’s pathogenesis. Here, we used lymphoblast cell lines generated from Parkinson’s disease patient and healthy age- and sex-matched control groups and obtained their whole-cell transcriptomes and proteomes. Our analysis revealed, in both the transcriptomes and the proteomes of PD cells, a global downregulation of genes involved in protein synthesis, as well as the upregulation of immune processes and sphingolipid metabolism. In contrast, we discovered an uncoupling of mRNA and protein expression in processes associated with mitochondrial respiration in the form of a general downregulation in associated transcripts and an upregulation in proteins. Complex V was different to the other oxidative phosphorylation complexes in that the levels of its associated transcripts were also lower, but the levels of their encoded polypeptides were not elevated. This may suggest that further layers of regulation specific to Complex V are in play.
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Pascual-Caro, Carlos, Maria Berrocal, Aida M. Lopez-Guerrero, Alberto Alvarez-Barrientos, Eulalia Pozo-Guisado, Carlos Gutierrez-Merino, Ana M. Mata, and Francisco Javier Martin-Romero. "STIM1 deficiency is linked to Alzheimer’s disease and triggers cell death in SH-SY5Y cells by upregulation of L-type voltage-operated Ca2+ entry." Journal of Molecular Medicine 96, no. 10 (August 7, 2018): 1061–79. http://dx.doi.org/10.1007/s00109-018-1677-y.
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Abstract STIM1 is an endoplasmic reticulum protein with a role in Ca2+ mobilization and signaling. As a sensor of intraluminal Ca2+ levels, STIM1 modulates plasma membrane Ca2+ channels to regulate Ca2+ entry. In neuroblastoma SH-SY5Y cells and in familial Alzheimer’s disease patient skin fibroblasts, STIM1 is cleaved at the transmembrane domain by the presenilin-1-associated γ-secretase, leading to dysregulation of Ca2+ homeostasis. In this report, we investigated expression levels of STIM1 in brain tissues (medium frontal gyrus) of pathologically confirmed Alzheimer’s disease patients, and observed that STIM1 protein expression level decreased with the progression of neurodegeneration. To study the role of STIM1 in neurodegeneration, a strategy was designed to knock-out the expression of STIM1 gene in the SH-SY5Y neuroblastoma cell line by CRISPR/Cas9-mediated genome editing, as an in vitro model to examine the phenotype of STIM1-deficient neuronal cells. It was proved that, while STIM1 is not required for the differentiation of SH-SY5Y cells, it is absolutely essential for cell survival in differentiating cells. Differentiated STIM1-KO cells showed a significant decrease of mitochondrial respiratory chain complex I activity, mitochondrial inner membrane depolarization, reduced mitochondrial free Ca2+ concentration, and higher levels of senescence as compared with wild-type cells. In parallel, STIM1-KO cells showed a potentiated Ca2+ entry in response to depolarization, which was sensitive to nifedipine, pointing to L-type voltage-operated Ca2+ channels as mediators of the upregulated Ca2+ entry. The stable knocking-down of CACNA1C transcripts restored mitochondrial function, increased mitochondrial Ca2+ levels, and dropped senescence to basal levels, demonstrating the essential role of the upregulation of voltage-operated Ca2+ entry through Cav1.2 channels in STIM1-deficient SH-SY5Y cell death. Key messages STIM1 protein expression decreases with the progression of neurodegeneration in Alzheimer’s disease. STIM1 is essential for cell viability in differentiated SH-SY5Y cells. STIM1 deficiency triggers voltage-regulated Ca2+ entry-dependent cell death. Mitochondrial dysfunction and senescence are features of STIM1-deficient differentiated cells.
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Alfadhel, Majid. "Multiple Mitochondrial Dysfunctions Syndrome 4 Due to ISCA2 Gene Defects: A Review." Child Neurology Open 6 (January 1, 2019): 2329048X1984737. http://dx.doi.org/10.1177/2329048x19847377.
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Multiple mitochondrial dysfunctions syndrome 4, caused by ISCA2 gene defects (OMIM #616370), was first described by Al-Hassnan et al in 2015. To date, 20 cases have been reported: 13 females and 7 males from 18 different families. All cases are from Saudi Arabia except those from one Italian family. Typically, the patients have normal antenatal and birth history and attain normal development initially. Rapid deterioration occurs between 2 and 7 months of age, with the triad of neurodevelopmental regression, optic atrophy with nystagmus, and diffuse white matter disease. Magnetic resonance imaging findings include 75% of patients have cerebellar white matter abnormalities, and the spinal cord was affected in 55%. Magnetic resonance spectroscopy showed elevated glycine peaks in 2 (10%) cases and elevated lactate peaks in 5 (25%) cases. Biochemical abnormalities include high cerebrospinal fluid glycine and lactate and high plasma glycine and lactate, but these findings were not consistent. Diagnosis is based on the detection of biallelic mutations in the ISCA2 gene. To date, no curative treatment has been discovered, and disease management is exclusively supportive. In this report, the authors review the published cases of ISCA2 gene defects and retrospectively characterize disease phenotypes, the affected biochemical pathways, neuroradiological abnormalities, diagnosis, genetics, and treatment.
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Walden, Helen, and Miratul M. K. Muqit. "Ubiquitin and Parkinson's disease through the looking glass of genetics." Biochemical Journal 474, no. 9 (April 13, 2017): 1439–51. http://dx.doi.org/10.1042/bcj20160498.
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Biochemical alterations found in the brains of Parkinson's disease (PD) patients indicate that cellular stress is a major driver of dopaminergic neuronal loss. Oxidative stress, mitochondrial dysfunction, and ER stress lead to impairment of the homeostatic regulation of protein quality control pathways with a consequent increase in protein misfolding and aggregation and failure of the protein degradation machinery. Ubiquitin signalling plays a central role in protein quality control; however, prior to genetic advances, the detailed mechanisms of how impairment in the ubiquitin system was linked to PD remained mysterious. The discovery of mutations in the α-synuclein gene, which encodes the main protein misfolded in PD aggregates, together with mutations in genes encoding ubiquitin regulatory molecules, including PTEN-induced kinase 1 (PINK1), Parkin, and FBX07, has provided an opportunity to dissect out the molecular basis of ubiquitin signalling disruption in PD, and this knowledge will be critical for developing novel therapeutic strategies in PD that target the ubiquitin system.
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Sharma, Sushil, Joseph Choga, Pearl Doghor, Fredy N-Kalala, Ankur Chauhan, Vineet Gupta, Christopher Wright, et al. "Charnoly body as a novel biomarker of nutritional stress in Alzheimer’s Disease." Functional Foods in Health and Disease 6, no. 6 (June 29, 2016): 344. http://dx.doi.org/10.31989/ffhd.v6i6.259.
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Background: Charnoly body (CB) was discovered as universal biomarker of cell injury in the developing undernourished rat cerebellar Purkinje neurons and in the intrauterine Domoic acid and Kainic acid-exposed mice hippocampus and hypothalamic neurons. The incidence of CB increased with the severity of nutritional and environmental neurotoxic insult. Purpose: We proposed that stress (nutritional/environmental)-induced cortisol release augments, whereas metallothioneins (MTs), insulin-like growth factor (IGF-1), and brain-derived neurotropic factor (BDNF inhibit CB formation to prevent progressive neurodegeneration, early morbidity, and mortality in Alzheimer’s disease (AD).Results: CB is a pre-apoptotic biomarker of compromised mitochondrial bioenergetics and is formed in the most vulnerable cell in response to nutritional stress, intrauterine infection, environmental toxins, and/or drugs of abuse due to free radical overproduction and mitochondrial genome down-regulation. It appears as a pleomorphic, electron-dense multi-lamellar, quasi-crystalline stack of degenerated mitochondrial membranes in highly susceptible neurons and may be induced by microbial infection. CB formation was accompanied with stunted neuritogenesis in the aging mitochondrial genome knock out (RhOmgko) human dopaminergic (SK-N-SH, SHS-Y-5Y) neurons due to down-regulation of ubiquinone NADH oxidoreductase (complex-1). Transfection of RhOmgko neurons with ubiquinone NADH oxidoreductase (complex-1) gene and CoQ10, inhibited CB formation and augmented neuritogenesis, as confirmed in α-synuclein-metallothioneins triple knock out and weaver mutant mice. CB formation was attenuated in MTs-over-expressing weaver mutant mice.Findings: Accumulation of CB at the junction of axon hillock impairs axoplasmic transport of enzymes, neurotransmitters, hormones, neurotropic factors (NGF, BDNF), and mitochondria at the synaptic terminals to cause cognitive impairment, early morbidity, and mortality. Nonspecific induction of CB causes alopecia, myelosuppression, and GIT symptoms in multi-drug-resistant malignancies. Antioxidants and MTs inhibit CB formation as free radical scavengers by zinc-mediated transcriptional regulation of genes involved in growth, proliferation, differentiation, and development. Hence drugs may be developed to prevent CB formation and/or enhance charnolophagy as a basic molecular mechanism of intracellular detoxification to avert cognitive impairments in AD.Conclusion: Brain regional monoamine oxidase-specific CBs can be detected by 11C or 18F-labeled MAO-A or MAO-B inhibitors in vivo in addition to 18FdG-PET neuroimaging to quantitatively assess and improve the mitochondrial bioenergetics in AD. Key Words: Charnoly Body, Nutrition, Metallothioneins, Mitochondrial DNA, RhOmgko Neurons, Cortisol, IGF-1, BDNF, Alzheimer’s Disease
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Gao, Yurong, Sungwoo Kim, Yun-Il Lee, and Jaemin Lee. "Cellular Stress-Modulating Drugs Can Potentially Be Identified by in Silico Screening with Connectivity Map (CMap)." International Journal of Molecular Sciences 20, no. 22 (November 9, 2019): 5601. http://dx.doi.org/10.3390/ijms20225601.
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Accompanied by increased life span, aging-associated diseases, such as metabolic diseases and cancers, have become serious health threats. Recent studies have documented that aging-associated diseases are caused by prolonged cellular stresses such as endoplasmic reticulum (ER) stress, mitochondrial stress, and oxidative stress. Thus, ameliorating cellular stresses could be an effective approach to treat aging-associated diseases and, more importantly, to prevent such diseases from happening. However, cellular stresses and their molecular responses within the cell are typically mediated by a variety of factors encompassing different signaling pathways. Therefore, a target-based drug discovery method currently being used widely (reverse pharmacology) may not be adequate to uncover novel drugs targeting cellular stresses and related diseases. The connectivity map (CMap) is an online pharmacogenomic database cataloging gene expression data from cultured cells treated individually with various chemicals, including a variety of phytochemicals. Moreover, by querying through CMap, researchers may screen registered chemicals in silico and obtain the likelihood of drugs showing a similar gene expression profile with desired and chemopreventive conditions. Thus, CMap is an effective genome-based tool to discover novel chemopreventive drugs.
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Gucev, Zoran, Velibor Tasic, and Momir Polenakovic. "The 6th Rare Disease South Eastern Europe (See) Meeting, Skopje, Macedonia (November 11th, 2017)." PRILOZI 38, no. 3 (December 1, 2017): 163–68. http://dx.doi.org/10.2478/prilozi-2018-0018.
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Abstract The sixth SEE meeting on rare diseases (RDs) was held in MASA the November 10th, 2017. A block of lectures on rare renal diseases started the meeting: nephrotic syndrome, Alport syndrome, atypical HUS, hypophosphatemic rickets, CAKUT were presented in all complexities. Their molecular and genetic mechanisms were discussed. The discovery of a dozen of newly genes in CAKUT, congenital overgrowth, spodilocostal dysplasia, precocious puberty has been done with collaboration of Macedonian and foreign researchers. NGS and other molecular methods in diagnosis of RDs have been presented by several presenters. The mitochondrial diseases, the novelties and importance of early discovery were comprehensively presented and discussed. The genetics and treatment of persistent neonatal hypoglcaemia were of special interest. Dysmorphic syndromes (Klippel Feil) were also presented. A session of oral electronic posters was reach and inspiring. Several lectures dealt with mucopolisaccaridoses, glycogen storage diseases and the possibilities for their diagnosis and treatment. Enzyme replacement treatement (ERT), its availability, effects (or the lack of it on the brain), intratecal ERT administration and further prospects of eventual gene treatment were comprehensively exposed and discussed. The main purposes of this traditional meeting are hopefully fulfilled: increased number of patients with RDs treated and cutting edge presentations got.
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Chowdhury, Anisa, and Anto P. Rajkumar. "Systematic review of gene expression studies in people with Lewy body dementia." Acta Neuropsychiatrica 32, no. 6 (March 17, 2020): 281–92. http://dx.doi.org/10.1017/neu.2020.13.
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AbstractObjectives:Lewy body dementia (LBD) is the second most prevalent neurodegenerative dementia and it causes more morbidity and mortality than Alzheimer’s disease. Several genetic associations of LBD have been reported and their functional implications remain uncertain. Hence, we aimed to do a systematic review of all gene expression studies that investigated people with LBD for improving our understanding of LBD molecular pathology and for facilitating discovery of novel biomarkers and therapeutic targets for LBD.Methods:We systematically reviewed five online databases (PROSPERO protocol: CRD42017080647) and assessed the functional implications of all reported differentially expressed genes (DEGs) using Ingenuity Pathway Analyses.Results:We screened 3,809 articles and identified 31 eligible studies. In that, 1,242 statistically significant (p < 0.05) DEGs including 70 microRNAs have been reported in people with LBD. Expression levels of alternatively spliced transcripts of SNCA, SNCB, PRKN, APP, RELA, and ATXN2 significantly differ in LBD. Several mitochondrial genes and genes involved in ubiquitin proteasome system and autophagy–lysosomal pathway were significantly downregulated in LBD. Evidence supporting chronic neuroinflammation in LBD was inconsistent. Our functional analyses highlighted the importance of ribonucleic acid (RNA)-mediated gene silencing, neuregulin signalling, and neurotrophic factors in the molecular pathology of LBD.Conclusions:α-synuclein aggregation, mitochondrial dysfunction, defects in molecular networks clearing misfolded proteins, and RNA-mediated gene silencing contribute to neurodegeneration in LBD. Larger longitudinal transcriptomic studies investigating biological fluids of people living with LBD are needed for molecular subtyping and staging of LBD. Diagnostic biomarker potential and therapeutic promise of identified DEGs warrant further research.
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Gucev, Zoran, Velibor Tasic, and Momir Polenakovic. "5th Rare Disease South Eastern Europe (SEE) Meeting, Skopje, Macedonia (November 15th, 2016)." PRILOZI 38, no. 1 (March 1, 2017): 119–23. http://dx.doi.org/10.1515/prilozi-2017-0016.
Full textAbstract:
Abstract The fifth SEE meeting on rare diseases (RDs) was held in Macedonian Academy of Sciences and Arts (MASA) the November 11th, 2016. Several lectures dealt with mucopolysaccharidosis, glycogen storage diseases and the possibilities for their diagnosis and treatment. Enzyme replacement treatment (ERT), its availability, effects (or the lack of it) on the brain, and further prospects of eventual gene treatment were comprehensively exposed and discussed. Special accent was on Gaucher, Morquio IVA, Hunter and the audience was given new knowledge on the complexities of diagnosis and treatment. A block of lectures on rare renal diseases was also impressive. From renal stones, their molecular and genetic mechanisms to different forms of CAKUT the use of NGS and other molecular methods in diagnosis of RDs. Mitochondrial diseases, the novelties and importance of early discovery were comprehensively exposed. Special lecture was given on the complement system. Endocrine disruptors, microprolactinomas were also the topic of the meeting. A rather reach session of posters was also presented.
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Taurino, Chiara, William H. Miller, Martin W. McBride, John D. McClure, Raya Khanin, María U. Moreno, Jane A. Dymott, Christian Delles, and Anna F. Dominiczak. "Gene expression profiling in whole blood of patients with coronary artery disease." Clinical Science 119, no. 8 (July 6, 2010): 335–43. http://dx.doi.org/10.1042/cs20100043.
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Owing to the dynamic nature of the transcriptome, gene expression profiling is a promising tool for discovery of disease-related genes and biological pathways. In the present study, we examined gene expression in whole blood of 12 patients with CAD (coronary artery disease) and 12 healthy control subjects. Furthermore, ten patients with CAD underwent whole-blood gene expression analysis before and after the completion of a cardiac rehabilitation programme following surgical coronary revascularization. mRNA and miRNA (microRNA) were isolated for expression profiling. Gene expression analysis identified 365 differentially expressed genes in patients with CAD compared with healthy controls (175 up- and 190 down-regulated in CAD), and 645 in CAD rehabilitation patients (196 up- and 449 down-regulated post-rehabilitation). Biological pathway analysis identified a number of canonical pathways, including oxidative phosphorylation and mitochondrial function, as being significantly and consistently modulated across the groups. Analysis of miRNA expression revealed a number of differentially expressed miRNAs, including hsa-miR-140-3p (control compared with CAD, P=0.017), hsa-miR-182 (control compared with CAD, P=0.093), hsa-miR-92a and hsa-miR-92b (post- compared with pre-exercise, P<0.01). Global analysis of predicted miRNA targets found significantly reduced expression of genes with target regions compared with those without: hsa-miR-140-3p (P=0.002), hsa-miR-182 (P=0.001), hsa-miR-92a and hsa-miR-92b (P=2.2×10−16). In conclusion, using whole blood as a ‘surrogate tissue’ in patients with CAD, we have identified differentially expressed miRNAs, differentially regulated genes and modulated pathways which warrant further investigation in the setting of cardiovascular function. This approach may represent a novel non-invasive strategy to unravel potentially modifiable pathways and possible therapeutic targets in cardiovascular disease.
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Decano, Julius L., Sasha A. Singh, Cauê Gasparotto Bueno, Lang Ho Lee, Arda Halu, Sarvesh Chelvanambi, Joan T. Matamalas, et al. "Systems Approach to Discovery of Therapeutic Targets for Vein Graft Disease: PPARα Pivotally Regulates Metabolism, Activation, and Heterogeneity of Macrophages and Lesion Development." Circulation 143, no. 25 (June 22, 2021): 2454–70. http://dx.doi.org/10.1161/circulationaha.119.043724.
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Background: Vein graft failure remains a common clinical challenge. We applied a systems approach in mouse experiments to discover therapeutic targets for vein graft failure. Methods: Global proteomics and high-dimensional clustering on multiple vein graft tissues were used to identify potential pathogenic mechanisms. The PPARs (peroxisome proliferator-activated receptors) pathway served as an example to substantiate our discovery platform. In vivo mouse experiments with macrophage-targeted PPARα small interfering RNA, or the novel, selective activator pemafibrate demonstrate the role of PPARα in the development and inflammation of vein graft lesions. In vitro experiments further included metabolomic profiling, quantitative polymerase chain reaction, flow cytometry, metabolic assays, and single-cell RNA sequencing on primary human and mouse macrophages. Results: We identified changes in the vein graft proteome associated with immune responses, lipid metabolism regulated by the PPARs, fatty acid metabolism, matrix remodeling, and hematopoietic cell mobilization. PPARα agonism by pemafibrate retarded the development and inflammation of vein graft lesions in mice, whereas gene silencing worsened plaque formation. Pemafibrate also suppressed arteriovenous fistula lesion development. Metabolomics/lipidomics, functional metabolic assays, and single-cell analysis of cultured human macrophages revealed that PPARα modulates macrophage glycolysis, citrate metabolism, mitochondrial membrane sphingolipid metabolism, and heterogeneity. Conclusions: This study explored potential drivers of vein graft inflammation and identified PPARα as a novel potential pharmacological treatment for this unmet medical need.
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Ha, Byung, Sung Jung, You Jang, Byong Jeon, and Yun Shon. "Mineral-Enriched Deep-Sea Water Modulates Lactate Metabolism via PGC-1α-Mediated Metabolic Reprogramming." Marine Drugs 17, no. 11 (October 27, 2019): 611. http://dx.doi.org/10.3390/md17110611.
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Metabolic disorders such as diabetes and obesity are serious global health issues. These diseases are accelerated by mineral deficiencies, emphasizing the importance of addressing these deficiencies in disease management plans. Lactate metabolism is fundamentally linked to glucose metabolism, and several clinical studies have reported that blood lactate levels are higher in obese and diabetic patients than in healthy subjects. Balanced deep-sea water contains various minerals and exhibits antiobesity and antidiabetic activities in mice; however, the impact of balanced deep-sea water on lactate metabolism is unclear. Thus, we evaluated the effects of balanced deep-sea water on lactate metabolism in C2C12 myotubes, and found that balanced deep-sea water mediated lactate metabolism by regulating the gene expression levels of lactate dehydrogenases A and B, a monocarboxylate transporter, and a mitochondrial pyruvate carrier. The activities of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and signaling molecules involved in PGC-1α activation were also upregulated by treatment with balanced deep-sea water. These results suggest that balanced deep-sea water, which can mediate lactate metabolism, may be used to prevent or treat obesity and diabetes mellitus.
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Tan, Rongrong, Jiayang Li, Lu Liu, Qian Wu, Lei Fan, Ningning Ma, Chuwei Yu, et al. "CSAD Ameliorates Lipid Accumulation in High-Fat Diet-Fed Mice." International Journal of Molecular Sciences 23, no. 24 (December 14, 2022): 15931. http://dx.doi.org/10.3390/ijms232415931.
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Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic disease manifested in hepatic steatosis, inflammation, fibrosis, etc., which affects over one-quarter of the population around the world. Since no effective therapeutic drugs are available to cope with this widespread epidemic, the functional research of genes with altered expression during NAFLD helps understand the pathogenesis of this disease and the development of new potential therapeutic targets for drugs. In the current work, we discovered via the analysis of the Gene Expression Omnibus (GEO) dataset that cysteine sulfinic acid decarboxylase (CSAD) decreased significantly in NAFLD patients, which was also confirmed in multiple NAFLD mouse models (HFD-fed C57BL/6J, db/db and HFHFrHC-fed C57BL/6J mice). Next, CSAD’s function in the progression of NAFLD was explored using AAV-mediated liver-directed gene overexpression in an HFD-fed mouse model, where the overexpression of CSAD in the liver could alleviate NAFLD-associated pathologies, including body weight, liver/body weight ratio, hepatic triglyceride and total cholesterol, and the degree of steatosis. Mechanically, we found that the overexpression of CSAD could increase the expression of some genes related to fatty acid β-oxidation (Acad1, Ppara, and Acox1). Furthermore, we also detected that CSAD could improve mitochondrial injury in vitro and in vivo. Finally, we proposed that the effect of CSAD on lipid accumulation might be independent of the taurine pathway. In conclusion, we demonstrated that CSAD is involved in the development of NAFLD as a protective factor, which suggested that CSAD has the potential to become a new target for drug discovery in NAFLD.
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Tseng, Chung-Chih, Yu-Cheng Lai, Tsu-Jen Kuo, Jui-Hsin Su, Ping-Jyun Sung, Chien-Wei Feng, Yen-You Lin, et al. "Rhodoptilometrin, a Crinoid-Derived Anthraquinone, Induces Cell Regeneration by Promoting Wound Healing and Oxidative Phosphorylation in Human Gingival Fibroblast Cells." Marine Drugs 17, no. 3 (February 27, 2019): 138. http://dx.doi.org/10.3390/md17030138.
Full textAbstract:
Gingival recession (GR) potentially leads to the exposure of tooth root to the oral cavity microenvironment and increases susceptibility to dental caries, dentin hypersensitivity, and other dental diseases. Even though many etiological factors were reported, the specific mechanism of GR is yet to be elucidated. Given the species richness concerning marine biodiversity, it could be a treasure trove for drug discovery. In this study, we demonstrate the effects of a marine compound, (+)-rhodoptilometrin from crinoid, on gingival cell migration, wound healing, and oxidative phosphorylation (OXPHOS). Experimental results showed that (+)-rhodoptilometrin can significantly increase wound healing, migration, and proliferation of human gingival fibroblast cells, and it does not have effects on oral mucosa fibroblast cells. In addition, (+)-rhodoptilometrin increases the gene and protein expression levels of focal adhesion kinase (FAK), fibronectin, and type I collagen, changes the intracellular distribution of FAK and F-actin, and increases OXPHOS and the expression levels of complexes I~V in the mitochondria. Based on our results, we believe that (+)-rhodoptilometrin might increase FAK expression and promote mitochondrial function to affect cell migration and promote gingival regeneration. Therefore, (+)-rhodoptilometrin may be a promising therapeutic agent for GR.
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Vehns, Elena, Rouven Arnold, and Karima Djabali. "Impact of MnTBAP and Baricitinib Treatment on Hutchinson–Gilford Progeria Fibroblasts." Pharmaceuticals 15, no. 8 (July 29, 2022): 945. http://dx.doi.org/10.3390/ph15080945.
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Hutchinson–Gilford progeria syndrome (HGPS) is a rare premature aging disease. It is caused by a mutation in the LMNA gene, which results in a 50-amino-acid truncation of prelamin A. The resultant truncated prelamin A (progerin) lacks the cleavage site for the zinc-metallopeptidase ZMPSTE24. Progerin is permanently farnesylated, carboxymethylated, and strongly anchored to the nuclear envelope. This leads to abnormalities, such as altered nuclear shape, mitochondrial dysfunction, and inflammation. HGPS patients display symptoms of physiological aging, including atherosclerosis, alopecia, lipodystrophy, and arthritis. Currently, no cure for HGPS exists. Here we focus on a drug combination consisting of the superoxide dismutase mimetic MnTBAP and JAK1/2 inhibitor baricitinib (Bar) to restore phenotypic alterations in HGPS fibroblasts. Treating HGPS fibroblasts with the MnTBAP/Bar combination improved mitochondrial functions and sustained Bar’s positive effects on reducing progerin and pro-inflammatory factor levels. Collectively, MnTBAP/Bar combination treatment ameliorates the aberrant phenotype of HGPS fibroblasts and is a potential treatment strategy for patients with HGPS.
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Bagaria, Jaya, Eva Bagyinszky, and Seong Soo A. An. "Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration." International Journal of Molecular Sciences 23, no. 1 (January 4, 2022): 552. http://dx.doi.org/10.3390/ijms23010552.
Full textAbstract:
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases.
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Hayflick, Susan J. "Defective pantothenate metabolism and neurodegeneration." Biochemical Society Transactions 42, no. 4 (August 1, 2014): 1063–68. http://dx.doi.org/10.1042/bst20140098.
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Inborn errors of CoA (coenzyme A) biosynthesis lead to neurodegenerative disorders in humans. PKAN (pantothenate kinase-associated neurodegeneration) manifests with damage to brain, retina and testis and is caused by mutations in PANK2, the gene encoding the mitochondrial form of pantothenate kinase, a key regulatory enzyme in CoA synthesis. Further attention has been focused on this pathway by the recent discovery that mutations in the gene encoding CoA synthase lead to a similar neurodegenerative disorder, raising the spectre of a common mechanism of pathogenesis. How do defects in CoA production result in neurodegeneration? Why are certain tissues and cell types selectively vulnerable? And what is the underlying neurodegenerative process? Answers to some of these questions have come from animal models of disease, including flies and mice, as well as directly from humans. The damaged tissue types share key features that are likely to contribute to their selective vulnerability. These include the presence of a blood–tissue barrier, the milieu with respect to oxidative stress, tissue metabolic demand, relative expression of genes encoding similar proteins in these tissues and cell membrane composition. Substantial progress in understanding these important neurometabolic disorders has been made since the first gene discovery more than a decade ago. With rational therapeutics now in development for PKAN, we foresee prevention of neurodegeneration and hope for neuroregeneration or neuro-rescue.
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Kim, Eun. "Chemical Reporters and Their Bioorthogonal Reactions for Labeling Protein O-GlcNAcylation." Molecules 23, no. 10 (September 20, 2018): 2411. http://dx.doi.org/10.3390/molecules23102411.
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Protein O-GlcNAcylation is a non-canonical glycosylation of nuclear, mitochondrial, and cytoplasmic proteins with the attachment of a single O-linked β-N-acetyl-glucosamine (O-GlcNAc) moiety. Advances in labeling and identifying O-GlcNAcylated proteins have helped improve the understanding of O-GlcNAcylation at levels that range from basic molecular biology to cell signaling and gene regulation to physiology and disease. This review describes these advances in chemistry involving chemical reporters and their bioorthogonal reactions utilized for detection and construction of O-GlcNAc proteomes in a molecular mechanistic view. This detailed view will help better understand the principles of the chemistries utilized for biology discovery and promote continued efforts in developing new molecular tools and new strategies to further explore protein O-GlcNAcylation.
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Yan, Jing, C. Peter Bengtson, Bettina Buchthal, Anna M. Hagenston, and Hilmar Bading. "Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants." Science 370, no. 6513 (October 8, 2020): eaay3302. http://dx.doi.org/10.1126/science.aay3302.
Full textAbstract:
Excitotoxicity induced by NMDA receptors (NMDARs) is thought to be intimately linked to high intracellular calcium load. Unexpectedly, NMDAR-mediated toxicity can be eliminated without affecting NMDAR-induced calcium signals. Instead, excitotoxicity requires physical coupling of NMDARs to TRPM4. This interaction is mediated by intracellular domains located in the near-membrane portions of the receptors. Structure-based computational drug screening using the interaction interface of TRPM4 in complex with NMDARs identified small molecules that spare NMDAR-induced calcium signaling but disrupt the NMDAR/TRPM4 complex. These interaction interface inhibitors strongly reduce NMDA-triggered toxicity and mitochondrial dysfunction, abolish cyclic adenosine monophosphate–responsive element–binding protein (CREB) shutoff, boost gene induction, and reduce neuronal loss in mouse models of stroke and retinal degeneration. Recombinant or small-molecule NMDAR/TRPM4 interface inhibitors may mitigate currently untreatable human neurodegenerative diseases.
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Lynch, David R., Eric C. Deutsch, Robert B. Wilson, and Gihan Tennekoon. "Unanswered Questions in Friedreich Ataxia." Journal of Child Neurology 27, no. 9 (July 25, 2012): 1223–29. http://dx.doi.org/10.1177/0883073812453498.
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During the past 15 years, the pace of research advancement in Friedreich ataxia has been rapid. The abnormal gene has been discovered and its gene product characterized, leading to the development of new evidence-based therapies. Still, various unsettled issues remain that affect clinical trials. These include the level of frataxin deficiency needed to cause disease, the mechanism by which frataxin-deficient mitochondrial dysfunction leads to symptomatology, and the reason selected cells are most affected in Friedreich ataxia. In this review, we summarize these questions and propose testable hypotheses for their resolution.
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Wang, Huimei, Mingwei Zhang, Qiqi Xie, Jin Yu, Yan Qi, and Qiuyuan Yue. "Identification of diagnostic markers for major depressive disorder by cross-validation of data from whole blood samples." PeerJ 7 (June 21, 2019): e7171. http://dx.doi.org/10.7717/peerj.7171.
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Background Major depressive disorder (MDD) is a severe disease characterized by multiple pathological changes. However, there are no reliable diagnostic biomarkers for MDD. The aim of the current study was to investigate the gene network and biomarkers underlying the pathophysiology of MDD. Methods In this study, we conducted a comprehensive analysis of the mRNA expression profile of MDD using data from Gene Expression Omnibus (GEO). The MDD dataset (GSE98793) with 128 MDD and 64 control whole blood samples was divided randomly into two non-overlapping groups for cross-validated differential gene expression analysis. The gene ontology (GO) enrichment and gene set enrichment analysis (GSEA) were performed for annotation, visualization, and integrated discovery. Protein–protein interaction (PPI) network was constructed by STRING database and hub genes were identified by the CytoHubba plugin. The gene expression difference and the functional similarity of hub genes were investigated for further gene expression and function exploration. Moreover, the receiver operating characteristic curve was performed to verify the diagnostic value of the hub genes. Results We identified 761 differentially expressed genes closely related to MDD. The Venn diagram and GO analyses indicated that changes in MDD are mainly enriched in ribonucleoprotein complex biogenesis, antigen receptor-mediated signaling pathway, catalytic activity (acting on RNA), structural constituent of ribosome, mitochondrial matrix, and mitochondrial protein complex. The GSEA suggested that tumor necrosis factor signaling pathway, Toll-like receptor signaling pathway, apoptosis pathway, and NF-kappa B signaling pathway are all crucial in the development of MDD. A total of 20 hub genes were selected via the PPI network. Additionally, the identified hub genes were downregulated and show high functional similarity and diagnostic value in MDD. Conclusions Our findings may provide novel insight into the functional characteristics of MDD through integrative analysis of GEO data, and suggest potential biomarkers and therapeutic targets for MDD.
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Masotti, C., L. A. Brito, A. C. Nica, K. U. Ludwig, K. Nunes, C. P. Savastano, C. Malcher, et al. "MRPL53, a New Candidate Gene for Orofacial Clefting, Identified Using an eQTL Approach." Journal of Dental Research 97, no. 1 (October 20, 2017): 33–40. http://dx.doi.org/10.1177/0022034517735805.
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A valuable approach to understand how individual and population genetic differences can predispose to disease is to assess the impact of genetic variants on cellular functions (e.g., gene expression) of cell and tissue types related to pathological states. To understand the genetic basis of nonsyndromic cleft lip with or without cleft palate (NSCL/P) susceptibility, a complex and highly prevalent congenital malformation, we searched for genetic variants with a regulatory role in a disease-related tissue, the lip muscle (orbicularis oris muscle [OOM]), of affected individuals. From 46 OOM samples, which are frequently discarded during routine corrective surgeries on patients with orofacial clefts, we derived mesenchymal stem cells and correlated the individual genetic variants with gene expression from these cultured cells. Through this strategy, we detected significant cis-eQTLs (i.e., DNA variants affecting gene expression) and selected a few candidates to conduct an association study in a large Brazilian cohort (624 patients and 668 controls). This resulted in the discovery of a novel susceptibility locus for NSCL/P, rs1063588, the best eQTL for the MRPL53 gene, where evidence for association was mostly driven by the Native American ancestry component of our Brazilian sample. MRPL53 (2p13.1) encodes a 39S protein subunit of mitochondrial ribosomes and interacts with MYC, a transcription factor required for normal facial morphogenesis. Our study illustrates not only the importance of sampling admixed populations but also the relevance of measuring the functional effects of genetic variants over gene expression to dissect the complexity of disease phenotypes.
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Wang, Mei, Ya-Ping Huang, Han Wu, Ke Song, Cong Wan, A.-Ni Chi, Ya-Mei Xiao, and Xiao-Yang Zhao. "Mitochondrial complex I deficiency leads to the retardation of early embryonic development in Ndufs4 knockout mice." PeerJ 5 (May 18, 2017): e3339. http://dx.doi.org/10.7717/peerj.3339.
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Background The NDUFS4 gene encodes an 18-kD subunit of mitochondria complex I, and mutations in this gene lead to the development of a severe neurodegenerative disease called Leigh syndrome (LS) in humans. To investigate the disease phenotypes and molecular mechanisms of Leigh syndrome, the Ndufs4 knockout (KO) mouse has been widely used as a novel animal model. Because the homozygotes cannot survive beyond child-bearing age, whether Ndufs4 and mitochondrial complex I influence early embryonic development remains unknown. In our study, we attempted to investigate embryonic development in Ndufs4 KO mice, which can be regarded as a Leigh disease model and were created through the CRISPR (clustered regularly interspaced short palindromic repeat) and Cas9 (CRISPR associated)-mediated genome editing system. Methods We first designed a single guide RNA (sgRNA) targeting exon 2 of Ndufs4 to delete the NDUFS4 protein in mouse embryos to mimic Leigh syndrome. Then, we described the phenotypes of our mouse model by forced swimming and the open-field test as well as by assessing other behavioral characteristics. Intracytoplasmic sperm injection (ICSI) was performed to obtain KO embryos to test the influence of NDUFS4 deletion on early embryonic development. Results In this study, we first generated Ndufs4 KO mice with physical and behavioral phenotypes similar to Leigh syndrome using the CRISPR/Cas9 system. The low developmental rate of KO embryos that were derived from knockout gametes indicated that the absence of NDUFS4 impaired the development of preimplantation embryos. Discussion In this paper, we first obtained Ndufs4 KO mice that could mimic Leigh syndrome using the CRISPR/Cas9 system. Then, we identified the role of NDUFS4 in early embryonic development, shedding light on its roles in the respiratory chain and fertility. Our model provides a useful tool with which to investigate the function of Ndufs4. Although the pathological mechanisms of the disease need to be discovered, it helps to understand the pathogenesis of NDUFS4 deficiency in mice and its effects on human diseases.
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Taghvaei, Somayye, Leila Saremi, and Sepideh Babaniamansour. "Computational Analysis of Gly482Ser Single-Nucleotide Polymorphism in PPARGC1A Gene Associated with CAD, NAFLD, T2DM, Obesity, Hypertension, and Metabolic Diseases." PPAR Research 2021 (August 5, 2021): 1–12. http://dx.doi.org/10.1155/2021/5544233.
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Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PPARGC1A) regulates the expression of energy metabolism’s genes and mitochondrial biogenesis. The essential roles of PPARGC1A encouraged the researchers to assess the relation between metabolism-related diseases and its variants. To study Gly482Ser (+1564G/A) single-nucleotide polymorphism (SNP) after PPARGC1A modeling, we substitute Gly482 for Ser482. Stability prediction tools showed that this substitution decreases the stability of PPARGC1A or has a destabilizing effect on this protein. We then utilized molecular dynamics simulation of both the Gly482Ser variant and wild type of the PPARGC1A protein to analyze the structural changes and to reveal the conformational flexibility of the PPARGC1A protein. We observed loss flexibility in the RMSD plot of the Gly482Ser variant, which was further supported by a decrease in the SASA value in the Gly482Ser variant structure of PPARGC1A and an increase of H-bond with the increase of β-sheet and coil and decrease of turn in the DSSP plot of the Gly482Ser variant. Such alterations may significantly impact the structural conformation of the PPARGC1A protein, and it might also affect its function. It showed that the Gly482Ser variant affects the PPARGC1A structure and makes the backbone less flexible to move. In general, molecular dynamics simulation (MDS) showed more flexibility in the native PPARGC1A structure. Essential dynamics (ED) also revealed that the range of eigenvectors in the conformational space has lower extension of motion in the Gly482Ser variant compared with WT. The Gly482Ser variant also disrupts PPARGC1A interaction. Due to this single-nucleotide polymorphism in PPARGC1A, it became more rigid and might disarray the structural conformation and catalytic function of the protein and might also induce type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), and nonalcoholic fatty liver disease (NAFLD). The results obtained from this study will assist wet lab research in expanding potent treatment on T2DM.
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Zhang, Hanwen, Longping Yao, Zijian Zheng, Sumeyye Koc, and Guohui Lu. "The Role of Non-Coding RNAs in the Pathogenesis of Parkinson’s Disease: Recent Advancement." Pharmaceuticals 15, no. 7 (June 30, 2022): 811. http://dx.doi.org/10.3390/ph15070811.
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Parkinson’s disease (PD) is a prevalent neurodegenerative aging disorder that manifests as motor and non-motor symptoms, and its etiopathogenesis is influenced by non-coding RNAs (ncRNAs). Signal pathway and gene sequence studies have proposed that alteration of ncRNAs is relevant to the occurrence and development of PD. Furthermore, many studies on brain tissues and body fluids from patients with PD indicate that variations in ncRNAs and their target genes could trigger or exacerbate neurodegenerative pathogenesis and serve as potential non-invasive biomarkers of PD. Numerous ncRNAs have been considered regulators of apoptosis, α-syn misfolding and aggregation, mitochondrial dysfunction, autophagy, and neuroinflammation in PD etiology, and evidence is mounting for the determination of the role of competing endogenous RNA (ceRNA) mechanisms in disease development. In this review, we discuss the current knowledge regarding the regulation and function of ncRNAs as well as ceRNA networks in PD pathogenesis, focusing on microRNAs, long ncRNAs, and circular RNAs to increase the understanding of the disease and propose potential target identification and treatment in the early stages of PD.
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Villaseñor, Rodrigo, Loren Miraglia, Angelica Romero, Buu Tu, Tanel Punga, Philip Knuckles, Stephan Duss, Tony Orth, and Marc Bühler. "Genome-Engineering Tools to Establish Accurate Reporter Cell Lines That Enable Identification of Therapeutic Strategies to Treat Friedreich’s Ataxia." Journal of Biomolecular Screening 20, no. 6 (January 23, 2015): 760–67. http://dx.doi.org/10.1177/1087057114568071.
Full textAbstract:
Friedreich’s ataxia is a neurodegenerative disease caused by deficiency of the mitochondrial protein frataxin. This deficiency results from expansion of a trinucleotide repeat in the first intron of the frataxin gene. Because this repeat expansion resides in an intron and hence does not alter the amino acid sequence of the frataxin protein, gene reactivation could be of therapeutic benefit. High-throughput screening for frataxin activators has so far met with limited success because current cellular models may not accurately assess endogenous frataxin gene regulation. Here we report the design and validation of genome-engineering tools that enable the generation of human cell lines that express the frataxin gene fused to a luciferase reporter gene from its endogenous locus. Performing a pilot high-throughput genomic screen in a newly established reporter cell line, we uncovered novel negative regulators of frataxin expression. Rational design of small-molecule inhibitors of the identified frataxin repressors and/or high-throughput screening of large siRNA or compound libraries with our system may yield treatments for Friedreich’s ataxia.
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di Punzio, Giulia, Micol Gilberti, Enrico Baruffini, Tiziana Lodi, Claudia Donnini, and Cristina Dallabona. "A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool." International Journal of Molecular Sciences 22, no. 22 (November 12, 2021): 12223. http://dx.doi.org/10.3390/ijms222212223.
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Mitochondrial DNA depletion syndromes (MDS) are clinically heterogenous and often severe diseases, characterized by a reduction of the number of copies of mitochondrial DNA (mtDNA) in affected tissues. In the context of MDS, yeast has proved to be both an excellent model for the study of the mechanisms underlying mitochondrial pathologies and for the discovery of new therapies via high-throughput assays. Among the several genes involved in MDS, it has been shown that recessive mutations in MPV17 cause a hepatocerebral form of MDS and Navajo neurohepatopathy. MPV17 encodes a non selective channel in the inner mitochondrial membrane, but its physiological role and the nature of its cargo remains elusive. In this study we identify ten drugs active against MPV17 disorder, modelled in yeast using the homologous gene SYM1. All ten of the identified molecules cause a concomitant increase of both the mitochondrial deoxyribonucleoside triphosphate (mtdNTP) pool and mtDNA stability, which suggests that the reduced availability of DNA synthesis precursors is the cause for the mtDNA deletion and depletion associated with Sym1 deficiency. We finally evaluated the effect of these molecules on mtDNA stability in two other MDS yeast models, extending the potential use of these drugs to a wider range of MDS patients.