Journal articles: 'Mitochondrial pathology'

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Sarnat, Harvey B., and José Marín-García. "Pathology of Mitochondrial Encephalomyopathies." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 32, no. 2 (May 2005): 152–66. http://dx.doi.org/10.1017/s0317167100003929.

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ABSTRACT:Muscle biopsy provides the best tissue to confirm a mitochondrial cytopathy. Histochemical features often correlate with specific syndromes and facilitate the selection of biochemical and genetic studies. Ragged-red fibres nearly always indicate a combination defect of respiratory complexes I and IV. Increased punctate lipid within myofibers is a regular feature of Kearns-Sayre and PEO, but not of MELAS and MERRF. Total deficiency of succinate dehydrogenase indicates a severe defect in Complex II; total absence of cytochrome-c-oxidase activity in all myofibres correlates with a severe deficiency of Complex IV or of coenzyme-Q10. The selective loss of cytochrome-c-oxidase activity in scattered myofibers, particularly if accompanied by strong succinate dehydrogenase staining in these same fibres, is good evidence of mitochondrial cytopathy and often of a significant mtDNA mutation, though not specific for Complex IV disorders. Glycogen may be excessive in ragged-red zones. Ultrastructure provides morphological evidence of mitochondrial cytopathy, in axons and endothelial cells as well as myocytes. Abnormal axonal mitochondria may contribute to neurogenic atrophy of muscle, a secondary chronic feature. Quantitative determinations of respiratory chain enzyme complexes, with citrate synthase as an internal control, confirm the histochemical impressions or may be the only evidence of mitochondrial disease. Biological and technical artifacts may yield falsely low enzymatic activities. Genetic studies screen common point mutations in mtDNA. The brain exhibits characteristic histopathological alterations in mitochondrial diseases. Skin biopsy is useful for mitochondrial ultrastructure in smooth erector pili muscles and axons; skin fibroblasts may be grown in culture. Mitochondrial alterations occur in many nonmitochondrial diseases and also may be induced by drugs and toxins.

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Feng, Baoyi, Chenxi Jin, Zhenzhe Cheng, Xingle Zhao, Zhuoer Sun, Xiaofei Zheng, Xiang Li, Tingting Dong, Yong Tao, and Hao Wu. "Mitochondrial Dysfunction and Therapeutic Targets in Auditory Neuropathy." Neural Plasticity 2020 (August 28, 2020): 1–10. http://dx.doi.org/10.1155/2020/8843485.

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Sensorineural hearing loss (SNHL) becomes an inevitable worldwide public health issue, and deafness treatment is urgently imperative; yet their current curative therapy is limited. Auditory neuropathies (AN) were proved to play a substantial role in SNHL recently, and spiral ganglion neuron (SGN) dysfunction is a dominant pathogenesis of AN. Auditory pathway is a high energy consumption system, and SGNs required sufficient mitochondria. Mitochondria are known treatment target of SNHL, but mitochondrion mechanism and pathology in SGNs are not valued. Mitochondrial dysfunction and pharmacological therapy were studied in neurodegeneration, providing new insights in mitochondrion-targeted treatment of AN. In this review, we summarized mitochondrial biological functions related to SGNs and discussed interaction between mitochondrial dysfunction and AN, as well as existing mitochondrion treatment for SNHL. Pharmaceutical exploration to protect mitochondrion dysfunction is a feasible and effective therapeutics for AN.

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Picone, Pasquale, Domenico Nuzzo, Luca Caruana, Valeria Scafidi, and Marta Di Carlo. "Mitochondrial Dysfunction: Different Routes to Alzheimer’s Disease Therapy." Oxidative Medicine and Cellular Longevity 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/780179.

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Mitochondria are dynamic ATP-generating organelle which contribute to many cellular functions including bioenergetics processes, intracellular calcium regulation, alteration of reduction-oxidation potential of cells, free radical scavenging, and activation of caspase mediated cell death. Mitochondrial functions can be negatively affected by amyloidβpeptide (Aβ), an important component in Alzheimer’s disease (AD) pathogenesis, and Aβcan interact with mitochondria and cause mitochondrial dysfunction. One of the most accepted hypotheses for AD onset implicates that mitochondrial dysfunction and oxidative stress are one of the primary events in the insurgence of the pathology. Here, we examine structural and functional mitochondrial changes in presence of Aβ. In particular we review data concerning Aβimport into mitochondrion and its involvement in mitochondrial oxidative stress, bioenergetics, biogenesis, trafficking, mitochondrial permeability transition pore (mPTP) formation, and mitochondrial protein interaction. Moreover, the development of AD therapy targeting mitochondria is also discussed.

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Nevzorova, V. A., V. M. Chertok, T. A. Brodskaya, P. A. Selyukova, and N. V. Zakharchuk. "Mitochondrial dysfunction and vascular aging in comorbid pathology." Pacific Medical Journal, no. 1 (March 25, 2022): 10–16. http://dx.doi.org/10.34215/1609-1175-2022-1-10-16.

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Cardiovascular diseases take a leading position in the structure of mortality in modern society. Most diseases are characterized by uncontrolled processes of oxidative stress, proteolysis, tissue and cellular hypoxia, which cause endothelial dysfunction. Tissue and cellular hypoxia accumulated with mitochondrial reactive forms of oxygen damaging lipoproteins, proteins, nucleic acids plays an important role in the pathogenesis of vascular aging. Cellular aging is characterized by a decrease in the number of mitochondria, a decrease in the number of copies of mitochondrial DNA, and the loss of mitochondrial protein. In addition to morphological changes, the function of mitochondria is oppressed, at the same time the activity of their proteins and enzymes decreases. Changes in the functions of mitochondria can be secondary in response to various stimuli and are associated with a violation of their structure and a change in activity in response to specific genetic and phenotypic conditions. Reprogramming of mitochondrial biogenesis occupies a central position in the theory of cellular aging and is one of the targets for interventions in prolonging active longevity.

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Abramov, Andrey Y., and Plamena R. Angelova. "Cellular mechanisms of complex I-associated pathology." Biochemical Society Transactions 47, no. 6 (November 26, 2019): 1963–69. http://dx.doi.org/10.1042/bst20191042.

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Mitochondria control vitally important functions in cells, including energy production, cell signalling and regulation of cell death. Considering this, any alteration in mitochondrial metabolism would lead to cellular dysfunction and the development of a disease. A large proportion of disorders associated with mitochondria are induced by mutations or chemical inhibition of the mitochondrial complex I — the entry point to the electron transport chain. Subunits of the enzyme NADH: ubiquinone oxidoreductase, are encoded by both nuclear and mitochondrial DNA and mutations in these genes lead to cardio and muscular pathologies and diseases of the central nervous system. Despite such a clear involvement of complex I deficiency in numerous disorders, the molecular and cellular mechanisms leading to the development of pathology are not very clear. In this review, we summarise how lack of activity of complex I could differentially change mitochondrial and cellular functions and how these changes could lead to a pathology, following discrete routes.

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Schumacker, Paul T., Mark N. Gillespie, Kiichi Nakahira, Augustine M. K. Choi, Elliott D. Crouser, Claude A. Piantadosi, and Jahar Bhattacharya. "Mitochondria in lung biology and pathology: more than just a powerhouse." American Journal of Physiology-Lung Cellular and Molecular Physiology 306, no. 11 (June 1, 2014): L962—L974. http://dx.doi.org/10.1152/ajplung.00073.2014.

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An explosion of new information about mitochondria reveals that their importance extends well beyond their time-honored function as the “powerhouse of the cell.” In this Perspectives article, we summarize new evidence showing that mitochondria are at the center of a reactive oxygen species (ROS)-dependent pathway governing the response to hypoxia and to mitochondrial quality control. The potential role of the mitochondrial genome as a sentinel molecule governing cytotoxic responses of lung cells to ROS stress also is highlighted. Additional attention is devoted to the fate of damaged mitochondrial DNA relative to its involvement as a damage-associated molecular pattern driving adverse lung and systemic cell responses in severe illness or trauma. Finally, emerging strategies for replenishing normal populations of mitochondria after damage, either through promotion of mitochondrial biogenesis or via mitochondrial transfer, are discussed.

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Patterson, Kathleen. "Mitochondrial Muscle Pathology." Pediatric and Developmental Pathology 7, no. 6 (November 2004): 629–32. http://dx.doi.org/10.1007/s10024-004-5051-4.

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Sengers, R. C. A., and A. M. Stadhouders. "Secondary mitochondrial pathology." Journal of Inherited Metabolic Disease 10, S1 (March 1987): 98–104. http://dx.doi.org/10.1007/bf01812850.

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Jhun, Bong, Jin O-Uchi, Stephanie Adaniya, Michael Cypress, and Yisang Yoon. "Adrenergic Regulation of Drp1-Driven Mitochondrial Fission in Cardiac Physio-Pathology." Antioxidants 7, no. 12 (December 18, 2018): 195. http://dx.doi.org/10.3390/antiox7120195.

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Abnormal mitochondrial morphology, especially fragmented mitochondria, and mitochondrial dysfunction are hallmarks of a variety of human diseases including heart failure (HF). Although emerging evidence suggests a link between mitochondrial fragmentation and cardiac dysfunction, it is still not well described which cardiac signaling pathway regulates mitochondrial morphology and function under pathophysiological conditions such as HF. Mitochondria change their shape and location via the activity of mitochondrial fission and fusion proteins. This mechanism is suggested as an important modulator for mitochondrial and cellular functions including bioenergetics, reactive oxygen species (ROS) generation, spatiotemporal dynamics of Ca2+ signaling, cell growth, and death in the mammalian cell- and tissue-specific manners. Recent reports show that a mitochondrial fission protein, dynamin-like/related protein 1 (DLP1/Drp1), is post-translationally modified via cell signaling pathways, which control its subcellular localization, stability, and activity in cardiomyocytes/heart. In this review, we summarize the possible molecular mechanisms for causing post-translational modifications (PTMs) of DLP1/Drp1 in cardiomyocytes, and further discuss how these PTMs of DLP1/Drp1 mediate abnormal mitochondrial morphology and mitochondrial dysfunction under adrenergic signaling activation that contributes to the development and progression of HF.

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Luna-Sánchez, Marta, Patrizia Bianchi, and Albert Quintana. "Mitochondria-Induced Immune Response as a Trigger for Neurodegeneration: A Pathogen from Within." International Journal of Molecular Sciences 22, no. 16 (August 7, 2021): 8523. http://dx.doi.org/10.3390/ijms22168523.

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Symbiosis between the mitochondrion and the ancestor of the eukaryotic cell allowed cellular complexity and supported life. Mitochondria have specialized in many key functions ensuring cell homeostasis and survival. Thus, proper communication between mitochondria and cell nucleus is paramount for cellular health. However, due to their archaebacterial origin, mitochondria possess a high immunogenic potential. Indeed, mitochondria have been identified as an intracellular source of molecules that can elicit cellular responses to pathogens. Compromised mitochondrial integrity leads to release of mitochondrial content into the cytosol, which triggers an unwanted cellular immune response. Mitochondrial nucleic acids (mtDNA and mtRNA) can interact with the same cytoplasmic sensors that are specialized in recognizing genetic material from pathogens. High-energy demanding cells, such as neurons, are highly affected by deficits in mitochondrial function. Notably, mitochondrial dysfunction, neurodegeneration, and chronic inflammation are concurrent events in many severe debilitating disorders. Interestingly in this context of pathology, increasing number of studies have detected immune-activating mtDNA and mtRNA that induce an aberrant production of pro-inflammatory cytokines and interferon effectors. Thus, this review provides new insights on mitochondria-driven inflammation as a potential therapeutic target for neurodegenerative and primary mitochondrial diseases.

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Park, Yong Ho, Soo Jung Shin, Hyeon soo Kim, Sang Bum Hong, Sujin Kim, Yunkwon Nam, Jwa-Jin Kim, et al. "Omega-3 Fatty Acid-Type Docosahexaenoic Acid Protects against Aβ-Mediated Mitochondrial Deficits and Pathomechanisms in Alzheimer’s Disease-Related Animal Model." International Journal of Molecular Sciences 21, no. 11 (May 29, 2020): 3879. http://dx.doi.org/10.3390/ijms21113879.

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It has been reported that damage to the mitochondria affects the progression of Alzheimer’s disease (AD), and that mitochondrial dysfunction is improved by omega-3. However, no animal or cell model studies have confirmed whether omega-3 inhibits AD pathology related to mitochondria deficits. In this study, we aimed to (1) identify mitigating effects of endogenous omega-3 on mitochondrial deficits and AD pathology induced by amyloid beta (Aβ) in fat-1 mice, a transgenic omega-3 polyunsaturated fatty acids (PUFAs)-producing animal; (2) identify if docosahexaenoic acid (DHA) improves mitochondrial deficits induced by Aβ in HT22 cells; and (3) verify improvement effects of DHA administration on mitochondrial deficits and AD pathology in B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax (5XFAD), a transgenic Aβ-overexpressing model. We found that omega-3 PUFAs significantly improved Aβ-induced mitochondrial pathology in fat-1 mice. In addition, our in vitro and in vivo findings demonstrate that DHA attenuated AD-associated pathologies, such as mitochondrial impairment, Aβ accumulation, neuroinflammation, neuronal loss, and impairment of adult hippocampal neurogenesis.

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Portz, Philipp, and Michael K. Lee. "Changes in Drp1 Function and Mitochondrial Morphology Are Associated with the α-Synuclein Pathology in a Transgenic Mouse Model of Parkinson’s Disease." Cells 10, no. 4 (April 13, 2021): 885. http://dx.doi.org/10.3390/cells10040885.

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Alterations in mitochondrial function and morphology are associated with many human diseases, including cancer and neurodegenerative diseases. Mitochondrial impairment is linked to Parkinson’s disease (PD) pathogenesis, and alterations in mitochondrial dynamics are seen in PD models. In particular, α-synuclein (αS) abnormalities are often associated with pathological changes to mitochondria. However, the relationship between αS pathology and mitochondrial dynamics remains poorly defined. Herein, we examined a mouse model of α-synucleinopathy for αS pathology-linked alterations in mitochondrial dynamics in vivo. We show that α-synucleinopathy in a transgenic (Tg) mouse model expressing familial PD-linked mutant A53T human αS (TgA53T) is associated with a decrease in Drp1 localization and activity in the mitochondria. In addition, we show that the loss of Drp1 function in the mitochondria is associated with two distinct phenotypes of enlarged neuronal mitochondria. Mitochondrial enlargement was only present in diseased animals and, apart from Drp1, other proteins involved in mitochondrial dynamics are unlikely to cause these changes, as their levels remained mostly unchanged. Further, the levels of Mfn1, a protein that facilitates mitochondrial fusion, was decreased nonspecifically with transgene expression. These results support the view that altered mitochondrial dynamics are a significant neuropathological factor in α-synucleinopathies.

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13

Millichap, J. Gordon. "Pathology of Mitochondrial Encephalomyopathies." Pediatric Neurology Briefs 19, no. 8 (August 1, 2005): 57. http://dx.doi.org/10.15844/pedneurbriefs-19-8-1.

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CARAFOLI, ERNESTO. "Mitochondrial Pathology: An Overview." Annals of the New York Academy of Sciences 488, no. 1 Membrane Path (December 1986): 1–18. http://dx.doi.org/10.1111/j.1749-6632.1986.tb46544.x.

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Papa, Sergio. "Mitochondrial Physiology and Pathology." Biochimica et Biophysica Acta (BBA) - Bioenergetics 1787, no. 5 (May 2009): 289. http://dx.doi.org/10.1016/j.bbabio.2009.03.016.

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Braun, Frederik, Andreas Hentschel, Albert Sickmann, Theodore Marteau, Swantje Hertel, Fabian Förster, Holger Prokisch, et al. "Muscular and Molecular Pathology Associated with SPATA5 Deficiency in a Child with EHLMRS." International Journal of Molecular Sciences 22, no. 15 (July 22, 2021): 7835. http://dx.doi.org/10.3390/ijms22157835.

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Mutations in the SPATA5 gene are associated with epilepsy, hearing loss and mental retardation syndrome (EHLMRS). While SPATA5 is ubiquitously expressed and is attributed a role within mitochondrial morphogenesis during spermatogenesis, there is only limited knowledge about the associated muscular and molecular pathology. This study reports on a comprehensive workup of muscular pathology, including proteomic profiling and microscopic studies, performed on an 8-year-old girl with typical clinical presentation of EHLMRS, where exome analysis revealed two clinically relevant, compound-heterozygous variants in SPATA5. Proteomic profiling of a quadriceps biopsy showed the dysregulation of 82 proteins, out of which 15 were localized in the mitochondrion, while 19 were associated with diseases presenting with phenotypical overlap to EHLMRS. Histological staining of our patient’s muscle biopsy hints towards mitochondrial pathology, while the identification of dysregulated proteins attested to the vulnerability of the cell beyond the mitochondria. Through our study we provide insights into the molecular etiology of EHLMRS and provide further evidence for a muscle pathology associated with SPATA5 deficiency, including a pathological histochemical pattern accompanied by dysregulated protein expression.

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Nesci, Salvatore, Fabiana Trombetti, Alessandra Pagliarani, Vittoria Ventrella, Cristina Algieri, Gaia Tioli, and Giorgio Lenaz. "Molecular and Supramolecular Structure of the Mitochondrial Oxidative Phosphorylation System: Implications for Pathology." Life 11, no. 3 (March 15, 2021): 242. http://dx.doi.org/10.3390/life11030242.

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Under aerobic conditions, mitochondrial oxidative phosphorylation (OXPHOS) converts the energy released by nutrient oxidation into ATP, the currency of living organisms. The whole biochemical machinery is hosted by the inner mitochondrial membrane (mtIM) where the protonmotive force built by respiratory complexes, dynamically assembled as super-complexes, allows the F1FO-ATP synthase to make ATP from ADP + Pi. Recently mitochondria emerged not only as cell powerhouses, but also as signaling hubs by way of reactive oxygen species (ROS) production. However, when ROS removal systems and/or OXPHOS constituents are defective, the physiological ROS generation can cause ROS imbalance and oxidative stress, which in turn damages cell components. Moreover, the morphology of mitochondria rules cell fate and the formation of the mitochondrial permeability transition pore in the mtIM, which, most likely with the F1FO-ATP synthase contribution, permeabilizes mitochondria and leads to cell death. As the multiple mitochondrial functions are mutually interconnected, changes in protein composition by mutations or in supercomplex assembly and/or in membrane structures often generate a dysfunctional cascade and lead to life-incompatible diseases or severe syndromes. The known structural/functional changes in mitochondrial proteins and structures, which impact mitochondrial bioenergetics because of an impaired or defective energy transduction system, here reviewed, constitute the main biochemical damage in a variety of genetic and age-related diseases.

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Baloyannis, Stavros J. "Mitochondria Are Related to Synaptic Pathology in Alzheimer's Disease." International Journal of Alzheimer's Disease 2011 (2011): 1–7. http://dx.doi.org/10.4061/2011/305395.

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Morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer's disease, been associated with oxidative stress and Aβ-peptide-induced toxicity. We proceeded to estimation of mitochondria on electron micrographs of autopsy specimens of Alzheimer's disease. We found substantial morphological and morphometric changes of the mitochondria in the neurons of the hippocampus, the neocortex, the cerebellar cortex, the thalamus, the globus pallidus, the red nucleus, the locus coeruleus, and the climbing fibers. The alterations consisted of considerable changes of the cristae, accumulation of osmiophilic material, and modification of the shape and size. Mitochondrial alterations were prominent in neurons, which showed a depletion of dendritic spines and loss of dendritic branches. Mitochondrial alterations are not related with the accumulation of amyloid deposits, but are prominent whenever fragmentation of the Golgi apparatus exists. Morphometric analysis showed also that mitochondria are significantly reduced in neurons, which demonstrated synaptic pathology.

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Peoples, Jessica N., Anita Saraf, Nasab Ghazal, Tyler T. Pham, and Jennifer Q. Kwong. "Mitochondrial dysfunction and oxidative stress in heart disease." Experimental & Molecular Medicine 51, no. 12 (December 2019): 1–13. http://dx.doi.org/10.1038/s12276-019-0355-7.

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AbstractBeyond their role as a cellular powerhouse, mitochondria are emerging as integral players in molecular signaling and cell fate determination through reactive oxygen species (ROS). While ROS production has historically been portrayed as an unregulated process driving oxidative stress and disease pathology, contemporary studies reveal that ROS also facilitate normal physiology. Mitochondria are especially abundant in cardiac tissue; hence, mitochondrial dysregulation and ROS production are thought to contribute significantly to cardiac pathology. Moreover, there is growing appreciation that medical therapies designed to mediate mitochondrial ROS production can be important strategies to ameliorate cardiac disease. In this review, we highlight evidence from animal models that illustrates the strong connections between mitochondrial ROS and cardiac disease, discuss advancements in the development of mitochondria-targeted antioxidant therapies, and identify challenges faced in bringing such therapies into the clinic.

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Kondratyeva, E. V., and T. I. Vitkina. "Functional state of mitochondria in chronic respiratory diseases." Bulletin Physiology and Pathology of Respiration 1, no. 84 (July 9, 2022): 116–26. http://dx.doi.org/10.36604/1998-5029-2022-84-116-126.

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Introduction. Chronic respiratory diseases are one of the most common types of non-communicable diseases and are an important problem of our time. The induction of oxidative stress, chronic inflammation and hypoxia, which underlie the pathogenesis of chronic diseases of the bronchopulmonary system, can be determined at the cellular and molecular level by impaired mitochondrial functioning.Aim. This review is devoted to the prospects for assessing the functional state of mitochondria as a fine indicator of the course of chronic respiratory diseases.Results. The data of domestic and foreign sources on the most important parameters of mitochondrial functioning in normal and chronic bronchopulmonary pathology were analyzed. It has been shown that mitochondria are highly sensitive to changes in both exogenous and endogenous homeostasis. Functional parameters of mitochondria, the level of mitochondrial reactive oxygen species, mitochondrial membrane potential, and fatty acid composition of mitochondrial membranes can be used as diagnostic and prognostic criteria for chronic respiratory diseases. The data presented in the review indicate the need for further studies of the functional state of mitochondria in chronic bronchopulmonary pathology.

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Shin, Soo Jung, Seong Gak Jeon, Jin-il Kim, Yu-on Jeong, Sujin Kim, Yong Ho Park, Seong-Kyung Lee, et al. "Red Ginseng Attenuates Aβ-Induced Mitochondrial Dysfunction and Aβ-mediated Pathology in an Animal Model of Alzheimer’s Disease." International Journal of Molecular Sciences 20, no. 12 (June 21, 2019): 3030. http://dx.doi.org/10.3390/ijms20123030.

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Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by neurodegeneration and cognitive deficits. Amyloid beta (Aβ) peptide is known to be a major cause of AD pathogenesis. However, recent studies have clarified that mitochondrial deficiency is also a mediator or trigger for AD development. Interestingly, red ginseng (RG) has been demonstrated to have beneficial effects on AD pathology. However, there is no evidence showing whether RG extract (RGE) can inhibit the mitochondrial deficit-mediated pathology in the experimental models of AD. The effects of RGE on Aβ-mediated mitochondrial deficiency were investigated in both HT22 mouse hippocampal neuronal cells and the brains of 5XFAD Aβ-overexpressing transgenic mice. To examine whether RGE can affect mitochondria-related pathology, we used immunohistostaining to study the effects of RGE on Aβ accumulation, neuroinflammation, neurodegeneration, and impaired adult hippocampal neurogenesis in hippocampal formation of 5XFAD mice. In vitro and in vivo findings indicated that RGE significantly improves Aβ-induced mitochondrial pathology. In addition, RGE significantly ameliorated AD-related pathology, such as Aβ deposition, gliosis, and neuronal loss, and deficits in adult hippocampal neurogenesis in brains with AD. Our results suggest that RGE may be a mitochondria-targeting agent for the treatment of AD.

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Huang, Zhenting, Qian Yan, Yangyang Wang, Qian Zou, Jing Li, Zhou Liu, and Zhiyou Cai. "Role of Mitochondrial Dysfunction in the Pathology of Amyloid-β." Journal of Alzheimer's Disease 78, no. 2 (November 10, 2020): 505–14. http://dx.doi.org/10.3233/jad-200519.

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Mitochondrial dysfunction has been widely reported in several neurodegenerative disorders, including in the brains of patients with Alzheimer’s disease (AD), Parkinson’s disease, and Huntington disease. An increasing number of studies have implicated altered glucose and energy metabolism in patients with AD. There is compelling evidence of abnormalities in some of the key mitochondrial enzymes involved in glucose metabolism, including the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes, which play a great significance role in the pathogenesis of AD. Changes in some of the enzyme activities of the mitochondria found in AD have been linked with the pathology of amyloid-β (Aβ). This review highlights the role of mitochondrial function in the production and clearance of Aβ and how the pathology of Aβ leads to a decrease in energy metabolism by affecting mitochondrial function.

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Aslam, Muhammad, and Yury Ladilov. "Regulation of Mitochondrial Homeostasis by sAC-Derived cAMP Pool: Basic and Translational Aspects." Cells 10, no. 2 (February 22, 2021): 473. http://dx.doi.org/10.3390/cells10020473.

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In contrast to the traditional view of mitochondria being solely a source of cellular energy, e.g., the “powerhouse” of the cell, mitochondria are now known to be key regulators of numerous cellular processes. Accordingly, disturbance of mitochondrial homeostasis is a basic mechanism in several pathologies. Emerging data demonstrate that 3′–5′-cyclic adenosine monophosphate (cAMP) signalling plays a key role in mitochondrial biology and homeostasis. Mitochondria are equipped with an endogenous cAMP synthesis system involving soluble adenylyl cyclase (sAC), which localizes in the mitochondrial matrix and regulates mitochondrial function. Furthermore, sAC localized at the outer mitochondrial membrane contributes significantly to mitochondrial biology. Disturbance of the sAC-dependent cAMP pools within mitochondria leads to mitochondrial dysfunction and pathology. In this review, we discuss the available data concerning the role of sAC in regulating mitochondrial biology in relation to diseases.

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Costanzini, Anna, Gianluca Sgarbi, Alessandra Maresca, Valentina Del Dotto, Giancarlo Solaini, and Alessandra Baracca. "Mitochondrial Mass Assessment in a Selected Cell Line under Different Metabolic Conditions." Cells 8, no. 11 (November 18, 2019): 1454. http://dx.doi.org/10.3390/cells8111454.

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Changes of quantity and/or morphology of cell mitochondria are often associated with metabolic modulation, pathology, and apoptosis. Exogenous fluorescent probes used to investigate changes in mitochondrial content and dynamics are strongly dependent, for their internalization, on the mitochondrial membrane potential and composition, thus limiting the reliability of measurements. To overcome this limitation, genetically encoded recombinant fluorescent proteins, targeted to different cellular districts, were used as reporters. Here, we explored the potential use of mitochondrially targeted red fluorescent probe (mtRFP) to quantify, by flow cytometry, mitochondrial mass changes in cells exposed to different experimental conditions. We first demonstrated that the mtRFP fluorescence intensity is stable during cell culture and it is related with the citrate synthase activity, an established marker of the mitochondrial mass. Incidentally, the expression of mtRFP inside mitochondria did not alter the oxygen consumption rate under both state 3 and 4 respiration conditions. In addition, using this method, we showed for the first time that different inducers of mitochondrial mass change, such as hypoxia exposure or resveratrol treatment of cells, could be consistently detected. We suggest that transfection and selection of stable clones expressing mtRFP is a reliable method to monitor mitochondrial mass changes, particularly when pathophysiological or experimental conditions change ΔΨm, as it occurs during mitochondrial uncoupling or hypoxia/anoxia conditions.

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Moro, Loredana. "Mitochondria at the Crossroads of Physiology and Pathology." Journal of Clinical Medicine 9, no. 6 (June 24, 2020): 1971. http://dx.doi.org/10.3390/jcm9061971.

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Mitochondria play a crucial role in cell life and death by regulating bioenergetic and biosynthetic pathways. They are able to adapt rapidly to different microenvironmental stressors by accommodating the metabolic and biosynthetic needs of the cell. Mounting evidence places mitochondrial dysfunction at the core of several diseases, notably in the context of pathologies of the cardiovascular and central nervous system. In addition, mutations in some mitochondrial proteins are bona fide cancer drivers. Better understanding of the functions of these multifaceted organelles and their components may finetune our knowledge on the molecular bases of certain diseases and suggest new therapeutic avenues.

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Wang, Luwen, Mengyu Liu, Ju Gao, Amber M. Smith, Hisashi Fujioka, Jingjing Liang, George Perry, and Xinglong Wang. "Mitochondrial Fusion Suppresses Tau Pathology-Induced Neurodegeneration and Cognitive Decline." Journal of Alzheimer's Disease 84, no. 3 (November 23, 2021): 1057–69. http://dx.doi.org/10.3233/jad-215175.

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Background: Abnormalities of mitochondrial fission and fusion, dynamic processes known to be essential for various aspects of mitochondrial function, have repeatedly been reported to be altered in Alzheimer’s disease (AD). Neurofibrillary tangles are known as a hallmark feature of AD and are commonly considered a likely cause of neurodegeneration in this devastating disease. Objective: To understand the pathological role of mitochondrial dynamics in the context of tauopathy. Methods: The widely used P301S transgenic mice of tauopathy (P301S mice) were crossed with transgenic TMFN mice with the forced expression of Mfn2 specifically in neurons to obtain double transgenic P301S/TMFN mice. Brain tissues from 11-month-old non-transgenic (NTG), TMFN, P301S, and P301S/TMFN mice were analyzed by electron microscopy, confocal microscopy, immunoblot, histological staining, and immunostaining for mitochondria, tau pathology, and tau pathology-induced neurodegeneration and gliosis. The cognitive function was assessed by the Barnes maze. Results: P301S mice exhibited mitochondrial fragmentation and a consistent decrease in Mfn2 compared to age-matched NTG mice. When P301S mice were crossed with TMFN mice (P301S/TMFN mice), neuronal loss, as well as mitochondria fragmentation were significantly attenuated. Greatly alleviated tau hyperphosphorylation, filamentous aggregates, and thioflavin-S positive tangles were also noted in P301S/TMFN mice. Furthermore, P301S/TMFN mice showed marked suppression of neuroinflammation and improved cognitive performance in contrast to P301S mice. Conclusion: These in vivo findings suggest that promoted mitochondrial fusion suppresses toxic tau accumulation and associated neurodegeneration, which may protect against the progression of AD and related tauopathies.

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Yin, Xinghua, Grahame J. Kidd, Nobuhiko Ohno, Guy A. Perkins, Mark H. Ellisman, Chinthasagar Bastian, Sylvain Brunet, Selva Baltan, and Bruce D. Trapp. "Proteolipid protein–deficient myelin promotes axonal mitochondrial dysfunction via altered metabolic coupling." Journal of Cell Biology 215, no. 4 (November 21, 2016): 531–42. http://dx.doi.org/10.1083/jcb.201607099.

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Hereditary spastic paraplegia (HSP) is a neurological syndrome characterized by degeneration of central nervous system (CNS) axons. Mutated HSP proteins include myelin proteolipid protein (PLP) and axon-enriched proteins involved in mitochondrial function, smooth endoplasmic reticulum (SER) structure, and microtubule (MT) stability/function. We characterized axonal mitochondria, SER, and MTs in rodent optic nerves where PLP is replaced by the peripheral nerve myelin protein, P0 (P0-CNS mice). Mitochondrial pathology and degeneration were prominent in juxtaparanodal axoplasm at 1 mo of age. In wild-type (WT) optic nerve axons, 25% of mitochondria–SER associations occurred on extensions of the mitochondrial outer membrane. Mitochondria–SER associations were reduced by 86% in 1-mo-old P0-CNS juxtaparanodal axoplasm. 1-mo-old P0-CNS optic nerves were more sensitive to oxygen-glucose deprivation and contained less adenosine triphosphate (ATP) than WT nerves. MT pathology and paranodal axonal ovoids were prominent at 6 mo. These data support juxtaparanodal mitochondrial degeneration, reduced mitochondria–SER associations, and reduced ATP production as causes of axonal ovoid formation and axonal degeneration.

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Hollander, John M., Dharendra Thapa, and Danielle L. Shepherd. "Physiological and structural differences in spatially distinct subpopulations of cardiac mitochondria: influence of cardiac pathologies." American Journal of Physiology-Heart and Circulatory Physiology 307, no. 1 (July 1, 2014): H1—H14. http://dx.doi.org/10.1152/ajpheart.00747.2013.

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Cardiac tissue contains discrete pools of mitochondria that are characterized by their subcellular spatial arrangement. Subsarcolemmal mitochondria (SSM) exist below the cell membrane, interfibrillar mitochondria (IFM) reside in rows between the myofibrils, and perinuclear mitochondria are situated at the nuclear poles. Microstructural imaging of heart tissue coupled with the development of differential isolation techniques designed to sequentially separate spatially distinct mitochondrial subpopulations have revealed differences in morphological features including shape, absolute size, and internal cristae arrangement. These findings have been complemented by functional studies indicating differences in biochemical parameters and, potentially, functional roles for the ATP generated, based upon subcellular location. Consequently, mitochondrial subpopulations appear to be influenced differently during cardiac pathologies including ischemia/reperfusion, heart failure, aging, exercise, and diabetes mellitus. These influences may be the result of specific structural and functional disparities between mitochondrial subpopulations such that the stress elicited by a given cardiac insult differentially impacts subcellular locales and the mitochondria contained within. The goal of this review is to highlight some of the inherent structural and functional differences that exist between spatially distinct cardiac mitochondrial subpopulations as well as provide an overview of the differential impact of various cardiac pathologies on spatially distinct mitochondrial subpopulations. As an outcome, we will instill a basis for incorporating subcellular spatial location when evaluating the impact of cardiac pathologies on the mitochondrion. Incorporation of subcellular spatial location may offer the greatest potential for delineating the influence of cardiac pathology on this critical organelle.

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García-Escudero, Vega, Patricia Martín-Maestro, George Perry, and Jesús Avila. "Deconstructing Mitochondrial Dysfunction in Alzheimer Disease." Oxidative Medicine and Cellular Longevity 2013 (2013): 1–13. http://dx.doi.org/10.1155/2013/162152.

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There is mounting evidence showing that mitochondrial damage plays an important role in Alzheimer disease. Increased oxygen species generation and deficient mitochondrial dynamic balance have been suggested to be the reason as well as the consequence of Alzheimer-related pathology. Mitochondrial damage has been related to amyloid-beta or tau pathology or to the presence of specific presenilin-1 mutations. The contribution of these factors to mitochondrial dysfunction is reviewed in this paper. Due to the relevance of mitochondrial alterations in Alzheimer disease, recent works have suggested the therapeutic potential of mitochondrial-targeted antioxidant. On the other hand, autophagy has been demonstrated to play a fundamental role in Alzheimer-related protein stress, and increasing data shows that this pathway is altered in the disease. Moreover, mitochondrial alterations have been related to an insufficient clearance of dysfunctional mitochondria by autophagy. Consequently, different approaches for the removal of damaged mitochondria or to decrease the related oxidative stress in Alzheimer disease have been described. To understand the role of mitochondrial function in Alzheimer disease it is necessary to generate human cellular models which involve living neurons. We have summarized the novel protocols for the generation of neurons by reprogramming or direct transdifferentiation, which offer useful tools to achieve this result.

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Sekigawa, Akio, Yoshiki Takamatsu, Kazunari Sekiyama, Takato Takenouchi, Shuei Sugama, Masaaki Waragai, Masayo Fujita, and Makoto Hashimoto. "Diversity of Mitochondrial Pathology in a Mouse Model of Axonal Degeneration in Synucleinopathies." Oxidative Medicine and Cellular Longevity 2013 (2013): 1–6. http://dx.doi.org/10.1155/2013/817807.

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There is mounting evidence for a role of mitochondrial dysfunction in the pathogenesis ofα-synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In particular, recent studies have demonstrated that failure of mitochondrial quality control caused by loss of function of the PTEN-induced kinase 1 (PINK1, PARK6) Parkin (PARK2) pathway may be causative in some familial PD. In sporadic PD,α-synuclein aggregation may interfere with mitochondrial function, and this might be further exacerbated by leucine-rich repeat kinase 2 (LRRK2). The majority of these findings have been obtained inDrosophilaand cell cultures, whereas the objective of this paper is to discuss our recent results on the axonal pathology of brains derived from transgenic mice expressingα-synuclein or DLB-linked P123Hβ-synuclein. In line with the current view of the pathogenesis of sporadic PD, mitochondria abnormally accumulated inα-synuclein/LRRK2-immunopositive axonal swellings in mice expressingα-synuclein. Curiously, neither mitochondria nor LRRK2 was present in the swellings of mice expressing P123Hβ-synuclein, suggesting thatα- andβ-synuclein might play differential roles in the mitochondrial pathology ofα-synucleinopathies.

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Huang, Michael L. H., Shannon Chiang, Danuta S. Kalinowski, Dong-Hun Bae, Sumit Sahni, and Des R. Richardson. "The Role of the Antioxidant Response in Mitochondrial Dysfunction in Degenerative Diseases: Cross-Talk between Antioxidant Defense, Autophagy, and Apoptosis." Oxidative Medicine and Cellular Longevity 2019 (April 7, 2019): 1–26. http://dx.doi.org/10.1155/2019/6392763.

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The mitochondrion is an essential organelle important for the generation of ATP for cellular function. This is especially critical for cells with high energy demands, such as neurons for signal transmission and cardiomyocytes for the continuous mechanical work of the heart. However, deleterious reactive oxygen species are generated as a result of mitochondrial electron transport, requiring a rigorous activation of antioxidative defense in order to maintain homeostatic mitochondrial function. Indeed, recent studies have demonstrated that the dysregulation of antioxidant response leads to mitochondrial dysfunction in human degenerative diseases affecting the nervous system and the heart. In this review, we outline and discuss the mitochondrial and oxidative stress factors causing degenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and Friedreich’s ataxia. In particular, the pathological involvement of mitochondrial dysfunction in relation to oxidative stress, energy metabolism, mitochondrial dynamics, and cell death will be explored. Understanding the pathology and the development of these diseases has highlighted novel regulators in the homeostatic maintenance of mitochondria. Importantly, this offers potential therapeutic targets in the development of future treatments for these degenerative diseases.

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Chan, David C. "Mitochondrial Dynamics and Its Involvement in Disease." Annual Review of Pathology: Mechanisms of Disease 15, no. 1 (January 24, 2020): 235–59. http://dx.doi.org/10.1146/annurev-pathmechdis-012419-032711.

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The dynamic properties of mitochondria—including their fusion, fission, and degradation—are critical for their optimal function in energy generation. The interplay of fusion and fission confers widespread benefits on mitochondria, including efficient transport, increased homogenization of the mitochondrial population, and efficient oxidative phosphorylation. These benefits arise through control of morphology, content exchange, equitable inheritance of mitochondria, maintenance of high-quality mitochondrial DNA, and segregation of damaged mitochondria for degradation. The key components of the machinery mediating mitochondrial fusion and fission belong to the dynamin family of GTPases that utilize GTP hydrolysis to drive mechanical work on biological membranes. Defects in this machinery cause a range of diseases that especially affect the nervous system. In addition, several common diseases, including neurodegenerative diseases and cancer, strongly affect mitochondrial dynamics.

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Wu, Longhuo, Haiqing Liu, Linfu Li, Hai Liu, Qilai Cheng, Hongliang Li, and Hao Huang. "Mitochondrial Pathology in Osteoarthritic Chondrocytes." Current Drug Targets 15, no. 7 (June 2014): 710–19. http://dx.doi.org/10.2174/1389450115666140417120305.

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Kotov, S. V., O. P. Sidorova, and E. V. Borodataya. "Mitochondrial disorders in neuromuscular pathology." Neuromuscular Diseases 9, no. 3 (November 20, 2019): 22–31. http://dx.doi.org/10.17650/2222-8721-2019-9-3-22-31.

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Marin-Garcia, J. "Mitochondrial pathology in cardiac failure." Cardiovascular Research 49, no. 1 (January 2001): 17–26. http://dx.doi.org/10.1016/s0008-6363(00)00241-8.

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Lax⁎, Nichola Z., Amy K. Reeve, Philippa Hepplewhite, Evelyn Jaros, Robert W. Taylor, and Doug M. Turnbull. "Vascular pathology in mitochondrial disease." Mitochondrion 11, no. 4 (July 2011): 654–55. http://dx.doi.org/10.1016/j.mito.2011.03.060.

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Schapira, Anthony H. V. "Mitochondrial Pathology in Parkinson's Disease." Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine 78, no. 6 (November 2011): 872–81. http://dx.doi.org/10.1002/msj.20303.

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Kunji, Edmund R. S., Martin S. King, Jonathan J. Ruprecht, and Chancievan Thangaratnarajah. "The SLC25 Carrier Family: Important Transport Proteins in Mitochondrial Physiology and Pathology." Physiology 35, no. 5 (September 1, 2020): 302–27. http://dx.doi.org/10.1152/physiol.00009.2020.

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Members of the mitochondrial carrier family (SLC25) transport a variety of compounds across the inner membrane of mitochondria. These transport steps provide building blocks for the cell and link the pathways of the mitochondrial matrix and cytosol. An increasing number of diseases and pathologies has been associated with their dysfunction. In this review, the molecular basis of these diseases is explained based on our current understanding of their transport mechanism.

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Haslem, Landon, Jennifer M. Hays, and Franklin A. Hays. "p66Shc in Cardiovascular Pathology." Cells 11, no. 11 (June 6, 2022): 1855. http://dx.doi.org/10.3390/cells11111855.

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p66Shc is a widely expressed protein that governs a variety of cardiovascular pathologies by generating, and exacerbating, pro-apoptotic ROS signals. Here, we review p66Shc’s connections to reactive oxygen species, expression, localization, and discuss p66Shc signaling and mitochondrial functions. Emphasis is placed on recent p66Shc mitochondrial function discoveries including structure/function relationships, ROS identity and regulation, mechanistic insights, and how p66Shc-cyt c interactions can influence p66Shc mitochondrial function. Based on recent findings, a new p66Shc mitochondrial function model is also put forth wherein p66Shc acts as a rheostat that can promote or antagonize apoptosis. A discussion of how the revised p66Shc model fits previous findings in p66Shc-mediated cardiovascular pathology follows.

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40

Zhang, Linlin, Jingyi Qi, Xu Zhang, Xiya Zhao, Peng An, Yongting Luo, and Junjie Luo. "The Regulatory Roles of Mitochondrial Calcium and the Mitochondrial Calcium Uniporter in Tumor Cells." International Journal of Molecular Sciences 23, no. 12 (June 15, 2022): 6667. http://dx.doi.org/10.3390/ijms23126667.

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Mitochondria, as the main site of cellular energy metabolism and the generation of oxygen free radicals, are the key switch for mitochondria-mediated endogenous apoptosis. Ca2+ is not only an important messenger for cell proliferation, but it is also an indispensable signal for cell death. Ca2+ participates in and plays a crucial role in the energy metabolism, physiology, and pathology of mitochondria. Mitochondria control the uptake and release of Ca2+ through channels/transporters, such as the mitochondrial calcium uniporter (MCU), and influence the concentration of Ca2+ in both mitochondria and cytoplasm, thereby regulating cellular Ca2+ homeostasis. Mitochondrial Ca2+ transport-related processes are involved in important biological processes of tumor cells including proliferation, metabolism, and apoptosis. In particular, MCU and its regulatory proteins represent a new era in the study of MCU-mediated mitochondrial Ca2+ homeostasis in tumors. Through an in-depth analysis of the close correlation between mitochondrial Ca2+ and energy metabolism, autophagy, and apoptosis of tumor cells, we can provide a valuable reference for further understanding of how mitochondrial Ca2+ regulation helps diagnosis and therapy.

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Mohamad Noor, Rabiatul Adawiyah, Wan Azman Wan Sulaiman, Anani Aila Mat Zin, and Nurul Syazana Mohamad Shah. "A Systematic Review of the Role of Mitochondria in Cleft Pathology: A Forgotten General?" Archives of Orofacial Sciences 17, no. 1 (June 23, 2022): 21–30. http://dx.doi.org/10.21315/aos2022.1701.rv03.

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Orofacial clefts (OFC) are one of the most common birth defects that affects the lip, palate, or lip and palate of an infant. The deterioration of clefts is multifactorial involving multiple genes, various interactions from environmental factor and most forgotten, mitochondrial abnormality. The aim of this review is to highlight the importance of mitochondrial activity related to non-syndromic OFC deformity. Despite its important role in cells, the study on mitochondrial activity in cleft pathology was scarce and almost forgotten compared to other genetic investigations. This systematic review was completed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. The literature search was done via the following databases: Google Scholar, Pubmed and Scopus with a total of nine studies of mitochondrial abnormalities were included. We hypothesise that mitochondria play an important role in early craniofacial development. A decreased in its function or activity may result in cleft lip formation. Hence, we would like to shed light on the remarkable role of mitochondria activity in the pathogenesis of non-syndromic OFC.

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Murphy, Michael P. "Understanding and preventing mitochondrial oxidative damage." Biochemical Society Transactions 44, no. 5 (October 15, 2016): 1219–26. http://dx.doi.org/10.1042/bst20160108.

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Mitochondrial oxidative damage has long been known to contribute to damage in conditions such as ischaemia–reperfusion (IR) injury in heart attack. Over the past years, we have developed a series of mitochondria-targeted compounds designed to ameliorate or determine how this damage occurs. I will outline some of this work, from MitoQ to the mitochondria-targeted S-nitrosating agent, called MitoSNO, that we showed was effective in preventing reactive oxygen species (ROS) formation in IR injury with therapeutic implications. In addition, the protection by this compound suggested that ROS production in IR injury was mainly coming from complex I. This led us to investigate the mechanism of the ROS production and using a metabolomic approach, we found that the ROS production in IR injury came from the accumulation of succinate during ischaemia that then drove mitochondrial ROS production by reverse electron transport at complex I during reperfusion. This surprising mechanism led us to develop further new therapeutic approaches to have an impact on the damage that mitochondrial ROS do in pathology and also to explore how mitochondrial ROS can act as redox signals. I will discuss how these approaches have led to a better understanding of mitochondrial oxidative damage in pathology and also to the development of new therapeutic strategies.

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Meimaridou, Eirini, Edgar Lobos, and John S. Hothersall. "Renal oxidative vulnerability due to changes in mitochondrial-glutathione and energy homeostasis in a rat model of calcium oxalate urolithiasis." American Journal of Physiology-Renal Physiology 291, no. 4 (October 2006): F731—F740. http://dx.doi.org/10.1152/ajprenal.00024.2006.

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Calcium oxalate monohydrate (COM) crystals are the commonest component of kidney stones. Oxalate and COM crystals in renal cells are thought to contribute to pathology via prooxidant events. Using an in vivo rat model of crystalluria induced by hyperoxaluria plus hypercalciuria [ethylene glycol (EG) plus 1,25-dihydroxycholecalciferol (DHC)], we measured glutathione and energy homeostasis of kidney mitochondria. Hyperoxaluria or hypercalciuria without crystalluria was also investigated. After 1–3 wk of treatment, kidney cryosections were analyzed by light microscopy. In kidney subcellular fractions, glutathione and antioxidant enzymes were measured. In mitochondria, oxygen consumption and superoxide formation as well as cytochrome c content were measured. EG plus DHC treatment increased formation of renal birefringent crystal. Histology revealed increased renal tubular pathology characterized by obstruction, distension, and interstitial inflammation. Crystalluria at all time points led to oxidative stress manifest as decreased cytosolic and mitochondrial glutathione and increased activity of the antioxidant enzymes glutathione reductase and -peroxidase (mitochondria) and glucose-6-phosphate dehydrogenase (cytosol). These changes were followed by a significant decrease in mitochondrial cytochrome c content at 2–3 wk, suggesting the involvement of apoptosis in the renal pathology. Mitochondrial oxygen consumption was severely impaired in the crystalluria group without increased mitochondrial superoxide formation. Some of these changes were also evident in hyperoxaluria at week 1 but were absent at later times and in all calciuric groups. Our data indicate that impaired electron flow did not cause superoxide formation; however, mitochondrial dysfunction contributes to pathological events when tubular crystal-cell interactions are uncontrolled, as in kidney stones disease.

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Lautenschläger, Janin, Sara Wagner-Valladolid, Amberley D. Stephens, Ana Fernández-Villegas, Colin Hockings, Ajay Mishra, James D. Manton, et al. "Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies." Journal of Biological Chemistry 295, no. 30 (May 8, 2020): 10138–52. http://dx.doi.org/10.1074/jbc.ra119.011650.

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Mitochondrial dysfunction has long been implicated in the neurodegenerative disorder Parkinson's disease (PD); however, it is unclear how mitochondrial impairment and α-synuclein pathology are coupled. Using specific mitochondrial inhibitors, EM analysis, and biochemical assays, we report here that intramitochondrial protein homeostasis plays a major role in α-synuclein aggregation. We found that interference with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import significantly aggravates α-synuclein seeding. In contrast, direct inhibition of mitochondrial complex I, an increase in intracellular calcium concentration, or formation of reactive oxygen species, all of which have been associated with mitochondrial stress, did not affect α-synuclein pathology. We further demonstrate that similar mechanisms are involved in amyloid-β 1-42 (Aβ42) aggregation. Our results suggest that, in addition to other protein quality control pathways, such as the ubiquitin–proteasome system, mitochondria per se can influence protein homeostasis of cytosolic aggregation-prone proteins. We propose that approaches that seek to maintain mitochondrial fitness, rather than target downstream mitochondrial dysfunction, may aid in the search for therapeutic strategies to manage PD and related neuropathologies.

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Esteras, Noemi, and Andrey Y. Abramov. "Mitochondrial Calcium Deregulation in the Mechanism of Beta-Amyloid and Tau Pathology." Cells 9, no. 9 (September 21, 2020): 2135. http://dx.doi.org/10.3390/cells9092135.

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Aggregation and deposition of β-amyloid and/or tau protein are the key neuropathological features in neurodegenerative disorders such as Alzheimer’s disease (AD) and other tauopathies including frontotemporal dementia (FTD). The interaction between oxidative stress, mitochondrial dysfunction and the impairment of calcium ions (Ca2+) homeostasis induced by misfolded tau and β-amyloid plays an important role in the progressive neuronal loss occurring in specific areas of the brain. In addition to the control of bioenergetics and ROS production, mitochondria are fine regulators of the cytosolic Ca2+ homeostasis that induce vital signalling mechanisms in excitable cells such as neurons. Impairment in the mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) or release through the Na+/Ca2+ exchanger may lead to mitochondrial Ca2+ overload and opening of the permeability transition pore inducing neuronal death. Recent evidence suggests an important role for these mechanisms as the underlying causes for neuronal death in β-amyloid and tau pathology. The present review will focus on the mechanisms that lead to cytosolic and especially mitochondrial Ca2+ disturbances occurring in AD and tau-induced FTD, and propose possible therapeutic interventions for these disorders.

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Schapira, Anthony. "Mitochondrial DNA and disease: What happens when things go wrong." Biochemist 27, no. 3 (June 1, 2005): 24–27. http://dx.doi.org/10.1042/bio02703024.

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Mitochondria are ubiquitous in eukaryotic cells and one of their important functions is to provide ATP via oxidative phosphorylation (OXPHOS). The mitochondria also host other biochemical pathways, including -oxidation, Krebs' citric acid cycle and parts of the urea cycle. Thus, the mitochondria play a pivotal role in cellular biochemistry. The relationship of mitochondria to human disease has been identified only recently, but has now become one of the most rapidly expanding areas of human pathology. Mitochondrial disorders may be a consequence of inherited defects of either the nuclear or mitochondrial genomes or, alternatively, may be due to endogenous or exogenous environmental toxins. This article will focus upon abnormalities of mitochondrial DNA (mtDNA) and human disease.

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Lucas, Calixto-Hope G., and Marta Margeta. "Educational Case: Mitochondrial Myopathy." Academic Pathology 6 (January 1, 2019): 237428951988873. http://dx.doi.org/10.1177/2374289519888732.

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The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040 .1

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Nabi, Showkat Ul, Andleeb Khan, Ehraz Mehmood Siddiqui, Muneeb U. Rehman, Saeed Alshahrani, Azher Arafah, Sidharth Mehan, Rana M. Alsaffar, Athanasios Alexiou, and Bairong Shen. "Mechanisms of Mitochondrial Malfunction in Alzheimer’s Disease: New Therapeutic Hope." Oxidative Medicine and Cellular Longevity 2022 (May 14, 2022): 1–28. http://dx.doi.org/10.1155/2022/4759963.

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Mitochondria play a critical role in neuron viability or death as it regulates energy metabolism and cell death pathways. They are essential for cellular energy metabolism, reactive oxygen species production, apoptosis, Ca++ homeostasis, aging, and regeneration. Mitophagy and mitochondrial dynamics are thus essential processes in the quality control of mitochondria. Improvements in several fundamental features of mitochondrial biology in susceptible neurons of AD brains and the putative underlying mechanisms of such changes have made significant progress. AD’s etiology has been reported by mitochondrial malfunction and oxidative damage. According to several recent articles, a continual fusion and fission balance of mitochondria is vital in their normal function maintenance. As a result, the shape and function of mitochondria are inextricably linked. This study examines evidence suggesting that mitochondrial dysfunction plays a significant early impact on AD pathology. Furthermore, the dynamics and roles of mitochondria are discussed with the link between mitochondrial malfunction and autophagy in AD has also been explored. In addition, recent research on mitochondrial dynamics and mitophagy in AD is also discussed in this review. It also goes into how these flaws affect mitochondrial quality control. Furthermore, advanced therapy techniques and lifestyle adjustments that lead to improved management of the dynamics have been demonstrated, hence improving the conditions that contribute to mitochondrial dysfunction in AD.

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Kartawy, Maryam, Igor Khaliulin, and Haitham Amal. "Systems Biology Reveals S-Nitrosylation-Dependent Regulation of Mitochondrial Functions in Mice with Shank3 Mutation Associated with Autism Spectrum Disorder." Brain Sciences 11, no. 6 (May 21, 2021): 677. http://dx.doi.org/10.3390/brainsci11060677.

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder manifested in repetitive behavior, abnormalities in social interactions, and communication. The pathogenesis of this disorder is not clear, and no effective treatment is currently available. Protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification, targets key proteins implicated in synaptic and neuronal functions. Previously, we have shown that NO and SNO are involved in the ASD mouse model based on the Shank3 mutation. The energy supply to the brain mostly relies on oxidative phosphorylation in the mitochondria. Recent studies show that mitochondrial dysfunction and oxidative stress are involved in ASD pathology. In this work, we performed SNO proteomics analysis of cortical tissues of the Shank3 mouse model of ASD with the focus on mitochondrial proteins and processes. The study was based on the SNOTRAP technology followed by systems biology analysis. This work revealed that 63 mitochondrial proteins were S-nitrosylated and that several mitochondria-related processes, including those associated with oxidative phosphorylation, oxidative stress, and apoptosis, were enriched. This study implies that aberrant SNO signaling induced by the Shank3 mutation can target a wide range of mitochondria-related proteins and processes that may contribute to the ASD pathology. It is the first study to investigate the role of NO-dependent mitochondrial functions in ASD.

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Quntanilla, Rodrigo A., and Carola Tapia-Monsalves. "The Role of Mitochondrial Impairment in Alzheimer´s Disease Neurodegeneration: The Tau Connection." Current Neuropharmacology 18, no. 11 (November 9, 2020): 1076–91. http://dx.doi.org/10.2174/1570159x18666200525020259.

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: Accumulative evidence has shown that mitochondrial dysfunction plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial impairment actively contributes to the synaptic and cognitive failure that characterizes AD. The presence of soluble pathological forms of tau like hyperphosphorylated at Ser396 and Ser404 and cleaved at Asp421 by caspase 3, negatively impacts mitochondrial bioenergetics, transport, and morphology in neurons. These adverse effects against mitochondria health will contribute to the synaptic impairment and cognitive decline in AD. Current studies suggest that mitochondrial failure induced by pathological tau forms is likely the result of the opening of the mitochondrial permeability transition pore (mPTP). mPTP is a mitochondrial mega-channel that is activated by increases in calcium and is associated with mitochondrial stress and apoptosis. This structure is composed of different proteins, where Ciclophilin D (CypD) is considered to be the primary mediator of mPTP activation. Also, new studies suggest that mPTP contributes to Aβ pathology and oxidative stress in AD. : Further, inhibition of mPTP through the reduction of CypD expression prevents cognitive and synaptic impairment in AD mouse models. More importantly, tau protein contributes to the physiological regulation of mitochondria through the opening/interaction with mPTP in hippocampal neurons. Therefore, in this paper, we will discuss evidence that suggests an important role of pathological forms of tau against mitochondrial health. Also, we will discuss the possible role of mPTP in the mitochondrial impairment produced by the presence of tau pathology and its impact on synaptic function present in AD.

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Journal articles on the topic 'Mitochondrial pathology'

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