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Journal articles on the topic 'CHCHD4'

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Published: 9 March 2023

Last updated: 10 March 2023

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1

Al-Habib, Hasan, and Margaret Ashcroft. "CHCHD4 (MIA40) and the mitochondrial disulfide relay system." Biochemical Society Transactions 49, no. 1 (February 18, 2021): 17–27. http://dx.doi.org/10.1042/bst20190232.

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Mitochondria are pivotal for normal cellular physiology, as they perform a crucial role in diverse cellular functions and processes, including respiration and the regulation of bioenergetic and biosynthetic pathways, as well as regulating cellular signalling and transcriptional networks. In this way, mitochondria are central to the cell's homeostatic machinery, and as such mitochondrial dysfunction underlies the pathology of a diverse range of diseases including mitochondrial disease and cancer. Mitochondrial import pathways and targeting mechanisms provide the means to transport into mitochondria the hundreds of nuclear-encoded mitochondrial proteins that are critical for the organelle's many functions. One such import pathway is the highly evolutionarily conserved disulfide relay system (DRS) within the mitochondrial intermembrane space (IMS), whereby proteins undergo a form of oxidation-dependent protein import. A central component of the DRS is the oxidoreductase coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein 4 (CHCHD4, also known as MIA40), the human homologue of yeast Mia40. Here, we summarise the recent advances made to our understanding of the role of CHCHD4 and the DRS in physiology and disease, with a specific focus on the emerging importance of CHCHD4 in regulating the cellular response to low oxygen (hypoxia) and metabolism in cancer.

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2

Imai, Yuzuru, Hongrui Meng, Kahori Shiba-Fukushima, and Nobutaka Hattori. "Twin CHCH Proteins, CHCHD2, and CHCHD10: Key Molecules of Parkinson’s Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia." International Journal of Molecular Sciences 20, no. 4 (February 20, 2019): 908. http://dx.doi.org/10.3390/ijms20040908.

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Mutations of coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and 10 (CHCHD10) have been found to be linked to Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and/or frontotemporal lobe dementia (FTD). CHCHD2 and CHCHD10 proteins, which are homologous proteins with 54% identity in amino acid sequence, belong to the mitochondrial coiled-coil-helix-coiled-coil-helix (CHCH) domain protein family. A series of studies reveals that these twin proteins form a multimodal complex, producing a variety of pathophysiology by the disease-causing variants of these proteins. In this review, we summarize the present knowledge about the physiological and pathological roles of twin proteins, CHCHD2 and CHCHD10, in neurodegenerative diseases.

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3

Zhou, Wei, Dongrui Ma, and Eng-King Tan. "Mitochondrial CHCHD2 and CHCHD10: Roles in Neurological Diseases and Therapeutic Implications." Neuroscientist 26, no. 2 (September 16, 2019): 170–84. http://dx.doi.org/10.1177/1073858419871214.

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CHCHD2 mutations have been identified in various neurological diseases such as Parkinson’s disease (PD), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). It is also the first mitochondrial gene whose mutations lead to PD. CHCHD10 is a homolog of CHCHD2; similar to CHCHD2, various mutations of CHCHD10 have been identified in a broad spectrum of neurological disorders, including FTD and AD, with a high frequency of CHCHD10 mutations found in motor neuron diseases. Functionally, CHCHD2 and CHCHD10 have been demonstrated to interact with each other in mitochondria. Recent studies link the biological functions of CHCHD2 to the MICOS complex (mitochondrial inner membrane organizing system). Multiple experimental models suggest that CHCHD2 maintains mitochondrial cristae and disease-associated CHCHD2 mutations function in a loss-of-function manner. However, both CHCHD2 and CHCHD10 knockout mouse models appear phenotypically normal, with no obvious mitochondrial defects. Strategies to maintain or enhance mitochondria cristae could provide opportunities to correct the associated cellular defects in disease state and unravel potential novel targets for CHCHD2-linked neurological conditions.

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4

Hangen, Emilie, Olivier Féraud, Sylvie Lachkar, Haiwei Mou, Nunzianna Doti, Gian Maria Fimia, Ngoc-vy Lam, et al. "Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis." Molecular Cell 58, no. 6 (June 2015): 1001–14. http://dx.doi.org/10.1016/j.molcel.2015.04.020.

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5

Reinhardt, Camille, Giuseppe Arena, Kenza Nedara, Ruairidh Edwards, Catherine Brenner, Kostas Tokatlidis, and Nazanine Modjtahedi. "AIF meets the CHCHD4/Mia40-dependent mitochondrial import pathway." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1866, no. 6 (June 2020): 165746. http://dx.doi.org/10.1016/j.bbadis.2020.165746.

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6

Modjtahedi, Nazanine, and Guido Kroemer. "CHCHD4 links AIF to the biogenesis of respiratory chain complex I." Molecular & Cellular Oncology 3, no. 2 (July 29, 2015): e1074332. http://dx.doi.org/10.1080/23723556.2015.1074332.

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7

Gomez, Adriana Morales, Nathan Staff, and Stephen C. Ekker. "320 Genetic Compensation as a mechanism underlying patients with Rare ALS." Journal of Clinical and Translational Science 6, s1 (April 2022): 57. http://dx.doi.org/10.1017/cts.2022.178.

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OBJECTIVES/GOALS: Rare mutations in CHCHD10 gene are found in 1% of patients with familial Amyotrophic lateral sclerosis (ALS). The overall goal of this study is to utilize induced pluripotent stem cells (iPSCs) as an in vitro model organism for rare ALS variants to evaluate the mechanism of transcription adaptation of CHCHD10/2 as a potential therapeutic. METHODS/STUDY POPULATION: Point mutations on normal iPSCs was performed via Donorguide CRISPR/Cas9. The single stranded RNA/DNA donors contain genetic alterations of CHCHD10: Pro12Ser, Arg15Leu, Pro23Leu, Pro34Ser, Ser59Leu, Gly66Val, Pro80Leu, Tyr92Cys and Gln102His. Ribonucleoprotein electroporation was used to transfect iPSCs and DNA sequencing was used to validate gene editing. To validate transcriptional adaption, changes in levels of protein and gene expression were measured via immunoblot and quantification of CHCHD10 and CHCHCD2 was performed from whole cells lysates of the edited iPSCs. RESULTS/ANTICIPATED RESULTS: We anticipate that CHCHD2 transcriptional adaptation can functionally compensate for the locus loss of function of CHCHD10. This mechanism of transcriptional adaptation may contribute to an explanation for variation in clinical manifestations of patient phenotypes. DISCUSSION/SIGNIFICANCE: This study supplies further evidence for genetic modification as a treatment option for diseases with point mutation causal or enabling mechanisms, including some variants of ALS. Future work will explore the gene-correction from an ALS patient with a known CHCHD10-R15L variant.

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8

Zavileyskiy, Lev, and Victoria Bunik. "Regulation of p53 Function by Formation of Non-Nuclear Heterologous Protein Complexes." Biomolecules 12, no. 2 (February 18, 2022): 327. http://dx.doi.org/10.3390/biom12020327.

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A transcription factor p53 is activated upon cellular exposure to endogenous and exogenous stresses, triggering either homeostatic correction or cell death. Depending on the stress level, often measurable as DNA damage, the dual outcome is supported by p53 binding to a number of regulatory and metabolic proteins. Apart from the nucleus, p53 localizes to mitochondria, endoplasmic reticulum and cytosol. We consider non-nuclear heterologous protein complexes of p53, their structural determinants, regulatory post-translational modifications and the role in intricate p53 functions. The p53 heterologous complexes regulate the folding, trafficking and/or action of interacting partners in cellular compartments. Some of them mainly sequester p53 (HSP proteins, G6PD, LONP1) or its partners (RRM2B, PRKN) in specific locations. Formation of other complexes (with ATP2A2, ATP5PO, BAX, BCL2L1, CHCHD4, PPIF, POLG, SOD2, SSBP1, TFAM) depends on p53 upregulation according to the stress level. The p53 complexes with SIRT2, MUL1, USP7, TXN, PIN1 and PPIF control regulation of p53 function through post-translational modifications, such as lysine acetylation or ubiquitination, cysteine/cystine redox transformation and peptidyl-prolyl cis-trans isomerization. Redox sensitivity of p53 functions is supported by (i) thioredoxin-dependent reduction of p53 disulfides, (ii) inhibition of the thioredoxin-dependent deoxyribonucleotide synthesis by p53 binding to RRM2B and (iii) changed intracellular distribution of p53 through its oxidation by CHCHD4 in the mitochondrial intermembrane space. Increasing knowledge on the structure, function and (patho)physiological significance of the p53 heterologous complexes will enable a fine tuning of the settings-dependent p53 programs, using small molecule regulators of specific protein–protein interactions of p53.

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9

Modjtahedi, Nazanine, Emilie Hangen, Patrick Gonin, and Guido Kroemer. "Metabolic epistasis among apoptosis-inducing factor and the mitochondrial import factor CHCHD4." Cell Cycle 14, no. 17 (July 29, 2015): 2743–47. http://dx.doi.org/10.1080/15384101.2015.1068477.

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10

Erdogan, Alican J., Muna Ali, Markus Habich, Silja L. Salscheider, Laura Schu, Carmelina Petrungaro, Luke W. Thomas, et al. "The mitochondrial oxidoreductase CHCHD4 is present in a semi-oxidized state in vivo." Redox Biology 17 (July 2018): 200–206. http://dx.doi.org/10.1016/j.redox.2018.03.014.

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11

Gladyck, Stephanie, Siddhesh Aras, Maik Hüttemann, and Lawrence I. Grossman. "Regulation of COX Assembly and Function by Twin CX9C Proteins—Implications for Human Disease." Cells 10, no. 2 (January 20, 2021): 197. http://dx.doi.org/10.3390/cells10020197.

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Oxidative phosphorylation is a tightly regulated process in mammals that takes place in and across the inner mitochondrial membrane and consists of the electron transport chain and ATP synthase. Complex IV, or cytochrome c oxidase (COX), is the terminal enzyme of the electron transport chain, responsible for accepting electrons from cytochrome c, pumping protons to contribute to the gradient utilized by ATP synthase to produce ATP, and reducing oxygen to water. As such, COX is tightly regulated through numerous mechanisms including protein–protein interactions. The twin CX9C family of proteins has recently been shown to be involved in COX regulation by assisting with complex assembly, biogenesis, and activity. The twin CX9C motif allows for the import of these proteins into the intermembrane space of the mitochondria using the redox import machinery of Mia40/CHCHD4. Studies have shown that knockdown of the proteins discussed in this review results in decreased or completely deficient aerobic respiration in experimental models ranging from yeast to human cells, as the proteins are conserved across species. This article highlights and discusses the importance of COX regulation by twin CX9C proteins in the mitochondria via COX assembly and control of its activity through protein–protein interactions, which is further modulated by cell signaling pathways. Interestingly, select members of the CX9C protein family, including MNRR1 and CHCHD10, show a novel feature in that they not only localize to the mitochondria but also to the nucleus, where they mediate oxygen- and stress-induced transcriptional regulation, opening a new view of mitochondrial-nuclear crosstalk and its involvement in human disease.

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12

Murari, Anjaneyulu, Venkata Ramana Thiriveedi, Fareed Mohammad, Viswamithra Vengaldas, Madhavi Gorla, Prasad Tammineni, Thanuja Krishnamoorthy, and Naresh Babu V. Sepuri. "Human mitochondrial MIA40 (CHCHD4) is a component of the Fe–S cluster export machinery." Biochemical Journal 471, no. 2 (October 2, 2015): 231–41. http://dx.doi.org/10.1042/bj20150012.

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Human MIA40 harbours oxidative-sensitive Fe–S clusters and functions in the cellular iron homoeostasis pathway. Our study suggests that hMIA40 is an important component of the Fe–S cluster export machinery of mitochondria.

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13

Dickson-Murray, Eleanor, Kenza Nedara, Nazanine Modjtahedi, and Kostas Tokatlidis. "The Mia40/CHCHD4 Oxidative Folding System: Redox Regulation and Signaling in the Mitochondrial Intermembrane Space." Antioxidants 10, no. 4 (April 12, 2021): 592. http://dx.doi.org/10.3390/antiox10040592.

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Mitochondria are critical for several cellular functions as they control metabolism, cell physiology, and cell death. The mitochondrial proteome consists of around 1500 proteins, the vast majority of which (about 99% of them) are encoded by nuclear genes, with only 13 polypeptides in human cells encoded by mitochondrial DNA. Therefore, it is critical for all the mitochondrial proteins that are nuclear-encoded to be targeted precisely and sorted specifically to their site of action inside mitochondria. These processes of targeting and sorting are catalysed by protein translocases that operate in each one of the mitochondrial sub-compartments. The main protein import pathway for the intermembrane space (IMS) recognises proteins that are cysteine-rich, and it is the only import pathway that chemically modifies the imported precursors by introducing disulphide bonds to them. In this manner, the precursors are trapped in the IMS in a folded state. The key component of this pathway is Mia40 (called CHCHD4 in human cells), which itself contains cysteine motifs and is subject to redox regulation. In this review, we detail the basic components of the MIA pathway and the disulphide relay mechanism that underpins the electron transfer reaction along the oxidative folding mechanism. Then, we discuss the key protein modulators of this pathway and how they are interlinked to the small redox-active molecules that critically affect the redox state in the IMS. We present also evidence that the mitochondrial redox processes that are linked to iron–sulfur clusters biogenesis and calcium homeostasis coalesce in the IMS at the MIA machinery. The fact that the MIA machinery and several of its interactors and substrates are linked to a variety of common human diseases connected to mitochondrial dysfunction highlight the potential of redox processes in the IMS as a promising new target for developing new treatments for some of the most complex and devastating human diseases.

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14

Cornelissen, Tom, Marco Spinazzi, Shaun Martin, Dorien Imberechts, Peter Vangheluwe, Matthew Bird, Bart De Strooper, and Wim Vandenberghe. "CHCHD2 harboring Parkinson’s disease-linked T61I mutation precipitates inside mitochondria and induces precipitation of wild-type CHCHD2." Human Molecular Genetics 29, no. 7 (February 18, 2020): 1096–106. http://dx.doi.org/10.1093/hmg/ddaa028.

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Abstract The T61I mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a protein residing in the mitochondrial intermembrane space (IMS), causes an autosomal dominant form of Parkinson’s disease (PD), but the underlying pathogenic mechanisms are not well understood. Here, we compared the subcellular localization and solubility of wild-type (WT) and T61I mutant CHCHD2 in human cells. We found that mitochondrial targeting of both WT and T61I CHCHD2 depended on the four cysteine residues in the C-terminal coiled-coil-helix-coiled-coil-helix (CHCH) domain but not on the N-terminal predicted mitochondrial targeting sequence. The T61I mutation did not interfere with mitochondrial targeting of the mutant protein but induced its precipitation in the IMS. Moreover, T61I CHCHD2 induced increased mitochondrial production of reactive oxygen species and apoptosis, which was prevented by treatment with anti-oxidants. Retention of T61I CHCHD2 in the cytosol through mutation of the cysteine residues in the CHCH domain prevented its precipitation as well as its apoptosis-inducing effect. Importantly, T61I CHCHD2 potently impaired the solubility of WT CHCHD2. In conclusion, our data show that the T61I mutation renders mutant CHCHD2 insoluble inside mitochondria, suggesting loss of function of the mutant protein. In addition, T61I CHCHD2 exerts a dominant-negative effect on the solubility of WT CHCHD2, explaining the dominant inheritance of this form of PD.

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15

Arena, Giuseppe, Nazanine Modjtahedi, and Rejko Kruger. "Exploring the contribution of the mitochondrial disulfide relay system to Parkinson’s disease: the PINK1/CHCHD4 interplay." Neural Regeneration Research 16, no. 11 (2021): 2222. http://dx.doi.org/10.4103/1673-5374.310679.

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16

Sun, Yanyan, Tao Li, Cuicui Xie, Yiran Xu, Kai Zhou, Juan Rodriguez, Wei Han, et al. "Haploinsufficiency in the mitochondrial protein CHCHD4 reduces brain injury in a mouse model of neonatal hypoxia-ischemia." Cell Death & Disease 8, no. 5 (May 2017): e2781-e2781. http://dx.doi.org/10.1038/cddis.2017.196.

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17

Wang, Haiwei, Xinrui Wang, Liangpu Xu, Yingying Lin, and Ji Zhang. "CCT6A and CHCHD2 Are Coamplified with EGFR and Associated with the Unfavorable Clinical Outcomes of Lung Adenocarcinoma." Disease Markers 2022 (July 28, 2022): 1–16. http://dx.doi.org/10.1155/2022/1560199.

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Chaperonin containing TCP1 subunit 6A (CCT6A) and coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) are located at the chromosome 7p11 region proximal to epidermal growth factor receptor (EGFR). However, the amplifications, expressions, and the prognostic effects of CCT6A and CHCDH2 in lung adenocarcinoma (LUAD) are unclear. Here, using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, we found that CCT6A was coamplified and coexpressed with EGFR in LUAD patients. CCT6A amplification was correlated with the unfavorable outcomes of LUAD. Moreover, CCT6A was upregulated in LUAD tissues, and CCT6A overexpression was correlated with the unfavorable relapse free survival or overall survival of LUAD. On the contrary, CCT6A was hypomethylated in LUAD, and CCT6A hypermethylation was correlated with the favorable overall survival of LUAD. Similar expression and methylation profiling of CCT6A were obtained in 479 lung normal tissues and 544 LUAD tissues collected from 11 independent datasets. In 1,462 LUAD patients from eight independent cohorts, CCT6A was also correlated with LUAD relapse-free survival or overall survival. Furthermore, CCT6A overexpression promoted the cell growth and invasion of LUAD. Identification of genes differentially expressed in CCT6A highly expressed LUAD patients revealed that CHCHD2 was the most correlated with CCT6A expression. CHCHD2 was coamplified with CCT6A. CHCHD2 was upregulated in LUAD tissues, and overexpression of CHCHD2 was correlated with the shorted relapse-free survival or overall survival of LUAD. Overall, our results revealed that CCT6A and CHCHD2 were coamplifying and coexpressing with EGFR and were correlated with the unfavorable clinical outcomes of LUAD.

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18

Banci, Lucia, Ivano Bertini, Simone Ciofi-Baffoni, Deepa Jaiswal, Sara Neri, Riccardo Peruzzini, and Julia Winkelmann. "Structural characterization of CHCHD5 and CHCHD7: Two atypical human twin CX9C proteins." Journal of Structural Biology 180, no. 1 (October 2012): 190–200. http://dx.doi.org/10.1016/j.jsb.2012.07.007.

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19

Hagen, Thilo. "Oxygen versus Reactive Oxygen in the Regulation of HIF-1α: The Balance Tips." Biochemistry Research International 2012 (2012): 1–5. http://dx.doi.org/10.1155/2012/436981.

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Hypoxia inducible factor (HIF) is known as the master regulator of the cellular response to hypoxia and is of pivotal importance during development as well as in human disease, particularly in cancer. It is composed of a constitutively expressedβsubunit (HIF-1β) and an oxygen-regulatedαsubunit (HIF-1αand HIF-2α), whose stability is tightly controlled by a family of oxygen- and iron-dependent prolyl hydroxylase enzymes. Whether or not mitochondria-derived reactive oxygen species (ROS) are involved in the regulation of Hypoxia Inducible Factor-1αhas been a matter of contention for the last 10 years, with equally compelling evidence in favor and against their contribution. A number of recent papers appear to tip the balance against a role for ROS. Thus, it has been demonstrated that HIF prolyl hydroxylases are unlikely to be physiological targets of ROS and that the increase in ROS that is associated with downregulation of Thioredoxin Reductase in hypoxia does not affect HIF-1αstabilization. Finally, the protein CHCHD4, which modulates cellular HIF-1αconcentrations by promoting mitochondrial electron transport chain activity, has been proposed to exert its regulatory effect by affecting cellular oxygen availability. These reports are consistent with the hypothesis that mitochondria play a critical role in the regulation of HIF-1αby controlling intracellular oxygen concentrations.

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20

Zhuang, Jie, William M. Kamp, Jie Li, Chengyu Liu, Ju-Gyeong Kang, Ping-yuan Wang, and Paul M. Hwang. "Forkhead Box O3A (FOXO3) and the Mitochondrial Disulfide Relay Carrier (CHCHD4) Regulate p53 Protein Nuclear Activity in Response to Exercise." Journal of Biological Chemistry 291, no. 48 (September 29, 2016): 24819–27. http://dx.doi.org/10.1074/jbc.m116.745737.

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21

Huang, Xiaoping, Beverly P. Wu, Diana Nguyen, Yi-Ting Liu, Melika Marani, Jürgen Hench, Paule Bénit, et al. "CHCHD2 accumulates in distressed mitochondria and facilitates oligomerization of CHCHD10." Human Molecular Genetics 28, no. 2 (October 4, 2018): 349. http://dx.doi.org/10.1093/hmg/ddy340.

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22

Grossman, Lawrence I., Neeraja Purandare, Rooshan Arshad, Stephanie Gladyck, Mallika Somayajulu, Maik Hüttemann, and Siddhesh Aras. "MNRR1, a Biorganellar Regulator of Mitochondria." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/6739236.

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The central role of energy metabolism in cellular activities is becoming widely recognized. However, there are many gaps in our knowledge of the mechanisms by which mitochondria evaluate their status and call upon the nucleus to make adjustments. Recently, a protein family consisting of twin CX9C proteins has been shown to play a role in human pathophysiology. We focus here on two family members, the isoforms CHCHD2 (renamed MNRR1) and CHCHD10. The better studied isoform, MNRR1, has the unusual property of functioning in both the mitochondria and the nucleus and of having a different function in each. In the mitochondria, it functions by binding to cytochromecoxidase (COX), which stimulates respiration. Its binding to COX is promoted by tyrosine-99 phosphorylation, carried out by ABL2 kinase (ARG). In the nucleus, MNRR1 binds to a novel promoter element inCOX4I2and itself, increasing transcription at 4% oxygen. We discuss mutations in both MNRR1 and CHCHD10 found in a number of chronic, mostly neurodegenerative, diseases. Finally, we propose a model of a graded response to hypoxic and oxidative stresses, mediated under different oxygen tensions by CHCHD10, MNRR1, and HIF1, which operate at intermediate and very low oxygen concentrations, respectively.

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23

Thiriveedi, Venkata Ramana, Ushodaya Mattam, Prasad Pattabhi, Vandana Bisoyi, Noble Kumar Talari, Thanuja Krishnamoorthy, and Naresh Babu V. Sepuri. "Glutathionylated and Fe–S cluster containing hMIA40 (CHCHD4) regulates ROS and mitochondrial complex III and IV activities of the electron transport chain." Redox Biology 37 (October 2020): 101725. http://dx.doi.org/10.1016/j.redox.2020.101725.

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24

Yang, Jun, Oliver Staples, Luke W. Thomas, Thomas Briston, Mathew Robson, Evon Poon, Maria L. Simões, et al. "Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression." Journal of Clinical Investigation 122, no. 2 (February 1, 2012): 600–611. http://dx.doi.org/10.1172/jci58780.

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25

Straub, Isabella R., Alexandre Janer, Woranontee Weraarpachai, Lorne Zinman, Janice Robertson, Ekaterina Rogaeva, and Eric A. Shoubridge. "Loss of CHCHD10–CHCHD2 complexes required for respiration underlies the pathogenicity of a CHCHD10 mutation in ALS." Human Molecular Genetics 27, no. 1 (November 7, 2017): 178–89. http://dx.doi.org/10.1093/hmg/ddx393.

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26

Rubino, Elisa, Livia Brusa, Ming Zhang, Silvia Boschi, Flora Govone, Alessandro Vacca, Annalisa Gai, et al. "Genetic analysis of CHCHD2 and CHCHD10 in Italian patients with Parkinson's disease." Neurobiology of Aging 53 (May 2017): 193.e7–193.e8. http://dx.doi.org/10.1016/j.neurobiolaging.2016.12.027.

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27

Rubino, Elisa, Ming Zhang, Tiziana Mongini, Silvia Boschi, Liliana Vercelli, Alessandro Vacca, Flora Govone, et al. "Mutation analysis of CHCHD2 and CHCHD10 in Italian patients with mitochondrial myopathy." Neurobiology of Aging 66 (June 2018): 181.e1–181.e2. http://dx.doi.org/10.1016/j.neurobiolaging.2018.02.007.

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28

Zhou, Wei, Dongrui Ma, Alfred Xuyang Sun, Hoang-Dai Tran, Dong-liang Ma, Brijesh K. Singh, Jin Zhou, et al. "PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction." Human Molecular Genetics 28, no. 7 (November 29, 2018): 1100–1116. http://dx.doi.org/10.1093/hmg/ddy413.

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29

Ikeda, Aya, Kenya Nishioka, Hongrui Meng, Masashi Takanashi, Iwao Hasegawa, Tsuyoshi Inoshita, Kahori Shiba-Fukushima, et al. "Mutations in CHCHD2 cause α-synuclein aggregation." Human Molecular Genetics 28, no. 23 (October 10, 2019): 3895–911. http://dx.doi.org/10.1093/hmg/ddz241.

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Abstract Mutations in CHCHD2 are linked to a familial, autosomal dominant form of Parkinson’s disease (PD). The gene product may regulate mitochondrial respiratory function. However, whether mitochondrial dysfunction induced by CHCHD2 mutations further yields α-synuclein pathology is unclear. Here, we provide compelling genetic evidence that mitochondrial dysfunction induced by PD-linked CHCHD2 T61I mutation promotes α-synuclein aggregation using brain autopsy, induced pluripotent stem cells (iPSCs) and Drosophila genetics. An autopsy of an individual with CHCHD2 T61I revealed widespread Lewy pathology with both amyloid plaques and neurofibrillary tangles that appeared in the brain stem, limbic regions and neocortex. A prominent accumulation of sarkosyl-insoluble α-synuclein aggregates, the extent of which was comparable to that of a case with α-synuclein (SNCA) duplication, was observed in CHCHD2 T61I brain tissue. The prion-like activity and morphology of α-synuclein fibrils from the CHCHD2 T61I brain tissue were similar to those of fibrils from SNCA duplication and sporadic PD brain tissues. α-Synuclein insolubilization was reproduced in dopaminergic neuron cultures from CHCHD2 T61I iPSCs and Drosophila lacking the CHCHD2 ortholog or expressing the human CHCHD2 T61I. Moreover, the combination of ectopic α-synuclein expression and CHCHD2 null or T61I enhanced the toxicity in Drosophila dopaminergic neurons, altering the proteolysis pathways. Furthermore, CHCHD2 T61I lost its mitochondrial localization by α-synuclein in Drosophila. The mislocalization of CHCHD2 T61I was also observed in the patient brain. Our study suggests that CHCHD2 is a significant mitochondrial factor that determines α-synuclein stability in the etiology of PD.

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30

Liu, Yi-Ting, Xiaoping Huang, Diana Nguyen, Mario K. Shammas, Beverly P. Wu, Eszter Dombi, Danielle A. Springer, Joanna Poulton, Shiori Sekine, and Derek P. Narendra. "Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations." Human Molecular Genetics 29, no. 9 (April 27, 2020): 1547–67. http://dx.doi.org/10.1093/hmg/ddaa077.

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Abstract Dominant mutations in the mitochondrial paralogs coiled-helix-coiled-helix (CHCHD) domain 2 (C2) and CHCHD10 (C10) were recently identified as causing Parkinson’s disease and amyotrophic lateral sclerosis/frontotemporal dementia/myopathy, respectively. The mechanism by which they disrupt mitochondrial cristae, however, has been uncertain. Using the first C2/C10 double knockout (DKO) mice, we report that C10 pathogenesis and the normal function of C2/C10 are intimately linked. Similar to patients with C10 mutations, we found that C2/C10 DKO mice have disrupted mitochondrial cristae, because of cleavage of the mitochondrial-shaping protein long form of OPA1 (L-OPA1) by the stress-induced peptidase OMA1. OMA1 was found to be activated similarly in affected tissues of mutant C10 knock-in (KI) mice, demonstrating that L-OPA1 cleavage is a novel mechanism for cristae abnormalities because of both C10 mutation and C2/C10 loss. Using OMA1 activation as a functional assay, we found that C2 and C10 are partially functionally redundant, and some but not all disease-causing mutations have retained activity. Finally, C2/C10 DKO mice partially phenocopied mutant C10 KI mice with the development of cardiomyopathy and activation of the integrated mitochondrial integrated stress response in affected tissues, tying mutant C10 pathogenesis to C2/C10 function.

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Baisiwala, Shivani, Miranda Saathoff, Crismita Dmello, Jack Shireman, Li Chen, Cheol Park, Chidibere Awah, et al. "CBIO-17. IDENTIFYING A NETWORK OF ESSENTIAL & TUMORIGENIC GENES IN GLIOBLASTOMA USING WHOLE-GENOME CRISPR Cas9 SCREENING." Neuro-Oncology 22, Supplement_2 (November 2020): ii19. http://dx.doi.org/10.1093/neuonc/noaa215.077.

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Abstract GBM is the most common primary malignant brain tumor in adults, with a 100% recurrence rate and a median survival of 21 months. As such, advances in therapy are desperately needed. Genomic approaches have shown that GBM has high intra-tumoral heterogeneity. However, a comprehensive understanding of determinants of growth is required to identify new therapeutic targets. CRISPR-Cas9 screening technology has enabled whole-genome screens that allow objective identification of genes governing specific phenotypes. Here, we performed a genome-wide CRISPR knockout screen in H4 human glioma cells to identify genes that drive proliferation. Our screen identified ~150 novel essential growth genes. From this list, we identified 5 genes that were previously unstudied, show significant elevations in expression at the RNA and protein levels (p< 0.05), and show significant survival benefit in patient datasets (p< 0.05) – PSMB3, CHCHD4, THOC1, SPDYE5, HSPA1. Our validation experiments showed that knocking out these genes resulted in cell death in multiple GBM patient-derived xenograft (PDX) lines. In addition, animals with knockout cells implanted demonstrated extended survival (p< 0.01). Furthermore, overexpression of these genes in a normal neural stem cell line resulted in transformation to a cancer phenotype, as evidenced by sphere formation in a soft agar assay (p< 0.01). Further investigation of one of these genes, PSMB3, which is a subunit of the proteasome, showed that ubiquitinated proteins were significantly increased after PSMB3 knockdown, suggesting that disruption of the proteasome system was the likely cause of cell death. We performed a ubiquitin immunoprecipitation (IP) to identify which genes were being uniquely ubiquitinated in GBM. Results showed pathways involving retinoblastoma genes, DNA repair genes, and DNA replication. Together, this data suggests that both our CRISPR screens and our ubiquitin IP have yielded promising and novel therapeutic targets for GBM, a disease desperately in need of new strategies.

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Head, Brian P., Miren Zulaika, Sergey Ryazantsev, and Alexander M. van der Bliek. "A novel mitochondrial outer membrane protein, MOMA-1, that affects cristae morphology in Caenorhabditis elegans." Molecular Biology of the Cell 22, no. 6 (March 15, 2011): 831–41. http://dx.doi.org/10.1091/mbc.e10-07-0600.

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Three proteins with similar effects on mitochondrial morphology were identified in an RNA interference (RNAi) screen for mitochondrial abnormalities in Caenorhabditis elegans. One of these is the novel mitochondrial outer membrane protein MOMA-1. The second is the CHCHD3 homologue, CHCH-3, a small intermembrane space protein that may act as a chaperone. The third is a mitofilin homologue, IMMT-1. Mitofilins are inner membrane proteins that control the shapes of cristae. RNAi or mutations in each of these genes change the relatively constant diameters of mitochondria into highly variable diameters, ranging from thin tubes to localized swellings. Neither growth nor brood size of the moma-1, chch-3, or immt-1 single mutants is affected, suggesting that their metabolic functions are normal. However, growth of moma-1 or immt-1 mutants on chch-3(RNAi) leads to withered gonads, a lack of mitochondrial staining, and a dramatic reduction in fecundity, while moma-1; immt-1 double mutants are indistinguishable from single mutants. Mutations in moma-1 and immt-1 also have similar effects on cristae morphology. We conclude that MOMA-1 and IMMT-1 act in the same pathway. It is likely that the observed effects on mitochondrial diameter are an indirect effect of disrupting cristae morphology.

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Purandare, Neeraja, Mallika Somayajulu, Maik Hüttemann, Lawrence I. Grossman, and Siddhesh Aras. "The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction." Journal of Biological Chemistry 293, no. 17 (March 14, 2018): 6517–29. http://dx.doi.org/10.1074/jbc.ra117.001073.

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Mao, Chengyuan, Herui Wang, Haiyang Luo, Shuyu Zhang, Huisha Xu, Shuo Zhang, Jared Rosenblum, et al. "CHCHD10 is involved in the development of Parkinson's disease caused by CHCHD2 loss-of-function mutation p.T61I." Neurobiology of Aging 75 (March 2019): 38–41. http://dx.doi.org/10.1016/j.neurobiolaging.2018.10.020.

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Harjuhaahto, Sandra, Tiina S. Rasila, Svetlana M. Molchanova, Rosa Woldegebriel, Jouni Kvist, Svetlana Konovalova, Markus T. Sainio, et al. "ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons." Neurobiology of Disease 141 (July 2020): 104940. http://dx.doi.org/10.1016/j.nbd.2020.104940.

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Sato, Shigeto, Sachiko Noda, Satoru Torii, Taku Amo, Aya Ikeda, Manabu Funayama, Junji Yamaguchi, et al. "Homeostatic p62 levels and inclusion body formation in CHCHD2 knockout mice." Human Molecular Genetics 30, no. 6 (February 25, 2021): 443–53. http://dx.doi.org/10.1093/hmg/ddab057.

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Abstract Inactivation of constitutive autophagy results in the formation of cytoplasmic inclusions in neurones, but the relationship between impaired autophagy and Lewy bodies (LBs) remains unknown. α-Synuclein and p62, components of LBs, are the defining characteristic of Parkinson’s disease (PD). Until now, we have analyzed mice models and demonstrated p62 aggregates derived from an autophagic defect might serve as ‘seeds’ and can potentially be a cause of LB formation. P62 may be the key molecule for aggregate formation. To understand the mechanisms of LBs, we analyzed p62 homeostasis and inclusion formation using PD model mice. In PARK22-linked PD, intrinsically disordered mutant CHCHD2 initiates Lewy pathology. To determine the function of CHCHD2 for inclusions formation, we generated Chchd2-knockout (KO) mice and characterized the age-related pathological and motor phenotypes. Chchd2 KO mice exhibited p62 inclusion formation and dopaminergic neuronal loss in an age-dependent manner. These changes were associated with a reduction in mitochondria complex activity and abrogation of inner mitochondria structure. In particular, the OPA1 proteins, which regulate fusion of mitochondrial inner membranes, were immature in the mitochondria of CHCHD2-deficient mice. CHCHD2 regulates mitochondrial morphology and p62 homeostasis by controlling the level of OPA1. Our findings highlight the unexpected role of the homeostatic level of p62, which is regulated by a non-autophagic system, in controlling intracellular inclusion body formation, and indicate that the pathologic processes associated with the mitochondrial proteolytic system are crucial for loss of DA neurones.

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Zhu, Lili, Aurora Gomez-Duran, Gabriele Saretzki, Shibo Jin, Katarzyna Tilgner, Dario Melguizo-Sanchis, Georgios Anyfantis, et al. "The mitochondrial protein CHCHD2 primes the differentiation potential of human induced pluripotent stem cells to neuroectodermal lineages." Journal of Cell Biology 215, no. 2 (October 17, 2016): 187–202. http://dx.doi.org/10.1083/jcb.201601061.

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Human induced pluripotent stem cell (hiPSC) utility is limited by variations in the ability of these cells to undergo lineage-specific differentiation. We have undertaken a transcriptional comparison of human embryonic stem cell (hESC) lines and hiPSC lines and have shown that hiPSCs are inferior in their ability to undergo neuroectodermal differentiation. Among the differentially expressed candidates between hESCs and hiPSCs, we identified a mitochondrial protein, CHCHD2, whose expression seems to correlate with neuroectodermal differentiation potential of pluripotent stem cells. We provide evidence that hiPSC variability with respect to CHCHD2 expression and differentiation potential is caused by clonal variation during the reprogramming process and that CHCHD2 primes neuroectodermal differentiation of hESCs and hiPSCs by binding and sequestering SMAD4 to the mitochondria, resulting in suppression of the activity of the TGFβ signaling pathway. Using CHCHD2 as a marker for assessing and comparing the hiPSC clonal and/or line differentiation potential provides a tool for large scale differentiation and hiPSC banking studies.

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Saha, K., R. Ware, M. J. Yellin, L. Chess, and I. Lowy. "Herpesvirus saimiri-transformed human CD4+ T cells can provide polyclonal B cell help via the CD40 ligand as well as the TNF-alpha pathway and through release of lymphokines." Journal of Immunology 157, no. 9 (November 1, 1996): 3876–85. http://dx.doi.org/10.4049/jimmunol.157.9.3876.

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Abstract We have developed human CD4+ T cell lines from the PBL of normal donors by infection with Herpesvirus saimiri (HVS), to evaluate functional properties of these immortalized lymphocytes. In this report, we characterize two such CD4+ T cell lines, CHCD4 and MHCD4, which were derived from two different donors. These cells grew independent of exogenous IL-2 stimulation for over 1 yr, and expressed surface markers (CD25+, CD69+, HLA-DR+, and B7+) associated with an activated T cell phenotype. Both lines constitutively produced and released IFN-gamma, but no IL-2 or IL-4. However, the surface expression of the two cell lines differed in that CHCD4 constitutively expressed CD40 ligand (CD40L) and membrane TNF-alpha, but MHCD4 did not. Also, CHCD4, but not MHCD4, potently induced polyclonal B cell activation and differentiation in the absence of PWM, in an MHC-unrestricted fashion. The B cell help afforded by CHCD4 included contact-dependent and soluble components. Contact-dependent help was strongly inhibited by mAb against CD40L (5C8) and to a lesser extent, by anti-TNF-alpha Ab. The CD40L-dependent helper function of CHCD4 contrasts with the recent description of other HVS-transformed CD4+ T cells that provide B cell help primarily via the membrane TNF-alpha and TNF-alphaR pathways. Furthermore, CHCD4 cells also secreted soluble factors that could mediate CD40-linked B cell differentiation into Ab-producing cells. Interestingly, this factor is not likely to be IL-2, IL-4, IL-6, IL-10, IL-15, TNF-alpha, or IFN-gamma as Abs against these cytokines were not able to inhibit the contact-independent B cell help by CHCD4. These results indicate that HVS-immortalization of CD4+ lymphocytes may produce T cell clones with a spectrum of important contact-dependent, as well as contact-independent, B cell helper function capacities.

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Che, Xiangqian, and Gang Wang. "P3-130: GENETIC FEATURES OF MAPT , GRN , C9ORF72 CHCHD2 , CHCHD10 AND SIGMAR1 GENE MUTATIONS IN CHINESE PATIENTS WITH FRONTOTEMPORAL DEMENTIA." Alzheimer's & Dementia 15 (July 2019): P980—P981. http://dx.doi.org/10.1016/j.jalz.2019.06.3158.

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Jansen, Iris E., Jose M. Bras, Suzanne Lesage, Claudia Schulte, J. Raphael Gibbs, Mike A. Nalls, Alexis Brice, et al. "CHCHD2 and Parkinson's disease." Lancet Neurology 14, no. 7 (July 2015): 678–79. http://dx.doi.org/10.1016/s1474-4422(15)00094-0.

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Puschmann, Andreas, Dennis W. Dickson, Elisabet Englund, Zbigniew K. Wszolek, and Owen A. Ross. "CHCHD2 and Parkinson's disease." Lancet Neurology 14, no. 7 (July 2015): 679. http://dx.doi.org/10.1016/s1474-4422(15)00095-2.

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Iqbal, Zafar, and Mathias Toft. "CHCHD2 and Parkinson's disease." Lancet Neurology 14, no. 7 (July 2015): 680–81. http://dx.doi.org/10.1016/s1474-4422(15)00096-4.

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Foo, Jia Nee, Jianjun Liu, and Eng-King Tan. "CHCHD2 and Parkinson's disease." Lancet Neurology 14, no. 7 (July 2015): 681–82. http://dx.doi.org/10.1016/s1474-4422(15)00098-8.

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Liu, Guiyou, and Keshen Li. "CHCHD2 and Parkinson's disease." Lancet Neurology 14, no. 7 (July 2015): 679–80. http://dx.doi.org/10.1016/s1474-4422(15)00131-3.

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Xu, Hongwei, Haixia Li, Zhen Wang, Ayimuguli Abudureyimu, Jutian Yang, Xin Cao, Xianyong Lan, Rongxin Zang, and Yong Cai. "A Deletion Downstream of the CHCHD7 Gene Is Associated with Growth Traits in Sheep." Animals 10, no. 9 (August 21, 2020): 1472. http://dx.doi.org/10.3390/ani10091472.

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In sheep, the coiled-coil-helix-coiled-coil-helix domain containing 7 (CHCHD7) gene and the pleiomorphic adenoma gene 1 (PLAG1) are on the same growth-related major quantitative trait locus, positioned head-to-head approximately 420 bp apart on chromosome 9. PLAG1 affects sheep growth, but the effects of CHCHD7 have not been determined. In this study, an 8-bp deletion downstream of CHCHD7 was analyzed in 2350 sheep from seven breeds. The associations between the deletion and growth traits of Tan sheep were also determined. Both genotypes (homozygous wild-type and heterozygous) for the 8-bp deletion were found in Tan (TS), Luxi Blackhead (LXBH), Small-Tail Han (STHS), and Lanzhou Fat-Tail (LFTS) sheep. However, there were no polymorphic sites for the mutation in Hu (HS), Sartuul (SS), and Australian White (AUW) sheep. In TS, LXBH, STHS, and LFTS sheep, the deletion genotype was less frequent than the wild-type genotype, and the allele frequencies of the deletion variant were 0.007 (TS), 0.011 (LBXH), 0.008 (STHS), and 0.010 (LFTS). The 8-bp deletion was significantly associated with body length (p = 0.032), chest depth (p = 0.015), and chest width (p = 0.047) in Tan sheep. Thus, the 8-bp deletion downstream of the CHCHD7 gene might be associated with growth and development traits of sheep.

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Lee, Richard G., Maryam Sedghi, Mehri Salari, Anne-Marie J. Shearwood, Maike Stentenbach, Ariana Kariminejad, Hayley Goullee, et al. "Early-onset Parkinson disease caused by a mutation in CHCHD2 and mitochondrial dysfunction." Neurology Genetics 4, no. 5 (October 2018): e276. http://dx.doi.org/10.1212/nxg.0000000000000276.

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ObjectiveOur goal was to identify the gene(s) associated with an early-onset form of Parkinson disease (PD) and the molecular defects associated with this mutation.MethodsWe combined whole-exome sequencing and functional genomics to identify the genes associated with early-onset PD. We used fluorescence microscopy, cell, and mitochondrial biology measurements to identify the molecular defects resulting from the identified mutation.ResultsHere, we report an association of a homozygous variant in CHCHD2, encoding coiled-coil-helix-coiled-coil-helix domain containing protein 2, a mitochondrial protein of unknown function, with an early-onset form of PD in a 26-year-old Caucasian woman. The CHCHD2 mutation in PD patient fibroblasts causes fragmentation of the mitochondrial reticular morphology and results in reduced oxidative phosphorylation at complex I and complex IV. Although patient cells could maintain a proton motive force, reactive oxygen species production was increased, which correlated with an increased metabolic rate.ConclusionsOur findings implicate CHCHD2 in the pathogenesis of recessive early-onset PD, expanding the repertoire of mitochondrial proteins that play a direct role in this disease.

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Keith, Julia L., Emily Swinkin, Andrew Gao, Samira Alminawi, Ming Zhang, Philip McGoldrick, Paul McKeever, Janice Robertson, Ekaterina Rogaeva, and Lorne Zinman. "Neuropathologic description of CHCHD10 mutated amyotrophic lateral sclerosis." Neurology Genetics 6, no. 1 (January 13, 2020): e394. http://dx.doi.org/10.1212/nxg.0000000000000394.

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ObjectiveTo present the postmortem neuropathologic report of a patient with a CHCHD10 mutation exhibiting an amyotrophic lateral sclerosis (ALS) clinical phenotype.MethodsA 54-year-old man without significant medical history or family history presented with arm weakness, slowly progressed over 19 years to meet the El Escorial criteria for clinically probable ALS with bulbar and respiratory involvement, and was found to have a CHCHD10 p.R15L mutation. Postmortem neuropathologic examination took place including immunohistochemical staining with CHCHD10, and double immunofluorescence combining CHCHD10 with TDP43 and neurofilament was performed and the results were compared with normal controls and sporadic ALS cases.ResultsPostmortem examination of the CHCHD10 mutation carrier showed severe loss of hypoglossal and anterior horn motor neurons, mild corticospinal tract degeneration, and a relative lack of TDP43 immunopathology. CHCHD10 immunohistochemistry for the 3 controls and the 5 sporadic ALS cases showed strong neuronal cytoplasmic and axonal labeling, with the CHCHD10 mutation carrier also having numerous CHCHD10 aggregates within their anterior horns. These aggregates may be related to the CHCHD10 aggregates recently described to cause mitochondrial degeneration and disease in a tissue-selective toxic gain-of-function fashion in a CHCHD10 knock-in mouse model. The CHCHD10 aggregates did not colocalize with TDP43 and were predominantly extracellular on double immunofluorescence labeling with neurofilament.ConclusionsThe neuropathology of CHCHD10 mutated ALS includes predominantly lower motor neuron degeneration, absent TDP43 immunopathology, and aggregates of predominantly extracellular CHCHD10, which do not contain TDP43.

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McCann, Emily P., Jennifer A. Fifita, Natalie Grima, Jasmin Galper, Prachi Mehta, Sarah E. Freckleton, Katharine Y. Zhang, et al. "Genetic and immunopathological analysis of CHCHD10 in Australian amyotrophic lateral sclerosis and frontotemporal dementia and transgenic TDP-43 mice." Journal of Neurology, Neurosurgery & Psychiatry 91, no. 2 (November 5, 2019): 162–71. http://dx.doi.org/10.1136/jnnp-2019-321790.

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ObjectiveSince the first report of CHCHD10 gene mutations in amyotrophiclateral sclerosis (ALS)/frontotemporaldementia (FTD) patients, genetic variation in CHCHD10 has been inconsistently linked to disease. A pathological assessment of the CHCHD10 protein in patient neuronal tissue also remains to be reported. We sought to characterise the genetic and pathological contribution of CHCHD10 to ALS/FTD in Australia.MethodsWhole-exome and whole-genome sequencing data from 81 familial and 635 sporadic ALS, and 108 sporadic FTD cases, were assessed for genetic variation in CHCHD10. CHCHD10 protein expression was characterised by immunohistochemistry, immunofluorescence and western blotting in control, ALS and/or FTD postmortem tissues and further in a transgenic mouse model of TAR DNA-binding protein 43 (TDP-43) pathology.ResultsNo causal, novel or disease-associated variants in CHCHD10 were identified in Australian ALS and/or FTD patients. In human brain and spinal cord tissues, CHCHD10 was specifically expressed in neurons. A significant decrease in CHCHD10 protein level was observed in ALS patient spinal cord and FTD patient frontal cortex. In a TDP-43 mouse model with a regulatable nuclear localisation signal (rNLS TDP-43 mouse), CHCHD10 protein levels were unaltered at disease onset and early in disease, but were significantly decreased in cortex in mid-stage disease.ConclusionsGenetic variation in CHCHD10 is not a common cause of ALS/FTD in Australia. However, we showed that in humans, CHCHD10 may play a neuron-specific role and a loss of CHCHD10 function may be linked to ALS and/or FTD. Our data from the rNLS TDP-43 transgenic mice suggest that a decrease in CHCHD10 levels is a late event in aberrant TDP-43-induced ALS/FTD pathogenesis.

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Xiao, Yatao, Jianmin Zhang, Xiaoqiu Shu, Lei Bai, Wentao Xu, Ailian Wang, Aizhong Chen, et al. "Loss of mitochondrial protein CHCHD10 in skeletal muscle causes neuromuscular junction impairment." Human Molecular Genetics 29, no. 11 (July 2, 2019): 1784–96. http://dx.doi.org/10.1093/hmg/ddz154.

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Abstract The neuromuscular junction (NMJ) is a synapse between motoneurons and skeletal muscles to control motor behavior. Acetylcholine receptors (AChRs) are restricted at the synaptic region for proper neurotransmission. Mutations in the mitochondrial CHCHD10 protein have been identified in multiple neuromuscular disorders; however, the physiological roles of CHCHD10 at NMJs remain elusive. Here, we report that CHCHD10 is highly expressed at the postsynapse of NMJs in skeletal muscles. Muscle conditional knockout CHCHD10 mice showed motor defects, abnormal neuromuscular transmission and NMJ structure. Mechanistically, we found that mitochondrial CHCHD10 is required for ATP production, which facilitates AChR expression and promotes agrin-induced AChR clustering. Importantly, ATP could effectively rescue the reduction of AChR clusters in the CHCHD10-ablated muscles. Our study elucidates a novel physiological role of CHCHD10 at the peripheral synapse. It suggests that mitochondria dysfunction contributes to neuromuscular pathogenesis.

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Liu, Yong, and Yanping Zhang. "CHCHD2 connects mitochondrial metabolism to apoptosis." Molecular & Cellular Oncology 2, no. 4 (May 5, 2015): e1004964. http://dx.doi.org/10.1080/23723556.2015.1004964.

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