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PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction
Coiled-coil-helix-coiled-coil-helix domain containing protein 2 (CHCHD2) mutations were linked with autosomal dominant Parkinson’s disease (PD) and recently, Alzheimer’s disease/frontotemporal dementia. In the current study, we generated isogenic human embryonic stem cell (hESC) lines harboring PD-a...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423417/ https://www.ncbi.nlm.nih.gov/pubmed/30496485 http://dx.doi.org/10.1093/hmg/ddy413 |
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author | Zhou, Wei Ma, Dongrui Sun, Alfred Xuyang Tran, Hoang-Dai Ma, Dong-liang Singh, Brijesh K Zhou, Jin Zhang, Jinyan Wang, Danlei Zhao, Yi Yen, Paul M Goh, Eyleen Tan, Eng-King |
author_facet | Zhou, Wei Ma, Dongrui Sun, Alfred Xuyang Tran, Hoang-Dai Ma, Dong-liang Singh, Brijesh K Zhou, Jin Zhang, Jinyan Wang, Danlei Zhao, Yi Yen, Paul M Goh, Eyleen Tan, Eng-King |
author_sort | Zhou, Wei |
collection | PubMed |
description | Coiled-coil-helix-coiled-coil-helix domain containing protein 2 (CHCHD2) mutations were linked with autosomal dominant Parkinson’s disease (PD) and recently, Alzheimer’s disease/frontotemporal dementia. In the current study, we generated isogenic human embryonic stem cell (hESC) lines harboring PD-associated CHCHD2 mutation R145Q or Q126X via clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) method, aiming to unravel pathophysiologic mechanism and seek potential intervention strategy against CHCHD2 mutant-caused defects. By engaging super-resolution microscopy, we identified a physical proximity and similar distribution pattern of CHCHD2 along mitochondria with mitochondrial contact site and cristae organizing system (MICOS), a large protein complex maintaining mitochondria cristae. Isogenic hESCs and differentiated neural progenitor cells (NPCs) harboring CHCHD2 R145Q or Q126X mutation showed impaired mitochondria function, reduced CHCHD2 and MICOS components and exhibited nearly hollow mitochondria with reduced cristae. Furthermore, PD-linked CHCHD2 mutations lost their interaction with coiled-coil-helix-coiled-coil-helix domain containing protein 10 (CHCHD10), while transient knockdown of either CHCHD2 or CHCHD10 reduced MICOS and mitochondria cristae. Importantly, a specific mitochondria-targeted peptide, Elamipretide/MTP-131, now tested in phase 3 clinical trials for mitochondrial diseases, was found to enhance CHCHD2 with MICOS and mitochondria oxidative phosphorylation enzymes in isogenic NPCs harboring heterozygous R145Q, suggesting that Elamipretide is able to attenuate CHCHD2 R145Q-induced mitochondria dysfunction. Taken together, our results suggested CHCHD2–CHCHD10 complex may be a novel therapeutic target for PD and related neurodegenerative disorders, and Elamipretide may benefit CHCHD2 mutation-linked PD. |
format | Online Article Text |
id | pubmed-6423417 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-64234172019-03-22 PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction Zhou, Wei Ma, Dongrui Sun, Alfred Xuyang Tran, Hoang-Dai Ma, Dong-liang Singh, Brijesh K Zhou, Jin Zhang, Jinyan Wang, Danlei Zhao, Yi Yen, Paul M Goh, Eyleen Tan, Eng-King Hum Mol Genet General Article Coiled-coil-helix-coiled-coil-helix domain containing protein 2 (CHCHD2) mutations were linked with autosomal dominant Parkinson’s disease (PD) and recently, Alzheimer’s disease/frontotemporal dementia. In the current study, we generated isogenic human embryonic stem cell (hESC) lines harboring PD-associated CHCHD2 mutation R145Q or Q126X via clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) method, aiming to unravel pathophysiologic mechanism and seek potential intervention strategy against CHCHD2 mutant-caused defects. By engaging super-resolution microscopy, we identified a physical proximity and similar distribution pattern of CHCHD2 along mitochondria with mitochondrial contact site and cristae organizing system (MICOS), a large protein complex maintaining mitochondria cristae. Isogenic hESCs and differentiated neural progenitor cells (NPCs) harboring CHCHD2 R145Q or Q126X mutation showed impaired mitochondria function, reduced CHCHD2 and MICOS components and exhibited nearly hollow mitochondria with reduced cristae. Furthermore, PD-linked CHCHD2 mutations lost their interaction with coiled-coil-helix-coiled-coil-helix domain containing protein 10 (CHCHD10), while transient knockdown of either CHCHD2 or CHCHD10 reduced MICOS and mitochondria cristae. Importantly, a specific mitochondria-targeted peptide, Elamipretide/MTP-131, now tested in phase 3 clinical trials for mitochondrial diseases, was found to enhance CHCHD2 with MICOS and mitochondria oxidative phosphorylation enzymes in isogenic NPCs harboring heterozygous R145Q, suggesting that Elamipretide is able to attenuate CHCHD2 R145Q-induced mitochondria dysfunction. Taken together, our results suggested CHCHD2–CHCHD10 complex may be a novel therapeutic target for PD and related neurodegenerative disorders, and Elamipretide may benefit CHCHD2 mutation-linked PD. Oxford University Press 2019-04-01 2018-11-29 /pmc/articles/PMC6423417/ /pubmed/30496485 http://dx.doi.org/10.1093/hmg/ddy413 Text en © The Author(s) 2018. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | General Article Zhou, Wei Ma, Dongrui Sun, Alfred Xuyang Tran, Hoang-Dai Ma, Dong-liang Singh, Brijesh K Zhou, Jin Zhang, Jinyan Wang, Danlei Zhao, Yi Yen, Paul M Goh, Eyleen Tan, Eng-King PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction |
title | PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction |
title_full | PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction |
title_fullStr | PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction |
title_full_unstemmed | PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction |
title_short | PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction |
title_sort | pd-linked chchd2 mutations impair chchd10 and micos complex leading to mitochondria dysfunction |
topic | General Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423417/ https://www.ncbi.nlm.nih.gov/pubmed/30496485 http://dx.doi.org/10.1093/hmg/ddy413 |
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