Please use this identifier to cite or link to this item: https://doi.org/10.1093/hmg/ddy413
Title: PD-linked CHCHD2 mutations impair CHCHD10 and a MICOS complex leading to mitochondria dysfunction
Authors: 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 
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Genetics & Heredity
CRISTAE ORGANIZING SYSTEM
CONTACT SITE
FRONTOTEMPORAL DEMENTIA
MITOFILIN
DISEASE
CELLS
CARDIOLIPIN
INHIBITION
APOPTOSIS
REVEALS
Issue Date: 1-Apr-2019
Publisher: OXFORD UNIV PRESS
Citation: 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 (2019-04-01). PD-linked CHCHD2 mutations impair CHCHD10 and a MICOS complex leading to mitochondria dysfunction. HUMAN MOLECULAR GENETICS 28 (7) : 1100-1116. ScholarBank@NUS Repository. https://doi.org/10.1093/hmg/ddy413
Abstract: 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.
Source Title: HUMAN MOLECULAR GENETICS
URI: https://scholarbank.nus.edu.sg/handle/10635/226731
ISSN: 09646906
14602083
DOI: 10.1093/hmg/ddy413
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