PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction
Autor: | Paul M. Yen, Brijesh K. Singh, Eyleen L. K. Goh, Danlei Wang, Jin Zhou, Dongrui Ma, Jinyan Zhang, Yi Zhao, Eng-King Tan, Dongliang Ma, Hoang-Dai Tran, Alfred Xuyang Sun, Wei Zhou |
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Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine Mitochondrial Diseases Human Embryonic Stem Cells Oxidative phosphorylation Mitochondrion Biology medicine.disease_cause Cell Line Mitochondrial Proteins Mice 03 medical and health sciences 0302 clinical medicine Genetics medicine Animals Humans CRISPR Molecular Biology Genetic Association Studies Genetics (clinical) Gene knockdown Mutation MICOS complex Neurodegenerative Diseases Parkinson Disease General Medicine Elamipretide Neural stem cell Mitochondria Cell biology DNA-Binding Proteins Mice Inbred C57BL 030104 developmental biology Frontotemporal Dementia Mitochondrial Membranes General Article Oligopeptides 030217 neurology & neurosurgery Transcription Factors |
Zdroj: | Human Molecular Genetics |
ISSN: | 1460-2083 0964-6906 |
Popis: | 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. |
Databáze: | OpenAIRE |
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