PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction

作者：Wei Zhou, Dongrui Ma, Alfred Xuyang Sun, Hoang-Dai Tran, Dongliang Ma, Brijesh Kumar Singh, Jin Zhou, Jinyan Zhang, Danlei Wang, Yi Zhao, Paul M. Yen, Eyleen L. K. Goh, Eng‐King Tan · 发表于：Human Molecular Genetics · 年份：2018 · DOI：10.1093/hmg/ddy413 · 被引用次数：74 · 研究领域：Mitochondrial Function and Pathology、Genetics and Neurodevelopmental Disorders、Pluripotent Stem Cells Research

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 w...