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

CHCHD2 mutations were linked with autosomal dominant Parkinson's disease (PD) and recently, Alzheimer's disease/ Frontotemporal dementia. In current study, we generated isogenic human stem cell (hESC) lines harboring PD-associated CHCHD2 mutation R145Q or Q126X via CRISPR-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 MICOS (mitochondrial inner membrane organizing system), 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 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.