Role of oxidative stress in the susceptibility to mitophagy of the skin fibroblasts and iPSC-derived neurons of patients with MERRF syndrome.

Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is mainly caused by the m.8344A>G mutation and mitochondrial dysfunction, but the pathogenesis remains unclear. In this study, we demonstrated that carbonyl cyanide m-chlorophenyl hydrazine (CCCP) induced PINK1-mediated mitophagy and accelerated mitochondrial turnover in the skin fibroblasts of MERRF patients. We found that CCCP led to more pronounced increase of PINK1 accumulation, activation of LC3B II and degradation of Mfn1, Mfn2, OSCP and OPA1 cleavage in MERRF skin fibroblasts as compared with normal skin fibroblasts. Moreover, N-acetylcysteine suppressed PINK1 accumulation and ubiquitin phosphorylation, and thus impaired clearance of damaged mitochondria. This inhibitory effect was validated in MERRF patient iPSC-derived neurons harboring the m.8344A>G mutation, which displayed mitochondrial dysfunction, ROS overproduction and impaired electrophysiological function of mature neurons. These findings suggest that oxidative stress plays a crucial role in the susceptibility to mitophagy of skin fibroblasts and iPSC-derived neurons of MERRF patients and that restoring proper mitophagic flux is a potential therapeutic approach.