MitoQ alleviates m.3243A>G-induced mitochondrial dysfunction by stabilizing PINK1 and enhancing mitophagy.

The mitochondrial 3243A>G mutation (m.3243A>G) is associated with diverse clinical phenotypes. To elucidate the underlying mechanisms and explore intervention strategies in m.3243A>G patients, urine-derived stem cells (USCs) and a mitochondrial leucyl-tRNA synthetase gene (lars-2) deficient Caenorhabditis elegans (C. elegans) model are used to assess mitochondrial homeostasis and neuromuscular dysfunction. Patient-derived USCs with high levels of m.3243A>G heteroplasmy exhibit impaired mitochondrial function, disrupted mitochondrial dynamics, and inhibited mitophagy, which are reversed by MitoQ through suppression of OMA1 zinc metallopeptidase (OMA1)-induced mitochondrial phosphatase and tensin (PTEN) induced kinase 1 (PINK1) degradation. Furthermore, lars-2 knockdown in C. elegans induces mitochondrial stress and mimics the loss of neural and muscle functions observed in patients with the m.3243A>G mutation. MitoQ treatment partially improves neurobehavioral function by promoting the PINK1 pathway. These findings suggest that MitoQ has therapeutic potential in the context of the m.3243A>G mutation.