Mitochondrial diseases are a group of serious inherited multisystem disorders caused by mutations in mitochondrial DNA (mtDNA) or nuclear DNA and still have faced a significant challenge to therapy due to their complicated genotype–phenotype relationships and diverse clinical manifestations. Human induced pluripotent stem cell (hiPSC) offered novel opportunities for cell-based modeling mitochondrial diseases in a patient-specific level. This study aims to explore possibility to potential strategy against mutation-associated oxidative damage through hiPSCs derived from mitochondrial diseases patients. A human induced pluripotent stem cell line (mt-hiPSCs) from a patient harboring 70.70% heteroplasmic m.3243A>G mutation was established and exposed to hydrogen peroxide (H₂O₂). The cell viability, apoptosis level and mitochondrial function were measured through CCK-8, western blot, flow cytometry, RT-qPCR, fluorescence staining and compared to wild-type hiPSCs. Thereafter, the participation of mitogen-activated protein kinases (MAPK) pathway in the melatonin-mediated protection against H₂O₂-induced oxidative injury was also evaluated. Under prolonged low-dose hydrogen peroxide (H₂O₂) exposure, mt-hiPSCs showed significantly reduced viability, elevated apoptosis (52.13 vs. 25.62% in wild-type hiPSCs, P G mutant cells to oxidative stress and demonstrate melatonin's therapeutic potential in alleviating mitochondrial dysfunction via MAPK pathway modulation. This study provides a patient-derived model for exploring mitochondrial disorders and identifies melatonin as a promising cytoprotective agent against mutation-associated oxidative damage.
Pu et al. (2025) studied this question.