Pathological mitophagy disrupts mitochondrial homeostasis in Leber’s hereditary optic neuropathy

Leber’s hereditary optic neuropathy (LHON), a disease associated with a mitochondrial DNA mutation, is characterized by blindness due to degeneration of retinal ganglion cells (RGCs) and their axons, which form the optic nerve. We show that a sustained pathological autophagy and compartment-specific mitophagy activity affects LHON patient-derived cells and cybrids, as well as induced pluripotent-stem-cell-derived neurons. This is variably counterbalanced by compensatory mitobiogenesis. The aberrant quality control disrupts mitochondrial homeostasis as reflected by defective bioenergetics and excessive reactive oxygen species production, a stress phenotype that ultimately challenges cell viability by increasing the rate of apoptosis. We counteract this pathological mechanism by using autophagy regulators (clozapine and chloroquine) and redox modulators (idebenone), as well as genetically activating mitochondrial biogenesis (PGC1-α overexpression). This study substantially advances our understanding of LHON pathophysiology, providing an integrated paradigm for pathogenesis of mitochondrial diseases and druggable targets for therapy. [Display omitted] •Autophagy and mitophagy are abnormally activated in samples carrying LHON mutations•Autophagy and mitophagy affect LHON cells’ viability•Therapeutic approaches targeting autophagy reverts LHON cells’ apoptotic death Danese et al. show that autophagy and mitophagy are pathologically increased in Leber’s hereditary optic neuropathy (LHON)-affected individuals. These characteristics reflect a mitochondrial stress phenotype that activates the apoptotic response. Therapeutic strategies balancing the autophagy and mitophagy levels and the mitochondrial homeostasis reverse the pathologic phenotype of LHON-affected cells.