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 mitoph-agy 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 dis-rupts mitochondrial homeostasis as reflected by defective bioenergetics and excessive reactive oxygen spe-cies 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 chlo-roquine) and redox modulators (idebenone), as well as genetically activating mitochondrial biogenesis (PGC1-a overexpression). This study substantially advances our understanding of LHON pathophysiology, providing an integrated paradigm for pathogenesis of mitochondrial diseases and druggable targets for therapy.