Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.

ABSTRACT: 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 autoph

SUBMITTER: Danese A 

PROVIDER: S-EPMC9314546 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature