Pathological mitophagy disrupts mitochondrial homeostasis in Leber’s hereditary optic neuropathy
Alberto Danese, Simone Patergnani, Alessandra Maresca, Camille Peron, Andrea Raimondi, Leonardo Caporali, Saverio Marchi, Chiara La Morgia, Valentina Del Dotto, Claudia Zanna, Angelo Iannielli, Alice Segnali, Ivano Di Meo, Andrea Cavaliere, Magdalena Lebiedzińska, Mariusz R. Wiȩckowski, Andrea Martinuzzi, Milton N. Moraes-Filho, Solange Rios Salomão, Adriana Berezovsky, Rubens Belfort, Christopher Buser, Fred N. Ross‐Cisneros, Alfredo A. Sadun, Carlo Tacchetti, Vania Broccoli, Carlotta Giorgi, Valeria Tiranti, Valério Carelli, Paolo Pinton
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 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.