Sustained intracellular calcium rise mediates neuronal mitophagy in models of autosomal dominant optic atrophy
Marta Zaninello, Konstantinos Palikaras, Aggeliki Sotiriou, Nektarios Tavernarakis, Luca Scorrano
Abstract
Abstract Mitochondrial dysfunction and mitophagy are often hallmarks of neurodegenerative diseases such as autosomal dominant optic atrophy (ADOA) caused by mutations in the key mitochondrial dynamics protein optic atrophy 1 (Opa1). However, the second messengers linking mitochondrial dysfunction to initiation of mitophagy remain poorly characterized. Here, we show in mammalian and nematode neurons that Opa1 mutations trigger Ca 2+ -dependent mitophagy. Deletion or expression of mutated Opa1 in mouse retinal ganglion cells and Caenorhabditis elegans motor neurons lead to mitochondrial dysfunction, increased cytosolic Ca 2+ levels, and decreased axonal mitochondrial density. Chelation of Ca 2+ restores mitochondrial density in neuronal processes, neuronal function, and viability. Mechanistically, sustained Ca 2+ levels activate calcineurin and AMPK, placed in the same genetic pathway regulating axonal mitochondrial density. Our data reveal that mitophagy in ADOA depends on Ca 2+ -calcineurin-AMPK signaling cascade.