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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.

Sustained intracellular calcium rise mediates neuronal mitophagy in models of autosomal dominant optic atrophy