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

Citation:

Zaninello M, Palikaras K, Sotiriou A, Tavernarakis N, Scorrano L. Sustained intracellular calcium rise mediates neuronal mitophagy in models of autosomal dominant optic atrophy. Cell Death Differ. 2021.

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.

Notes:

Zaninello, MartaPalikaras, KonstantinosSotiriou, AggelikiTavernarakis, NektariosScorrano, LucaengGA695190/EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))GA737599/EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)GGP15091/Fondazione Telethon (Telethon Foundation)GGP19089/Fondazione Telethon (Telethon Foundation)EnglandCell Death Differ. 2021 Aug 13. pii: 10.1038/s41418-021-00847-3. doi: 10.1038/s41418-021-00847-3.