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Title:
Sustained intracellular calcium rise mediates neuronal mitophagy in models of autosomal dominant optic atrophy | Cell Death & Differentiation
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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 Ca2+-dependent mitophagy. Deletion or expression of mutated Opa1 in mouse retinal ganglion cells and Caenorhabditis elegans motor neurons lead to mitochondrial dysfunction, increased cytosolic Ca2+ levels, and decreased axonal mitochondrial density. Chelation of Ca2+ restores mitochondrial density in neuronal processes, neuronal function, and viability. Mechanistically, sustained Ca2+ levels activate calcineurin and AMPK, placed in the same genetic pathway regulating axonal mitochondrial density. Our data reveal that mitophagy in ADOA depends on Ca2+-calcineurin-AMPK signaling cascade.
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mitochondrial, pubmed, article, mitochondria, mitophagy, google, scholar, neurons, rgcs, cas, opa, axonal, cell, fig, neuronal, cna, central, dysfunction, cells, gabaergic, autophagy, death, density, ampk, nematodes, adoa, expressing, motor, inhibition, autophagosomes, nature, levels, supplementary, images, content, distribution, function, elegans, model, experiments, biol, calcium, mouse, mutants, axons, optic, anova, data, pathway, opaka,
Topics {✒️}
nature portfolio privacy policy advertising nature european research council telethon italy ggp15091 reprints ca2+-calcineurin-ampk signaling cascade opa1k301a-mediated cell death opak301a-driven neuronal death research resources dominant optic atrophy ca2+-dependent signaling cascade data represent average ± sd original author mitophagy inhibits amyloid-beta immuno-panning magnetic protocol mitochondria-shaping protein opa1 ca2+-dependent phosphatase calcineurin social media research middle panels wild-type bristol isolate culture media full size image ca2+-dependent fundc1 phosphorylation bottle-magnified calcium signaling ca2+-dependent phosphatase cna permissions cell death differ cell death dis sustained ca2+ levels retinal ganglion cells cna–ampk pathway activated pmscv-opa1k301a pmscv-opa1q297 cytoplasmic yfp-lc3 signal article zaninello ca2+ chelating agents treated opa1k301a-expressing nematodes tumor angiogenesis requires regulate mitochondrial content mitochondrial atp content 24 mm round coverslips neuronal death caused reduces mitochondrial content axonal mitochondrial content optic nerve structure optic neuropathies darius ex0023[punc-47opa1k301a] [12] autophagosome-mitochondria colocalization calculated
Questions {❓}
- Neuronal mitophagy: friend or foe?
- PINK1/Parkin mitophagy and neurodegeneration—what do we really know in vivo?
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description: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 Ca2+-dependent mitophagy. Deletion or expression of mutated Opa1 in mouse retinal ganglion cells and Caenorhabditis elegans motor neurons lead to mitochondrial dysfunction, increased cytosolic Ca2+ levels, and decreased axonal mitochondrial density. Chelation of Ca2+ restores mitochondrial density in neuronal processes, neuronal function, and viability. Mechanistically, sustained Ca2+ levels activate calcineurin and AMPK, placed in the same genetic pathway regulating axonal mitochondrial density. Our data reveal that mitophagy in ADOA depends on Ca2+-calcineurin-AMPK signaling cascade.
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description: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 Ca2+-dependent mitophagy. Deletion or expression of mutated Opa1 in mouse retinal ganglion cells and Caenorhabditis elegans motor neurons lead to mitochondrial dysfunction, increased cytosolic Ca2+ levels, and decreased axonal mitochondrial density. Chelation of Ca2+ restores mitochondrial density in neuronal processes, neuronal function, and viability. Mechanistically, sustained Ca2+ levels activate calcineurin and AMPK, placed in the same genetic pathway regulating axonal mitochondrial density. Our data reveal that mitophagy in ADOA depends on Ca2+-calcineurin-AMPK signaling cascade.
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