| RRC ID |
65196
|
| Author |
Zaninello M, Palikaras K, Naon D, Iwata K, Herkenne S, Quintana-Cabrera R, Semenzato M, Grespi F, Ross-Cisneros FN, Carelli V, Sadun AA, Tavernarakis N, Scorrano L.
|
| Title |
Inhibition of autophagy curtails visual loss in a model of autosomal dominant optic atrophy.
|
| Journal |
Nat Commun
|
| Abstract |
In autosomal dominant optic atrophy (ADOA), caused by mutations in the mitochondrial cristae biogenesis and fusion protein optic atrophy 1 (Opa1), retinal ganglion cell (RGC) dysfunction and visual loss occur by unknown mechanisms. Here, we show a role for autophagy in ADOA pathogenesis. In RGCs expressing mutated Opa1, active 5' AMP-activated protein kinase (AMPK) and its autophagy effector ULK1 accumulate at axonal hillocks. This AMPK activation triggers localized hillock autophagosome accumulation and mitophagy, ultimately resulting in reduced axonal mitochondrial content that is restored by genetic inhibition of AMPK and autophagy. In C. elegans, deletion of AMPK or of key autophagy and mitophagy genes normalizes the axonal mitochondrial content that is reduced upon mitochondrial dysfunction. In conditional, RGC specific Opa1-deficient mice, depletion of the essential autophagy gene Atg7 normalizes the excess autophagy and corrects the visual defects caused by Opa1 ablation. Thus, our data identify AMPK and autophagy as targetable components of ADOA pathogenesis.
|
| Volume |
11(1)
|
| Pages |
4029
|
| Published |
2020-8-12
|
| DOI |
10.1038/s41467-020-17821-1
|
| PII |
10.1038/s41467-020-17821-1
|
| PMID |
32788597
|
| PMC |
PMC7423926
|
| MeSH |
Adenylate Kinase / metabolism
Animals
Autophagy* / genetics
Axons / pathology
Caenorhabditis elegans / metabolism
Disease Models, Animal
Enzyme Activation
GTP Phosphohydrolases / genetics
Mice, Inbred C57BL
Mice, Knockout
Mitochondria / metabolism
Mitophagy
Mutation / genetics
Optic Atrophy, Autosomal Dominant / complications*
Phosphorylation
Retinal Ganglion Cells / pathology
Vision Disorders / complications*
|
| Resource |
| C.elegans |
tm5755
tm376 |
