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*
C.elegans tm5755 tm376