Inhibition of autophagy curtails visual loss in a model of autosomal dominant optic atrophy

TL;DR

This study shows that blocking autophagy can prevent vision loss in a mouse model of a genetic eye disorder caused by OPA1 mutations.

Contribution

The study identifies AMPK-induced autophagy as a novel therapeutic target for autosomal dominant optic atrophy.

Findings

AMPK and ULK1 accumulate at axonal hillocks in retinal ganglion cells with mutated Opa1, triggering autophagy.

Genetic inhibition of AMPK and autophagy restores mitochondrial content in axons affected by Opa1 mutations.

Depletion of Atg7 in mice reverses visual defects caused by Opa1 deficiency, highlighting autophagy as a targetable pathway.

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.

Autosomal dominant optic atrophy is caused by mutations in the mitochondrial fusion protein OPA1. Here, the authors show that AMPK-induced autophagy depletes mitochondria in axons of retinal ganglion cells and that autophagic inhibition reverses vision loss in a mouse model.

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