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

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.
K.P. was supported by a Bodossaki Foundation long-term fellowship, AXA Research Fund post-doctoral long-term fellowship and a grant from the Hellenic Foundation for Research and Innovation (HFRI) and the General Secretariat for Research and Technology (GSRT). S.H. was supported by a FP7-Cofund, an AIRC Postdoctoral Fellowship and a Fondazione Umberto Veronesi fellowship. K.I. is supported in part by the Japan Society for the Promotion of Science (S2603) and the Japan Foundation for Pediatric Research. This work was funded by Telethon Italy (TCR02016 and GGP15198), Italian Ministry of Health (GR 09.021), Italian Ministry of Research (FIRB RBAP11Z3YA_005), Fondation Leducq (TNE004015) to L.S.; by ERC (GA282280 to L.S.; GA695190 and GA737599 to N.T.); the Greek General Secretariat for Research and Technology to N.T.; the International Foundation for Optic Nerve Diseases (IFOND) to V.C. and A.A.S.