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

• Published in: Nature communications Vol. 11; no. 1; p. 4029
• Main Authors: Zaninello, Marta, Palikaras, Konstantinos, Naon, Deborah, Iwata, Keiko, Herkenne, Stephanie, Quintana-Cabrera, Ruben, Semenzato, Martina, Grespi, Francesca, Ross-Cisneros, Fred N., Carelli, Valerio, Sadun, Alfredo A., Tavernarakis, Nektarios, Scorrano, Luca
• Format: Journal Article Web Resource
• Language: English
• Published: London Nature Publishing Group UK 12.08.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/2; 13/31; 13/89; 14/1; 14/19; 14/35; 14/63; 42/41; 631/80/304; 631/80/642/2384; 631/80/642/333; 64/11; 64/60; Ablation; Adenylate Kinase - metabolism; AMP; AMP-activated protein kinase; Animals; Atrophy; Autophagy; Autophagy - genetics; Axons; Axons - pathology; Biochemistry, biophysics & molecular biology; Biochimie, biophysique & biologie moléculaire; Caenorhabditis elegans - metabolism; Cristae; Depletion; Disease Models, Animal; Enzyme Activation; Evolution; Fusion protein; GTP Phosphohydrolases - genetics; Humanities and Social Sciences; Kinases; Life sciences; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondria - metabolism; Mitophagy; multidisciplinary; Mutation; Mutation - genetics; Optic atrophy; Optic Atrophy, Autosomal Dominant - complications; Pathogenesis; Phagocytosis; Phosphorylation; Proteins; Retina; Retinal ganglion cells; Retinal Ganglion Cells - pathology; Science; Science (multidisciplinary); Sciences du vivant; Vision Disorders - complications
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17821-1

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.