1. Inhibition of autophagy curtails visual loss in a model of autosomal dominant optic atrophy
- Author
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Bodossaki Foundation, AXA Research Fund, Hellenic Foundation for Research and Innovation, European Commission, Fondazione Umberto Veronesi, Japan Society for the Promotion of Science, Telethon Italia, Ministero della Salute, Ministero dell'Istruzione, dell'Università e della Ricerca, Fondation Leducq, European Research Council, General Secretariat of Research and Technology (Greece), International Foundation for Optic Nerve Disease, Palikaras, Konstantinos[0000-0001-6992-5560], Naon, Deborah [0000-0002-9726-4664], Quintana-Cabrera, Ruben [0000-0002-0601-349X], Tavernarakis, Nektarios [0000-0002-5253-1466], Scorrano, Luca [0000-0002-8515-8928], 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, Bodossaki Foundation, AXA Research Fund, Hellenic Foundation for Research and Innovation, European Commission, Fondazione Umberto Veronesi, Japan Society for the Promotion of Science, Telethon Italia, Ministero della Salute, Ministero dell'Istruzione, dell'Università e della Ricerca, Fondation Leducq, European Research Council, General Secretariat of Research and Technology (Greece), International Foundation for Optic Nerve Disease, Palikaras, Konstantinos[0000-0001-6992-5560], Naon, Deborah [0000-0002-9726-4664], Quintana-Cabrera, Ruben [0000-0002-0601-349X], Tavernarakis, Nektarios [0000-0002-5253-1466], Scorrano, Luca [0000-0002-8515-8928], 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, and Scorrano, Luca
- 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.
- Published
- 2020