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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.

18 páginas, 7 figuras, Cyclooxygenase 2 (COX-2) is a key enzyme in prostanoid biosynthesis. The constitutive hepatocyte expression of COX-2 has a protective role in hepatic ischemia-reperfusion (I/R) injury (IRI), decreasing necrosis, reducing reactive oxygen species (ROS) levels, and increasing autophagy and antioxidant and anti-inflammatory response. The physiopathology of IRI directly impacts mitochondrial activity, causing ATP depletion and being the main source of ROS. Using genetically modified mice expressing human COX-2 (h-COX-2 Tg) specifically in hepatocytes, and performing I/R surgery on the liver, we demonstrate that COX-2 expression has a beneficial effect at the mitochondrial level. Mitochondria derived from h-COX-2 Tg mice livers have an increased respiratory rate associated with complex I electron-feeding pathways compared to Wild-type (Wt) littermates, without affecting complex I expression or assembly. Furthermore, Wt-derived mitochondria show a loss of mitochondrial membrane potential (ΔΨm) that correlates to increased proteolysis of fusion-related OPA1 through OMA1 protease activity. All these effects are not observed in h-COX-2 Tg mitochondria, which behave similarly to the Sham condition. These results suggest that COX-2 attenuates IRI at a mitochondrial level, preserving the proteolytic processing of OPA1, in addition to the maintenance of mitochondrial respiration., The experiments were performed in laboratories where projects are supported by: Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación 10.13039/501100011033 (SAF2016- 75004-R and PID2019-108977RB-I00), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CB06/04/1069), Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CB/11/00222), Consorcio de Investigación en Red de la Comunidad de Madrid, S2017/BMD-3686,and Fondo Europeo de Desarrollo Regional. M.F.-A. and M.L.-T. are recipient of FPI fellowship from MINECO (BES-2017-081928 and PRE2020-094885, respectively).