Localized Accumulation of Autophagosomes at Axonal Hillocks Depletes Axons from Damaged Mitochondria
Luca Scorrano Venetian Institute of Molecular Medicine and Dept. of Biology, University of Padua, Padova, Italy
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 occurs by unknown mechanisms. Here we show that expression of mutated Opa1 in RGCs causes heterogenous mitochondrial dysfunction and triggers AMPK dependent autophagosome accumulation at axonal hillocks of RGC. Pharmacological or genetic inhibition of this autophagy signaling pathway restores axonal mitochondrial content and rescues RGCs from excess apoptosis caused by mutated Opa1. In C. elegans, deletion of AMPK or of the key autophagy gene LC3 rescues axonal mitochondrial content in neurons exposed to oxidative stress or where mitochondrial dysfunction was genetically caused. In conditional, RGC specific Opa1-deficient mice, excess autophagy is normalized by monoallelic deletion of the essential autophagy gene Atg7 that also fully corrected the visual defects caused by Opa1 ablation. Thus, accumulation of autophagosomes at axonal hillocks is a conserved mechanism regulating axonal mitochondrial content and crucial for ADOA pathogenesis.
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