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.
Highlights
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
We decided to investigate the effect of the expression of mutated Opa[1] in RGCs, the cell type primarily affected by the disease
RGCs were electroporated and the efficiency of transfection was validated by OPA1 immunostaining: all vectors were expressed at the same level because the intensities of the OPA1 fluorescence were comparable (Supplementary Fig. 1a, b)
Summary
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. It leads to the accumulation of autophagosomes in vitro and in vivo[19,20] This latter feature is perhaps not surprising, considering that hallmarks of autophagy often accompany neuronal mitochondrial damage and that autophagy has been linked to axonal and dendritic dysfunction[21,22,23,24]. It is unclear whether activation of autophagy is per se a trigger of neurodegeneration caused by impaired mitochondrial function, or a compensatory response of the stressed RGC25. Opa[1] mutations or deletion cause the accumulation of autophagosomes at the axonal hillock and reduced axonal mitochondrial content in primary RGCs. Genetic inhibition of AMPK, of autophagy and of mitophagy restores axonal mitochondrial content. Autophagy inhibition prevents the autophagosome accumulation and the loss of vision in a mouse model of ADOA generated by targeted RGCs Opa[1] deletion
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