Abstract
AbstractOPA1 mutations are the commonest cause of dominantly inherited optic atrophy (DOA) and so‐called DOA plus. The Opa1 protein is essential for normal mitochondrial fusion. In mouse DOA, autophagy (recycling of spent cellular components) is dysregulated in retinal ganglion cells (RGCs), and mitophagy (mitochondrial recycling) has been implicated. We validated and used novel ImageStream technology to quantitate mitophagy in primary cells. Co‐localisation of mitochondria and autophagosomes was increased in fibroblasts in five patients from four families with severe OPA1 phenotypes indicating increased mitophagy. ImageStream also showed that basal mitophagy was increased when control cultures were depleted of Opa1 by siRNA. Western blotting confirmed increased basal autophagy and autophagic flux in the presence of activators. Increased mitochondrial fragmentation, mitophagy and failure of mitochondrial transport may together cause local depletion of mitochondria in critical regions of the retinal ganglion cells, such as axons or synapses. Fragmentation may also impair stress induced mitochondrial hyperfusion. Increased mitochondrial fragmentation, mislocalisation and mitophagy thus link low OPA1 to neurodegeneration.
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