A model of Dominant Optic Atrophy
Mitophagy is increased in the OPA1Q285STOP/RedMIT/GFP‐LC3 mouse: a model of Dominant Optic Atrophy for identifying drug modulators of mitophagy.
Mitophagy (recycling of damaged mitochondria) is central to the pathogenesis of Parkinson’s disease and is likely to be an important determinant of mitochondrial disease severity. It occurs when a LC3‐positive membrane structure, the phagophore, encloses mitochondrial fragments, resulting in a double‐membrane autophagosome that fuses with a lysosome to become an autolysosome able to degrade its content. Dominant optic atrophy (DOA) is the most common inherited optic neuropathy (prevalence 1:12 000), largely caused by mutations in OPA1. This gene encodes a ubiquitous protein involved in mitochondrial dynamics. Some of these patients develop a severe form of this disorder, known as DOA plus, with additional symptoms including deafness, peripheral neuropathies and occasionally Parkinson’s disease. We previously showed that mitophagy is increased in patients with severe DOA plus.
In the OPA1Q285STOP mouse model of DOA, loss of vision is accompanied by dendronopathy in retinal ganglion cells (RGCs), electron microscopy shows signs of autophagy and aberrant cristae that are consistent with, but not definitive evidence of, increased mitophagy. We crossed these mice with our RedMIT/GFP‐LC3 mouse and then used high throughput imaging to quantitate mitophagy in mouse embryonic fibroblasts (MEFs) and splenocytes from this RedMIT/GFPLC3/OPA1Q285STOP mouse.