Mitochondrial transport along RGC axons: Strategies to restore energy homeostasis and visual function

Abstract Deficits in mitochondria anterograde axonal transport is a common feature of neurodegenerative diseases including glaucoma. Whether aberrant expression of components in the transport machinery impinge directly on metabolic stress, neuronal death, and circuit dysfunction, is currently unknown. We used multiphoton microscope live imaging to monitor mitochondrial transport along the axons of retinal ganglion cells (RGC), the neurons that die in glaucoma. We found that high intraocular pressure, the most important risk factor to develop the disease, impairs anterograde movement of mitochondria along RGC axons leading to mitochondria depletion and energy decline. Molecular profiling of motor and adaptor proteins revealed loss of Disrupted in schizophrenia (Disc1) expression in glaucomatous RGC. Adeno‐associated virus (AAV)‐based Disc1 gene delivery rescued anterograde transport and replenished mitochondria in proximal and distal axonal segments. Delivery of a genetically encoded ATP sensor combined with longitudinal live imaging revealed that Disc1 supplementation increased ATP production in stressed neurons. Strikingly, Disc1 gene therapy promoted neuronal survival, reversed abnormal RGC calcium dynamics, and restored light‐evoked retinal responses and visual behaviour. Our study provides proof‐of‐principle that enhancing mitochondrial anterograde transport is an effective strategy to alleviate metabolic stress and glaucomatous neurodegeneration.