Deciphering the role of mitochondrial dysfunction in retinal degeneration

Mitochondria regulate multiple cellular processes, yet their cell-specific roles in health and disease remain poorly understood. This research will define key roles for mitochondria in photoreceptor maintenance and how their dysregulation drives cell death in inherited retinal dystrophies (IRDs), a leading cause of blindness, aiming to identify therapeutic targets. Photoreceptor mitochondria operate at near maximal respiratory capacity, rendering them acutely vulnerable to shifts in energy demand. In keeping, mutations in genes governing mitochondrial homeostasis and mitochondrial quality control frequently cause IRDs. I recently demonstrated that IRD mouse models harbouring mutations in non-mitochondrial genes develop mitochondrial dysfunction and disrupted quality control prior to sight loss. I therefore hypothesise that mitochondrial dysfunction represents a common pathway driving photoreceptor death across mechanistically distinct IRDs. To test this, I will integrate clinical ophthalmology, molecular genetics, and mitochondrial biology, employing genetic and small-molecule approaches in mouse models and reporter lines to define: 1. The cell pathways regulated by mitochondria in photoreceptors; 2. Molecular mechanisms regulating mitochondrial network structure and mitochondrial quality control; 3. The capacity to halt photoreceptor degeneration by inhibiting necroptosis. This systematic investigation will uncover fundamental insights into photoreceptor biology, identifying therapeutic targets with broad relevance across the IRD disease spectrum.