CAPN5 encodes calpain-5, a calcium-dependent cysteine protease with distinct subcellular localizations and functions. The protein localizes to photoreceptor synapses in the outer plexiform layer and mitochondria, where it undergoes autoproteolysis at low calcium concentrations and becomes activated during endoplasmic reticulum stress 1 2. CAPN5 appears to regulate synaptic proteins including DLGAP4, IQSEC1, and MPDZ, as well as neurodegeneration-related proteins through limited proteolysis 3. The enzyme shows moderate retinal expression and strong expression during zebrafish CNS development, with increased expression during photoreceptor degeneration and regeneration 4. Pathogenic mutations in CAPN5 cause autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a progressive autoimmune eye disease characterized by retinal vasculitis, macular edema, and tractional membranes 5 6. These mutations lead to dysfunction of innate and adaptive immune systems, contributing to the inflammatory phenotype 7. The clinical spectrum varies significantly among patients, ranging from typical neovascular inflammation to atypical presentations with macular holes and retinitis pigmentosa-like features 6. Understanding CAPN5's substrate repertoire and mitochondrial activation may inform therapeutic approaches for ADNIV and related neurodegenerative conditions.