Compartmentalized coenzyme A and ferroptosis vulnerability in PKAN and CoPAN

Ferroptotic vulnerability may arise from the failure of a local antioxidant defense even when whole-cell metabolite abundance appears preserved. Pantothenate kinase-associated neurodegeneration (PKAN) and COASY protein-associated neurodegeneration (CoPAN), two forms of neurodegeneration with brain iron accumulation caused by defects in coenzyme A (CoA) synthesis, provide a genetically defined setting for examining this possibility. We propose that impairment of the mitochondrial CoA pool can weaken a CoA-dependent redox defense without requiring a measurable whole-cell CoA deficit, while regional iron burden and oxidative demand lower the threshold for ferroptotic death. This model could reconcile apparently preserved bulk CoA with selective neuronal vulnerability. It is testable, remains to be validated directly in patient-derived models, and distinguishes mitochondrial CoA availability from total cellular CoA as the disease-relevant variable.