Fig. 3

Integrative representation showing the mitochondrial dysfunction as an etiology of the axonal degeneration. a Mutations associated with mitochondrial dynamics can cause axonal damage in CMT2 phenotype. b Role of PNKP in the maintenance of mtDNA stability. When PNKP is mutated, ROS/NOS generate an environment of genotoxic stress, that can impair the normal axonal function. Since the glycolytic capacity of neurons is restricted, mitochondrial oxidative phosphorylation is essential for neuronal ATP supply [36]. ATM-dependent phosphorylation of PNKP at serines 114 and 126 in response to oxidative DNA damage inhibits degradation of PNKP. This PNKP stability is required for DNA repair [45]. ATM can also activate p53 which undergoes apoptosis in the presence of high levels of mtDNA damage. ER: endoplasmic reticulum. OXPHOS: oxidative phosphorylation