NAD⁺: The convergence of DNA repair and mitophagy

ATM is a 350 kDa serine/threonine kinase best known for its role in DNA repair and multiple cellular homeostasis pathways. Mutation in ATM causes the disease ataxia telangiectasia (A-T) with clinical features including ataxia, severe cerebellar atrophy and Purkinje cell loss. In a cross-species study, using primary rat neurons, the roundworm C. elegans, and a mouse model of A-T, we showed that loss of ATM induces mitochondrial dysfunction and compromised mitophagy due to NAD⁺ insufficiency. Remarkably, NAD⁺ repletion mitigates both the DNA repair defect and mitochondrial dysfunction in ATM-deficient neurons. In C. elegans, NAD⁺ repletion can clear accumulated dysfunctional mitochondria through restoration of compromised mitophagy via upregulation of DCT-1. Thus, NAD⁺ ties together DNA repair and mitophagy in neuroprotection and intimates immediate translational applications for A-T and related neurodegenerative DNA repair-deficient diseases.