Autophagy is an essential catabolic process that promotes the clearance of surplus or damaged intracellular components1. As a recycling process, autophagy is also important for the maintenance of cellular metabolites to aid metabolic homeostasis2. Loss of autophagy in animal models or malfunction of this process in a number of age-related human pathologies, including neurodegenerative and lysosomal storage diseases, contributes to tissue degeneration3-9. However, it remains unclear which of the many cellular functions of autophagy primarily underlies its role in cell survival. Here we have identified an evolutionarily conserved role of autophagy from yeast to humans in the preservation of nicotinamide adenine dinucleotide (NAD+/NADH) levels, which are critical for cellular survival. In respiring cells, loss of autophagy caused hyperactivation of PARP and Sirtuin families of NADases. Uncontrolled depletion of NAD(H) pool by these enzymes resulted in mitochondrial membrane depolarisation and cell death. Supplementation with NAD(H) precursors improved cell viability in autophagy-deficient models including human pluripotent stem cell-derived neurons with autophagy deficiency or patient-derived neurons with autophagy dysfunction. Our study provides a mechanistic link between autophagy and NAD(H) metabolism, and suggests that boosting NAD(H) levels may have therapeutic benefits in human diseases associated with autophagy dysfunction.
