Autophagy promotes cell survival by maintaining NAD levels

Autophagy is an essential catabolic process that promotes the clearance of surplus or damaged intracellular components. Loss of autophagy in age-related human pathologies contributes to tissue degeneration through a poorly understood mechanism. Here, we identify an evolutionarily conserved role of autophagy from yeast to humans in the preservation of nicotinamide adenine dinucleotide (NAD) levels, which are critical for cell survival. In respiring mouse fibroblasts with autophagy deficiency, loss of mitochondrial quality con-trol was found to trigger hyperactivation of stress responses mediated by NADases of PARP and Sirtuin fam-ilies. Uncontrolled depletion of the NAD(H) pool by these enzymes ultimately contributed to mitochondrial membrane depolarization and cell death. Pharmacological and genetic interventions targeting several key elements of this cascade improved the survival of autophagy-deficient yeast, mouse fibroblasts, and human neurons. Our study provides a mechanistic link between autophagy and NAD metabolism and identifies tar-gets for interventions in human diseases associated with autophagic, lysosomal, and mitochondrial dysfunction.

Automated summary

This study identifies the importance of autophagy in maintaining cellular levels of NAD and reveals the mechanism by which autophagy deficiency leads to cell death.