Autophagy is Required for the Maintenance of NAD

Abstract

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 by a poorly understood mechanism. Here we identified 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 cells with autophagy deficiency, loss of mitochondrial quality control was found to trigger hyperactivation of stress responses mediated by NADases of PARP and Sirtuin families. Uncontrolled depletion of NAD(H) pool by these enzymes ultimately contributed to mitochondrial membrane depolarisation and cell death. Pharmacological and genetic interventions targeting several key elements of this cascade improved the survival of autophagy-deficient cells and organisms. Our study provides a mechanistic link between autophagy and NAD metabolism, and identifies novel targets for interventions in human diseases associated with autophagic, lysosomal and mitochondrial dysfunction.

Keywords: Ageing, autophagy, mitophagy, Mitochondria, Metabolism, NAD, DNA damage, PARP, sirtuins