Metabolic function of autophagy is essential for cell survival

Age-related human pathologies present with a multitude of molecular and metabolic phenotypes, which individually or synergistically contribute to tissue degeneration. However, current lack of understanding of the interdependence of these molecular pathologies limits the potential range of existing therapeutic intervention strategies. In our study, we set out to understand the chain of molecular events, which underlie the loss of cellular viability in macroautophagy/autophagy deficiency associated with aging and age-related disease. We discover a novel axis linking autophagy, a cellular waste disposal pathway, and a metabolite, nicotinamide adenine dinucleotide (NAD). The axis connects multiple organelles, molecules and stress response pathways mediating cellular demise when autophagy becomes dysfunctional. By elucidating the steps on the path from efficient mitochondrial recycling to NAD maintenance and ultimately cell viability, we highlight targets potentially receptive to therapeutic interventions in a range of genetic and age-related diseases associated with autophagy dysfunction.

Automated summary

Age-related human pathologies present with a multitude of molecular and metabolic phenotypes, which contribute to tissue degeneration. Lack of understanding of the interdependence of these molecular pathologies limits therapeutic intervention strategies. In this study, we investigate the molecular events underlying cellular viability loss in autophagy deficiency associated with aging and age-related disease. We discover a novel axis linking autophagy and a metabolite, NAD, which mediates cellular demise. By elucidating the steps from mitochondrial recycling to NAD maintenance, we identify targets for therapeutic interventions in autophagy dysfunction.