Autophagy promotes cell and organismal survival by maintaining NAD(H) pools

Abstract

Autophagy is an essential catabolic process that promotes clearance of surplus or damaged intracellular components 1 . As a recycling process, autophagy is also important for the maintenance of cellular metabolites during periods of starvation 2 . Loss of autophagy is sufficient to cause cell death in animal models and is likely to contribute to tissue degeneration in a number of human diseases including neurodegenerative and lysosomal storage disorders 3-7 . However, it remains unclear which of the many cellular functions of autophagy primarily underlies its role in cell survival. Here we have identified a critical role of autophagy in the maintenance of nicotinamide adenine dinucleotide (NAD + /NADH) levels. In respiring cells, loss of autophagy caused NAD(H) depletion resulting in mitochondrial membrane depolarisation and cell death. We also found that maintenance of NAD(H) is an evolutionary conserved function of autophagy from yeast to human cells. Importantly, cell death and reduced viability of autophagy-deficient animal models can be partially reversed by supplementation with an NAD(H) precursor. Our study provides a mechanistic link between autophagy and NAD(H) metabolism and suggests that boosting NAD(H) levels may be an effective intervention strategy to prevent cell death and tissue degeneration in human diseases associated with autophagy dysfunction.Macroautophagy, hereinafter autophagy, is a cellular trafficking pathway mediated by the formation of double-membraned vesicles called autophagosomes, which ultimately fuse with lysosomes, where their cargo is degraded. By sequestering and clearing dysfunctional cellular components, such as protein aggregates and damaged organelles, autophagy maintains cellular homeostasis whilst also providing metabolites and energy during periods of starvation. Studies using a range of laboratory models from yeast to mammals have established that autophagy is essential for cellular and organismal survival. For example, inducible knockout of core autophagy genes, such as Atg5, results in cell death and tissue degeneration in adult mice 3,8,9 . However, autophagy-deficient cells such as Atg5 -/mouse embryonic fibroblasts (MEFs) are viable in cell culture, which hinders in vitro studies of the mechanisms leading to cell death [8][9][10] . We hypothesized that this apparent discrepancy between the requirement for functional autophagy in vivo and in vitro could be due to a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis. Indeed, whilst differentiated cells with high energy demand, such as neurons, rely on aerobic ATP generation via OXPHOS, the abundance of glucose in standard cell culture conditions allows cells to generate sufficient levels of ATP via glycolysis. This decreased reliance on mitochondrial respiration could then mask an underlying viability defect 11 .A well-established strategy to reverse cellular reliance on energy generation via aerobic glycolysis and promote mitochondrial OXPHOS, is to replace glucose, the major carbon source in tissu...

Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders

“…However, autophagic processes play a critical role in mitochondrial quality control through selective mitochondrial degradation termed mitophagy, and there is evidence to suggest this is impaired in LB diseases, thus suggesting autophagic deficits could induce accumulation of dysfunctional mitochondria [ 32 , 91 ]. Furthermore, our recent work indicates NAD(H), an essential cofactor for mitochondrial metabolism, is depleted by selective inhibition of autophagy, demonstrating that deficient autophagy induces mitochondrial dysfunction [ 105 ]. In summary, whilst autophagy may relate to α-synuclein aggregation by impeding its degradation, this seems a sub-optimal explanation given the likely impact this would have on aggregation-prone proteins beyond α-synuclein.…”

Potential Therapeutic Benefit of NAD+ Supplementation for Glaucoma and Age-Related Macular Degeneration

“…Accumulation of waste material in the lamina cribrosa (LC) and accumulation of lipofuscin have been found in LC donors cells with a consequence on dysregulated autophagic clearance at the level of LC with a clear impact on the ONH [ 196 ]. Targeting this other mechanism might be a problem considering the multitude of glaucoma correlated events if would not be treatable in the same way as the others, however NAD + is strongly linked to autophagy suggests its utility here as well [ 197 , 198 ]. The neuroprotection afforded by nicotinamide may not only be due to improved mitochondrial function but also due to the NAD + /SIRT1 axis [ 199 , 200 ] or to protection from various other insults that affect RGCs, such as ischemia/reperfusion or light [ 201 ].…”