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Review
. 2025 Sep 24;14(19):1495.
doi: 10.3390/cells14191495.

NAD+ Homeostasis and Autophagy: Integrated Control Through Nutrient Signaling in Yeast and Mammals

Affiliations
Review

NAD+ Homeostasis and Autophagy: Integrated Control Through Nutrient Signaling in Yeast and Mammals

Matilda McDaniel et al. Cells. .

Abstract

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite facilitating redox and biochemical reactions in many cellular processes. Maintaining NAD+ homeostasis is critical for proper cellular function, and abnormalities in NAD+ metabolism have been associated with various human diseases. However, the mechanisms underlying its regulation and interconnection with nutrient-sensing pathways remain incompletely understood. Recent studies show that autophagy, a conserved catabolic pathway essential for cellular homeostasis, plays an important role in maintaining the NAD+ pool. NAD+ may also impact autophagy through its regulation of cellular metabolism and sirtuins, a family of NAD+-dependent deacetylases. Given the complexity of these pathways, their mechanistic interconnection is not fully understood. Here, we discuss studies examining the interactions of NAD+ metabolism, autophagy, and nutrient-sensing pathways, with a focus on the budding yeast Saccharomyces cerevisiae and connections to mammalian systems. We also discuss the role of sirtuins in these pathways and the impacts of NAD+ precursor supplementation. This review provides insights into how nutrient-sensing pathways may mediate the co-regulation of NAD+, autophagy, and cellular homeostasis. The studies discussed provide the basis for the development of future research directions that may inform potential therapeutic targets for human disorders associated with the dysregulation of NAD+ metabolism and autophagy.

Keywords: NAD+; autophagy; nutrient sensing; sirtuin.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
NAD+ biosynthesis pathways in yeast. Biosynthesis: the de novo pathway (left panel, simplified view) converts L-tryptophan (L-Trp) to quinolinic acid (QA) via Bna2, Bna7, Bna4, Bna5, and Bna1. QA is converted to nicotinic acid mononucleotide (NaMN) via Bna6. NA-NAM salvage (middle panel) also produces NaMN by conversion of nicotinamide (NAM) to nicotinic acid (NA) via Pnc1. Npt1 converts NA to NaMN, which is then converted to nicotinic acid adenine dinucleotide (NaAD) by the NMNATs, Nma1 and Nma2. NaAD is converted to NAD+ by Qns1. In NR salvage (right panel), nicotinamide riboside (NR) is converted to nicotinamide mononucleotide (NMN) by NR kinase Nrk1, which is then converted to NAD+ by Pof1, Nma1, and Nma2. Degradation and recycling: NAD+ is converted to NAM by the Sir2 family of sirtuins or to NMN by NADases. NMN is converted to NR nucleotidases/phosphatases Isn1, Sdt1, and Pho8. NR can be converted to NAM via nucleosidases Urh1 and Pnp1, which then enters NA-NAM salvage.
Figure 2
Figure 2
Overview of major steps in autophagy. Atg proteins are represented in circles with their corresponding number. Initiation and Nucleation: Autophagy is induced by the recruitment of the Atg1 kinase complex, consisting of the Atg1-Atg13 dimer and the Atg17-Atg29-Atg31 ternary subcomplex, to the phagophore assembly site (PAS). Atg9 delivers membrane to the phagophore. The phosphatidylinositol 3-(PI3) kinase complex deposits phosphatidylinositol-3-phosphate (PI3P) (not depicted) throughout the phagophore. Atg2, Atg9, and Atg18 recruit membrane to the expanding phagophore. Expansion: Atg8 and Atg12 are ubiquitin-like proteins used in the two (I and II) ubiquitin-like conjugation systems. The Atg12-Atg5-Atg16 complex conjugates Atg8 to PE. Atg8-PE (small red circles) is conjugated to PI3P on the membrane on both sides of the phagophore. Maturation: the phagophore fully sequesters the cargo, becoming the autophagosome. Atg4 cleaves external Atg8-PE. Docking and Fusion: Atg proteins disassociate, and fusion machinery facilitates docking of autophagosome to the vacuole (yeast) or lysosome (mammals). The inner membrane (autophagic body) is released to the vacuolar/lysosomal lumen. Degradation and Recycling: The autophagic body is degraded by Atg15 and cargo is recycled by hydrolases. Recycled cargo is exported to the cytosol.
Figure 3
Figure 3
Factors regulating NAD+ metabolism and autophagy. Nutrient signaling pathways (lower box) that affect both NAD+ metabolism and autophagy: TOR, PKA, PHO, Snf1/AMPK, Mac1/Cu2+, and acetyl-CoA. Acetylation by proteins (upper box) that affect both NAD+ metabolism and autophagy: NatB, Rpd3, Sir2, and Hst1 using acetyl-CoA. Arrows between autophagy (left) and NAD+ metabolism (right) indicate interplay between pathways. Arrows between Acetylation and Nutrient Signaling indicate that regulation of nutrient signaling pathways by acetylation and regulation of acetylation factors by nutrient signaling pathways.

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