Autophagy promotes cell survival by maintaining NAD levels
- Author(s)
- Kataura, T; Sedlackova, L; Otten, EG; Kumari, R; Shapira, D; Scialo, F; Stefanatos, R; Ishikawa, KI; Kelly, G; Seranova, E; Sun, C; Maetzel, D; Kenneth, N; Trushin, S; Zhang, T; Trushina, E; Bascom, CC; Tasseff, R; Isfort, RJ; Oblong, JE; Miwa, S; Lazarou, M; Jaenisch, R; Imoto, M; Saiki, S; Papamichos-Chronakis, M; Manjithaya, R; Maddocks, ODK; Sanz, A; Sarkar, S; Korolchuk, VI;
- Details
- Publication Year 2022-11-21,Volume 57,Issue #22,Page 2584-2598.e11
- Journal Title
- Developmental Cell
- 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 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 control was found to trigger hyperactivation of stress responses mediated by NADases of PARP and Sirtuin families. 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 targets for interventions in human diseases associated with autophagic, lysosomal, and mitochondrial dysfunction.
- Publisher
- Cell Press
- Keywords
- Animals; Mice; Humans; Cell Survival; *nad; *Saccharomyces cerevisiae; Autophagy; Cell Death; DNA damage; Nad; Parp; Sirtuins; ageing; metabolism; mitochondria; mitophagy
- Research Division(s)
- Ubiquitin Signalling
- PubMed ID
- 36413951
- Publisher's Version
- https://doi.org/10.1016/j.devcel.2022.10.008
- Open Access at Publisher's Site
https://doi.org/10.1016/j.devcel.2022.10.008- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2022-12-13 03:12:50
Last Modified: 2022-12-13 03:35:55