Autophagy promotes cell survival by maintaining NAD levels

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Kataura, Tetsushi, Sedlackova, Lucia, Otten, Elsje G, Kumari, Ruchika, Shapira, David, Scialo, Filippo, Stefanatos, Rhoda, Ishikawa, Kei-ichi, Kelly, George, Seranova, Elena et al (show 21 more authors) , Sun, Congxin, Maetzel, Dorothea, Kenneth, Niall ORCID: 0000-0001-8528-1021, Trushin, Sergey, Zhang, Tong, Trushina, Eugenia, Bascom, Charles C, Tasseff, Ryan, Isfort, Robert J, Oblong, John E, Miwa, Satomi, Lazarou, Michael, Jaenisch, Rudolf, Imoto, Masaya, Saiki, Shinji, Papamichos-Chronakis, Manolis ORCID: 0000-0002-4144-2070, Manjithaya, Ravi, Maddocks, Oliver DK, Sanz, Alberto, Sarkar, Sovan and Korolchuk, Viktor I (2022) Autophagy promotes cell survival by maintaining NAD levels. DEVELOPMENTAL CELL, 57 (22). 2584-+.

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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.

Item Type:	Article
Uncontrolled Keywords:	Animals, Humans, Mice, Saccharomyces cerevisiae, NAD, Cell Death, Cell Survival, Autophagy
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	24 Nov 2022 14:08
Last Modified:	18 Jan 2023 19:43
DOI:	10.1016/j.devcel.2022.10.008
Open Access URL:	https://www.cell.com/developmental-cell/fulltext/S...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3166360