Autophagy promotes cell survival by maintaining NAD levels

Kataura, T. et al. (2022) Autophagy promotes cell survival by maintaining NAD levels. Developmental Cell, 57(22), 2584-2598.e11. (doi: 10.1016/j.devcel.2022.10.008) (PMID:36413951) (PMCID:36413951)

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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:Articles
Additional Information:This study was supported by Fellowships from Uehara Memorial Foundation, the International Medical Research Foundation and JSPS (19J12969) to T.K.; Sir Henry Wellcome Postdoctoral Fellowship to R.S. (204715/Z/16/Z); grants from NIH RF1 (AG 55549-06) and UG3/UH3NS (113776-2) to E.T.; grants from NIH (R37HD045022, R01-NS088538, and R01-MH104610), Emerald Foundation, LEO Foundation (L18015), and St. Baldrick's Foundation to R.J.; CRUK Fellowship (C53309/A19702) to O.D.K.M.; JSPS (18KK0242) to S. Saiki, K.-i.I., M.I., and V.I.K.; NHMRC (GNT1106471 and GNT1160315) and Australian Research Council (FT1601100063, DP200100347) to M.L.; Wellcome Trust Senior Fellowship to A.S.; Wellcome Trust (109626/Z/15/Z, 1516ISSFFEL10), LifeArc (P2019-0004), UKIERI (2016-17-0087), and Birmingham Fellowship to S. Sarkar; BBSRC (BB/M023389/1) and MRC studentship (BH174490) to V.I.K.; and BBSRC (BB/R008167/2) to A.S. and V.I.K.
Glasgow Author(s) Enlighten ID:Sanz Montero, Professor Alberto
Authors: Kataura, T., Sedlackova, L., Otten, E. G., Kumari, R., Shapira, D., Scialo, F., Stefanatos, R., Ishikawa, K.-I., Kelly, G., Seranova, E., Sun, C., Maetzel, D., Kenneth, N., Trushin, S., Zhang, T., Trushina, E., Bascom, C. C., Tasseff, R., Isfort, R. J., Oblong, J. E., Miwa, S., Lazarou, M., Jaenisch, R., Imoto, M., Saiki, S., Papamichos-Chronakis, M., Manjithaya, R., Maddocks, O. D.K., Sanz Montero, A., Sarkar, S., and Korolchuk, V. I.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Developmental Cell
ISSN (Online):1878-1551
Published Online:21 November 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Developmental Cell 57(22):2584-2598.e11
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
311154Rate of AutophagyAlberto Sanz MonteroBiotechnology and Biological Sciences Research Council (BBSRC)BB/R008167/2School of Molecular Biosciences