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Lookup NU author(s): Dr Tetsushi Kataura, Lucy Sedlackova, Gisela Otten, David Shapira, Dr Filippo Scialo, Dr Rhoda StefanatosORCiD, George Kelly, Dr Niall Kenneth, Dr Satomi Miwa, Dr Manolis Papamichos Chronakis, Professor Viktor KorolchukORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022 The Author(s). 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.
Author(s): Kataura T, Sedlackova L, Otten EG, 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 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
Publication type: Article
Publication status: Published
Journal: Developmental Cell
Year: 2022
Volume: 57
Issue: 22
Pages: 2584-2598.e11
Print publication date: 21/11/2022
Online publication date: 21/11/2022
Acceptance date: 24/10/2022
Date deposited: 30/03/2023
ISSN (print): 1534-5807
ISSN (electronic): 1878-1551
Publisher: Cell Press
URL: https://doi.org/10.1016/j.devcel.2022.10.008
DOI: 10.1016/j.devcel.2022.10.008
PubMed id: 36413951
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