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Autophagy promotes cell survival by maintaining NAD levels

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, Dr Viktor Korolchuk

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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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Funding

Funder referenceFunder name
109626/Z/15/Z
113776-2
1516ISSFFEL10
19J12969
2016-17-0087
18KK0242Japan Society for the Promotion of Science (JSPS)
204715/Z/16/ZWellcome Trust
BB/R008167/2
BH174490Procter & Gamble (Cincinnati)
AG 55549-06
DP200100347
BB/M023389/1Biotechnology and Biological Sciences Research Council (BBSRC)
C53309/A19702
FT1601100063
GNT1106471
GNT1160315
L18015
R01-MH104610
R01-NS088538
P2019-0004
R37HD045022

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