Autophagy promotes cell survival by maintaining NAD levels

Tetsushi Kataura; Lucia Sedlackova; Elsje G Otten; Ruchika Kumari; David Shapira; Filippo Scialo; Rhoda Stefanatos; Kei-Ichi Ishikawa; George Kelly; Elena Seranova; Congxin Sun; Dorothea Maetzel; Niall Kenneth; Sergey Trushin; Tong Zhang; Eugenia Trushina; Charles C Bascom; Ryan Tasseff; Robert J Isfort; John E Oblong; Satomi Miwa; Michael Lazarou; Rudolf Jaenisch; Masaya Imoto; Shinji Saiki; Manolis Papamichos-Chronakis; Ravi Manjithaya; Oliver D K Maddocks; Alberto Sanz; Sovan Sarkar; Viktor I Korolchuk

doi:10.1016/j.devcel.2022.10.008

Autophagy promotes cell survival by maintaining NAD levels

Dev Cell. 2022 Nov 21;57(22):2584-2598.e11. doi: 10.1016/j.devcel.2022.10.008.

Authors

Tetsushi Kataura¹, Lucia Sedlackova², Elsje G Otten², Ruchika Kumari³, David Shapira², Filippo Scialo², Rhoda Stefanatos⁴, Kei-Ichi Ishikawa⁵, George Kelly², Elena Seranova⁶, Congxin Sun⁶, Dorothea Maetzel⁷, Niall Kenneth⁸, Sergey Trushin⁹, Tong Zhang¹⁰, Eugenia Trushina¹¹, Charles C Bascom¹², Ryan Tasseff¹², Robert J Isfort¹², John E Oblong¹², Satomi Miwa², Michael Lazarou¹³, Rudolf Jaenisch¹⁴, Masaya Imoto¹⁵, Shinji Saiki¹⁶, Manolis Papamichos-Chronakis⁸, Ravi Manjithaya³, Oliver D K Maddocks¹⁷, Alberto Sanz¹⁸, Sovan Sarkar¹⁹, Viktor I Korolchuk²⁰

Affiliations

¹ Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK; Department of Biosciences and Informatics, Keio University, Yokohama, Kanagawa 223-8522, Japan; Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo 113-8421, Japan.
² Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.
³ Autophagy lab, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bangalore 560064, India.
⁴ Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK; Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK; School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
⁵ Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo 113-8421, Japan; Center for Genomic and Regenerative Medicine, Juntendo University Graduate School of Medicine, Bunkyo, Tokyo 113-8421, Japan.
⁶ Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
⁷ Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁸ Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK.
⁹ Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
¹⁰ Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; Novartis Institutes for Biomedical Research, Shanghai, China.
¹¹ Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
¹² The Procter & Gamble Company, Cincinnati, OH 45040, USA.
¹³ Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
¹⁴ Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
¹⁵ Department of Biosciences and Informatics, Keio University, Yokohama, Kanagawa 223-8522, Japan; Division for Development of Autophagy Modulating Drugs, Juntendo University Graduate School of Medicine, Bunkyo, Tokyo 113-8421, Japan.
¹⁶ Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo 113-8421, Japan; Division for Development of Autophagy Modulating Drugs, Juntendo University Graduate School of Medicine, Bunkyo, Tokyo 113-8421, Japan.
¹⁷ Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
¹⁸ School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
¹⁹ Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: [email protected].
²⁰ Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK. Electronic address: [email protected].

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.

Keywords: DNA damage; NAD; PARP; Sirtuins; ageing; autophagy; metabolism; mitochondria; mitophagy.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Animals
Autophagy
Cell Death
Cell Survival
Humans
Mice
NAD*
Saccharomyces cerevisiae*

Substances

NAD

Abstract

Publication types

MeSH terms

Substances

Grants and funding