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Autophagy promotes cell and organismal survival by maintaining NAD(H) pools

View ORCID ProfileLucia Sedlackova, Elsje G. Otten, Filippo Scialo, David Shapira, Tetsushi Kataura, Bernadette Carroll, Elena Seranova, Yoana Rabanal-Ruiz, George Kelly, Rhoda Stefanatos, Glyn Nelson, View ORCID ProfileAnimesh Acharjee, Niall Kenneth, Sergey Trushin, Tong Zhang, Charles C. Bascom, Ryan Tasseff, Robert J. Isfort, John E. Oblong, Eugenia Trushina, Masaya Imoto, Shinji Saiki, Michael Lazarou, Manolis Papamichos Chronakis, Oliver D.K. Maddocks, Sovan Sarkar, Alberto Sanz, Viktor I. Korolchuk
doi: https://doi.org/10.1101/2020.01.31.928424
Lucia Sedlackova
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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  • ORCID record for Lucia Sedlackova
Elsje G. Otten
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Filippo Scialo
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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David Shapira
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Tetsushi Kataura
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
2Department of Biosciences and Informatics, Keio University, Yokohama, Kanagawa, Japan
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Bernadette Carroll
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Elena Seranova
3Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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Yoana Rabanal-Ruiz
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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George Kelly
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Rhoda Stefanatos
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Glyn Nelson
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Animesh Acharjee
4Centre for Computational Biology, University of Birmingham, Birmingham, UK
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  • ORCID record for Animesh Acharjee
Niall Kenneth
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Sergey Trushin
5Department of Neurology, Mayo Clinic, Rochester, MN, USA
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Tong Zhang
6Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
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Charles C. Bascom
7The Procter & Gamble Company, Cincinnati, OH, USA
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Ryan Tasseff
7The Procter & Gamble Company, Cincinnati, OH, USA
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Robert J. Isfort
7The Procter & Gamble Company, Cincinnati, OH, USA
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John E. Oblong
7The Procter & Gamble Company, Cincinnati, OH, USA
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Eugenia Trushina
5Department of Neurology, Mayo Clinic, Rochester, MN, USA
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Masaya Imoto
2Department of Biosciences and Informatics, Keio University, Yokohama, Kanagawa, Japan
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Shinji Saiki
8Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan
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Michael Lazarou
9Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, 3800, Australia
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Manolis Papamichos Chronakis
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Oliver D.K. Maddocks
6Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
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Sovan Sarkar
3Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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  • For correspondence: s.sarkar@bham.ac.uk alberto.sanzmontero@glasgow.ac.uk viktor.korolchuk@newcastle.ac.uk
Alberto Sanz
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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  • For correspondence: s.sarkar@bham.ac.uk alberto.sanzmontero@glasgow.ac.uk viktor.korolchuk@newcastle.ac.uk
Viktor I. Korolchuk
1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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  • For correspondence: s.sarkar@bham.ac.uk alberto.sanzmontero@glasgow.ac.uk viktor.korolchuk@newcastle.ac.uk
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Abstract

Autophagy is an essential catabolic process that promotes clearance of surplus or damaged intracellular components1. As a recycling process, autophagy is also important for the maintenance of cellular metabolites during periods of starvation2. Loss of autophagy is sufficient to cause cell death in animal models and is likely to contribute to tissue degeneration in a number of human diseases including neurodegenerative and lysosomal storage disorders3–7. However, it remains unclear which of the many cellular functions of autophagy primarily underlies its role in cell survival. Here we have identified a critical role of autophagy in the maintenance of nicotinamide adenine dinucleotide (NAD+/NADH) levels. In respiring cells, loss of autophagy caused NAD(H) depletion resulting in mitochondrial membrane depolarisation and cell death. We also found that maintenance of NAD(H) is an evolutionary conserved function of autophagy from yeast to human cells. Importantly, cell death and reduced viability of autophagy-deficient animal models can be partially reversed by supplementation with an NAD(H) precursor. Our study provides a mechanistic link between autophagy and NAD(H) metabolism and suggests that boosting NAD(H) levels may be an effective intervention strategy to prevent cell death and tissue degeneration in human diseases associated with autophagy dysfunction.

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Posted January 31, 2020.
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Autophagy promotes cell and organismal survival by maintaining NAD(H) pools
Lucia Sedlackova, Elsje G. Otten, Filippo Scialo, David Shapira, Tetsushi Kataura, Bernadette Carroll, Elena Seranova, Yoana Rabanal-Ruiz, George Kelly, Rhoda Stefanatos, Glyn Nelson, Animesh Acharjee, Niall Kenneth, Sergey Trushin, Tong Zhang, Charles C. Bascom, Ryan Tasseff, Robert J. Isfort, John E. Oblong, Eugenia Trushina, Masaya Imoto, Shinji Saiki, Michael Lazarou, Manolis Papamichos Chronakis, Oliver D.K. Maddocks, Sovan Sarkar, Alberto Sanz, Viktor I. Korolchuk
bioRxiv 2020.01.31.928424; doi: https://doi.org/10.1101/2020.01.31.928424
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Autophagy promotes cell and organismal survival by maintaining NAD(H) pools
Lucia Sedlackova, Elsje G. Otten, Filippo Scialo, David Shapira, Tetsushi Kataura, Bernadette Carroll, Elena Seranova, Yoana Rabanal-Ruiz, George Kelly, Rhoda Stefanatos, Glyn Nelson, Animesh Acharjee, Niall Kenneth, Sergey Trushin, Tong Zhang, Charles C. Bascom, Ryan Tasseff, Robert J. Isfort, John E. Oblong, Eugenia Trushina, Masaya Imoto, Shinji Saiki, Michael Lazarou, Manolis Papamichos Chronakis, Oliver D.K. Maddocks, Sovan Sarkar, Alberto Sanz, Viktor I. Korolchuk
bioRxiv 2020.01.31.928424; doi: https://doi.org/10.1101/2020.01.31.928424

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