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Autophagy is Required for the Maintenance of NAD

75 Pages Posted: 14 Feb 2022 Publication Status: Under Review

See all articles by Tetsushi Kataura

Tetsushi Kataura

Newcastle University - Biosciences Institute

Lucia Sedlackova

Newcastle University

Elsje G. Otten

University of Cambridge - MRC Laboratory of Molecular Biology

David Shapira

affiliation not provided to SSRN

Filippo Scialo

affiliation not provided to SSRN

Rhoda Stefanatos

University of Glasgow

Kei-ichi Ishikawa

affiliation not provided to SSRN

George Kelly

Newcastle University - Biosciences Institute

Elena Seranova

University of Birmingham

Congxin Sun

University of Birmingham

Dorothea Maetzel

Massachusetts Institute of Technology (MIT) - Whitehead Institute for Biomedical Research

Niall Kenneth

University of Liverpool

Sergey Trushin

affiliation not provided to SSRN

Tong Zhang

University of Glasgow

Eugenia Trushina

affiliation not provided to SSRN

Charles C. Bascom

The Procter and Gamble Company

Ryan Tasseff

affiliation not provided to SSRN

Robert J. Isfort

affiliation not provided to SSRN

John E. Oblong

The Procter and Gamble Company

Satomi Miwa

Newcastle University - Biosciences Institute

Michael Lazarou

Monash University

Rudolf Jaenisch

Massachusetts Institute of Technology (MIT) - Whitehead Institute for Biomedical Research

Masaya Imoto

affiliation not provided to SSRN

Shinji Saiki

affiliation not provided to SSRN

Manolis Papamichos-Chronakis

University of Liverpool

Oliver D.K. Maddocks

University of Glasgow

Alberto Sanz

University of Glasgow

Sovan Sarkar

University of Birmingham - Institute of Cancer and Genomic Sciences

Viktor Korolchuk

Newcastle University - Biosciences Institute

More...

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 by a poorly understood mechanism. Here we identified 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 cells 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 NAD(H) pool by these enzymes ultimately contributed to mitochondrial membrane depolarisation and cell death. Pharmacological and genetic interventions targeting several key elements of this cascade improved the survival of autophagy-deficient cells and organisms. Our study provides a mechanistic link between autophagy and NAD metabolism, and identifies novel targets for interventions in human diseases associated with autophagic, lysosomal and mitochondrial dysfunction.

Keywords: Ageing, autophagy, mitophagy, Mitochondria, Metabolism, NAD, DNA damage, PARP, sirtuins

Suggested Citation

Kataura, Tetsushi and Sedlackova, Lucia and Otten, Elsje G. and Shapira, David and Scialo, Filippo and Stefanatos, Rhoda and Ishikawa, Kei-ichi and Kelly, George and Seranova, Elena and Sun, Congxin and Maetzel, Dorothea and Kenneth, Niall and Trushin, Sergey and Zhang, Tong and Trushina, Eugenia and Bascom, Charles C. and Tasseff, Ryan and Isfort, Robert J. and Oblong, John E. and Miwa, Satomi and Lazarou, Michael and Jaenisch, Rudolf and Imoto, Masaya and Saiki, Shinji and Papamichos-Chronakis, Manolis and Maddocks, Oliver D.K. and Sanz, Alberto and Sarkar, Sovan and Korolchuk, Viktor, Autophagy is Required for the Maintenance of NAD. Available at SSRN: https://ssrn.com/abstract=4034887 or http://dx.doi.org/10.2139/ssrn.4034887
This version of the paper has not been formally peer reviewed.

Tetsushi Kataura

Newcastle University - Biosciences Institute ( email )

Lucia Sedlackova

Newcastle University ( email )

Elsje G. Otten

University of Cambridge - MRC Laboratory of Molecular Biology ( email )

Cambridge Biomedical Campus
Francis Crick Avenue
Cambridge, CB2 0QH
United Kingdom

David Shapira

affiliation not provided to SSRN ( email )

No Address Available

Filippo Scialo

affiliation not provided to SSRN ( email )

No Address Available

Rhoda Stefanatos

University of Glasgow ( email )

Adam Smith Business School
Glasgow, G12 8LE
United Kingdom

Kei-ichi Ishikawa

affiliation not provided to SSRN ( email )

No Address Available

George Kelly

Newcastle University - Biosciences Institute ( email )

Elena Seranova

University of Birmingham ( email )

Congxin Sun

University of Birmingham ( email )

Dorothea Maetzel

Massachusetts Institute of Technology (MIT) - Whitehead Institute for Biomedical Research ( email )

455 Main Street
Cambridge, MA 02142
United States

Niall Kenneth

University of Liverpool ( email )

Chatham Street
Liverpool, L69 7ZA
United Kingdom

Sergey Trushin

affiliation not provided to SSRN ( email )

No Address Available

Tong Zhang

University of Glasgow ( email )

Adam Smith Business School
Glasgow, G12 8LE
United Kingdom

Eugenia Trushina

affiliation not provided to SSRN ( email )

No Address Available

Charles C. Bascom

The Procter and Gamble Company ( email )

Ryan Tasseff

affiliation not provided to SSRN ( email )

No Address Available

Robert J. Isfort

affiliation not provided to SSRN ( email )

No Address Available

John E. Oblong

The Procter and Gamble Company ( email )

Satomi Miwa

Newcastle University - Biosciences Institute ( email )

Michael Lazarou

Monash University ( email )

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Rudolf Jaenisch

Massachusetts Institute of Technology (MIT) - Whitehead Institute for Biomedical Research ( email )

455 Main Street
Cambridge, MA 02142
United States

Masaya Imoto

affiliation not provided to SSRN ( email )

No Address Available

Shinji Saiki

affiliation not provided to SSRN ( email )

No Address Available

Manolis Papamichos-Chronakis

University of Liverpool

Chatham Street
Liverpool, L69 7ZA
United Kingdom

Oliver D.K. Maddocks

University of Glasgow ( email )

Adam Smith Business School
Glasgow, G12 8LE
United Kingdom

Alberto Sanz

University of Glasgow ( email )

Adam Smith Business School
Glasgow, G12 8LE
United Kingdom

Sovan Sarkar

University of Birmingham - Institute of Cancer and Genomic Sciences ( email )

Edgbaston
Birminham, Birmingham B152TT
United Kingdom

Viktor Korolchuk (Contact Author)

Newcastle University - Biosciences Institute ( email )

Newcastle upon Tyne
United Kingdom

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