Cell Reports (May 2023)
NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency
- Congxin Sun,
- Elena Seranova,
- Malkiel A. Cohen,
- Miruna Chipara,
- Jennie Roberts,
- Dewi Astuti,
- Adina M. Palhegyi,
- Animesh Acharjee,
- Lucia Sedlackova,
- Tetsushi Kataura,
- Elsje G. Otten,
- Prashanta K. Panda,
- Samuel Lara-Reyna,
- Miriam E. Korsgen,
- Kevin J. Kauffman,
- Alejandro Huerta-Uribe,
- Malgorzata Zatyka,
- Luiz F.S.E. Silva,
- Jorge Torresi,
- Shupei Zhang,
- Georgina W. Hughes,
- Carl Ward,
- Erich R. Kuechler,
- David Cartwright,
- Sergey Trushin,
- Eugenia Trushina,
- Gaurav Sahay,
- Yosef Buganim,
- Gareth G. Lavery,
- Joerg Gsponer,
- Daniel G. Anderson,
- Eva-Maria Frickel,
- Tatiana R. Rosenstock,
- Timothy Barrett,
- Oliver D.K. Maddocks,
- Daniel A. Tennant,
- Haoyi Wang,
- Rudolf Jaenisch,
- Viktor I. Korolchuk,
- Sovan Sarkar
Affiliations
- Congxin Sun
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Elena Seranova
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Malkiel A. Cohen
- Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
- Miruna Chipara
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Jennie Roberts
- Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Dewi Astuti
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Adina M. Palhegyi
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Animesh Acharjee
- Institute of Cancer and Genomic Sciences, Centre for Computational Biology, University of Birmingham, Birmingham B15 2TT, UK; Institute of Translational Medicine, University Hospitals Birmingham, NHS Foundation Trust, Birmingham B15 2TT, UK; NIHR Surgical Reconstruction and Microbiology Research Centre, University Hospital Birmingham, Birmingham B15 2WB, UK
- Lucia Sedlackova
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
- Tetsushi Kataura
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
- Elsje G. Otten
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
- Prashanta K. Panda
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Samuel Lara-Reyna
- Institute of Microbiology and Infection, University of Birmingham, Birmingham B15 2TT, UK
- Miriam E. Korsgen
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Kevin J. Kauffman
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
- Alejandro Huerta-Uribe
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
- Malgorzata Zatyka
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Luiz F.S.E. Silva
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Jorge Torresi
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Shupei Zhang
- Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
- Georgina W. Hughes
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Carl Ward
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Erich R. Kuechler
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- David Cartwright
- Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Sergey Trushin
- Department of Neurology, Mayo Clinic, Rochester, MN 55901, USA
- Eugenia Trushina
- Department of Neurology, Mayo Clinic, Rochester, MN 55901, USA
- Gaurav Sahay
- Department of Pharmaceutical Sciences and Department of Biomedical Engineering, College of Pharmacy, Oregon State University, Portland, OR 97201, USA
- Yosef Buganim
- Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
- Gareth G. Lavery
- Department for Biosciences, Nottingham Trent University, Nottingham NG11 8NS, UK
- Joerg Gsponer
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- Daniel G. Anderson
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Eva-Maria Frickel
- Institute of Microbiology and Infection, University of Birmingham, Birmingham B15 2TT, UK
- Tatiana R. Rosenstock
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Timothy Barrett
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Department of Endocrinology, Birmingham Women’s and Children’s Hospital, Steelehouse Lane, Birmingham B4 6NH, UK
- Oliver D.K. Maddocks
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
- Daniel A. Tennant
- Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
- Haoyi Wang
- The State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
- Rudolf Jaenisch
- Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
- Viktor I. Korolchuk
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK; Corresponding author
- Sovan Sarkar
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 5
p. 112372
Abstract
Summary: Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5−/−) human embryonic stem cells (hESCs), from which we established a human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5−/− neurons exhibit basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes is found to trigger cell death via mitochondrial depolarization in ATG5−/− neurons. Boosting intracellular NAD levels improves cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5−/− neurons. Our findings elucidate a mechanistic link between autophagy deficiency and neuronal cell death that can be targeted for therapeutic interventions in neurodegenerative and lysosomal storage diseases associated with autophagic defect.
