NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency.

Autor:	Sun C; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Seranova E; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Cohen MA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA., Chipara M; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Roberts J; Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Astuti D; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Palhegyi AM; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Acharjee A; 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., Sedlackova L; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK., Kataura T; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK., Otten EG; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK., Panda PK; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Lara-Reyna S; Institute of Microbiology and Infection, University of Birmingham, Birmingham B15 2TT, UK., Korsgen ME; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Kauffman KJ; 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., Huerta-Uribe A; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK., Zatyka M; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Silva LFSE; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Torresi J; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Zhang S; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA., Hughes GW; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Ward C; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Kuechler ER; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada., Cartwright D; Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Trushin S; Department of Neurology, Mayo Clinic, Rochester, MN 55901, USA., Trushina E; Department of Neurology, Mayo Clinic, Rochester, MN 55901, USA., Sahay G; Department of Pharmaceutical Sciences and Department of Biomedical Engineering, College of Pharmacy, Oregon State University, Portland, OR 97201, USA., Buganim Y; Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel., Lavery GG; Department for Biosciences, Nottingham Trent University, Nottingham NG11 8NS, UK., Gsponer J; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada., Anderson DG; 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., Frickel EM; Institute of Microbiology and Infection, University of Birmingham, Birmingham B15 2TT, UK., Rosenstock TR; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Barrett T; 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., Maddocks ODK; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK., Tennant DA; Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Wang H; The State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China., Jaenisch R; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA., Korolchuk VI; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK. Electronic address: viktor.korolchuk@newcastle.ac.uk., Sarkar S; Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: s.sarkar@bham.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 May 30; Vol. 42 (5), pp. 112372. Date of Electronic Publication: 2023 Apr 21.
DOI:	10.1016/j.celrep.2023.112372
Abstrakt:	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. Competing Interests: Declaration of interests R.J. is cofounder of Fate Therapeutics, Fulcrum Therapeutics, and Omega Therapeutics and advisor to Dewpoint Therapeutics. E.S. is founder of NMN Bio Ltd. V.I.K. is a scientific advisor for Longaevus Technologies. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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