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

doi:10.1016/j.celrep.2023.112372

NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency

Cell Rep. 2023 May 30;42(5):112372. doi: 10.1016/j.celrep.2023.112372. Epub 2023 Apr 21.

Authors

Congxin Sun¹, Elena Seranova¹, Malkiel A Cohen², Miruna Chipara¹, Jennie Roberts³, Dewi Astuti¹, Adina M Palhegyi¹, Animesh Acharjee⁴, Lucia Sedlackova⁵, Tetsushi Kataura⁵, Elsje G Otten⁵, Prashanta K Panda¹, Samuel Lara-Reyna⁶, Miriam E Korsgen¹, Kevin J Kauffman⁷, Alejandro Huerta-Uribe⁸, Malgorzata Zatyka¹, Luiz F S E Silva¹, Jorge Torresi¹, Shupei Zhang², Georgina W Hughes¹, Carl Ward¹, Erich R Kuechler⁹, David Cartwright³, Sergey Trushin¹⁰, Eugenia Trushina¹⁰, Gaurav Sahay¹¹, Yosef Buganim¹², Gareth G Lavery¹³, Joerg Gsponer⁹, Daniel G Anderson¹⁴, Eva-Maria Frickel⁶, Tatiana R Rosenstock¹, Timothy Barrett¹⁵, Oliver D K Maddocks⁸, Daniel A Tennant³, Haoyi Wang¹⁶, Rudolf Jaenisch¹⁷, Viktor I Korolchuk¹⁸, Sovan Sarkar¹⁹

Affiliations

¹ Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
² Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
³ Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
⁴ 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.
⁵ Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.
⁶ Institute of Microbiology and Infection, University of Birmingham, Birmingham B15 2TT, UK.
⁷ 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.
⁸ Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
⁹ Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
¹⁰ Department of Neurology, Mayo Clinic, Rochester, MN 55901, USA.
¹¹ Department of Pharmaceutical Sciences and Department of Biomedical Engineering, College of Pharmacy, Oregon State University, Portland, OR 97201, USA.
¹² Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
¹³ Department for Biosciences, Nottingham Trent University, Nottingham NG11 8NS, UK.
¹⁴ 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.
¹⁵ 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.
¹⁶ The State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China.
¹⁷ Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
¹⁸ Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK. Electronic address: viktor.korolchuk@newcastle.ac.uk.
¹⁹ 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.

Abstract

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.

Keywords: CP: Cell biology; CP: Metabolism; NAD; NADases; NAM; NMN; NR; autophagy; cell death; cell survival, human embryonic stem cell-derived neurons; mitochondria; nicotinamide; nicotinamide adenine dinucleotide; nicotinamide mononucleotide; nicotinamide riboside.

Publication types

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

MeSH terms

Autophagy
Humans
Mitochondria / metabolism
NAD* / metabolism
Neurons / metabolism
Niacinamide / metabolism
Nicotinamide Mononucleotide* / metabolism

Substances

NAD
Nicotinamide Mononucleotide
Niacinamide

Abstract

Publication types

MeSH terms

Substances

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