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 ZhangGeorgina 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageAmerican English
Article number112372
JournalCell Reports
Volume42
Issue number5
DOIs
StatePublished - 30 May 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

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

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