Autophagy promotes cell survival by maintaining NAD levels

Tetsushi Kataura, Lucia Sedlackova, Elsje G. Otten, Ruchika Kumari, David Shapira, Filippo Scialo, Rhoda Stefanatos, Kei ichi Ishikawa, George Kelly, Elena Seranova, Congxin Sun, Dorothea Maetzel, Niall Kenneth, Sergey Trushin, Tong Zhang, Eugenia Trushina, Charles C. Bascom, Ryan Tasseff, Robert J. Isfort, John E. OblongSatomi Miwa, Michael Lazarou, Rudolf Jaenisch, Masaya Imoto, Shinji Saiki, Manolis Papamichos-Chronakis, Ravi Manjithaya, Oliver D.K. Maddocks, Alberto Sanz, Sovan Sarkar, Viktor I. Korolchuk

Research output: Contribution to journalArticlepeer-review


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

Original languageEnglish (US)
Pages (from-to)2584-2598.e11
JournalDevelopmental Cell
Issue number22
StatePublished - Nov 21 2022


  • DNA damage
  • NAD
  • PARP
  • Sirtuins
  • ageing
  • autophagy
  • metabolism
  • mitochondria
  • mitophagy

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology


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