@article{c690c3406da44bf7a2c83ed7df9536e4,
title = "Autophagy promotes cell survival by maintaining NAD levels",
abstract = "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.",
keywords = "DNA damage, NAD, PARP, Sirtuins, ageing, autophagy, metabolism, mitochondria, mitophagy",
author = "Tetsushi Kataura and Lucia Sedlackova and Otten, {Elsje G.} and Ruchika Kumari and David Shapira and Filippo Scialo and Rhoda Stefanatos and Ishikawa, {Kei ichi} and George Kelly and Elena Seranova and Congxin Sun and Dorothea Maetzel and Niall Kenneth and Sergey Trushin and Tong Zhang and Eugenia Trushina and Bascom, {Charles C.} and Ryan Tasseff and Isfort, {Robert J.} and Oblong, {John E.} and Satomi Miwa and Michael Lazarou and Rudolf Jaenisch and Masaya Imoto and Shinji Saiki and Manolis Papamichos-Chronakis and Ravi Manjithaya and Maddocks, {Oliver D.K.} and Alberto Sanz and Sovan Sarkar and Korolchuk, {Viktor I.}",
note = "Funding Information: We are grateful to B. Carroll, Y. Rabanal-Ruiz, F. Urselli, E. Bennet, and A.M. Palhegyi for technical assistance; R. Roduit and A. Corsinotti for providing pSin-TRE-GW-3xHa-puroR-mRFP-GFP-LC3 construct; N. Watson for electron microscopy; G. Nelson and Newcastle Bioimaging Unit for imaging assistance; H. Salmonowicz for graphical design; M. Coleman and S. Chakrabortee for manuscript feedback; and ChromaDex, Inc. for providing NR. This study was supported by Fellowships from Uehara Memorial Foundation, the International Medical Research Foundation and JSPS (19J12969) to T.K.; Sir Henry Wellcome Postdoctoral Fellowship to R.S. (204715/Z/16/Z); grants from NIH RF1 (AG 55549-06) and UG3/UH3NS (113776-2) to E.T.; grants from NIH (R37HD045022, R01-NS088538, and R01-MH104610), Emerald Foundation, LEO Foundation (L18015), and St. Baldrick's Foundation to R.J.; CRUK Fellowship (C53309/A19702) to O.D.K.M.; JSPS (18KK0242) to S. Saiki, K.-i.I. M.I. and V.I.K.; NHMRC (GNT1106471 and GNT1160315) and Australian Research Council (FT1601100063, DP200100347) to M.L.; Wellcome Trust Senior Fellowship to A.S.; Wellcome Trust (109626/Z/15/Z, 1516ISSFFEL10), LifeArc (P2019-0004), UKIERI (2016-17-0087), and Birmingham Fellowship to S. Sarkar; BBSRC (BB/M023389/1) and MRC studentship (BH174490) to V.I.K.; and BBSRC (BB/R008167/2) to A.S. and V.I.K. T.K. and L.S. developed experimental approaches and methodology and performed majority of experiments. E.G.O. initiated the project and established methodology. L.S. performed metabolomics. R.K. and D.S. performed yeast experiments. E.S. C.S. and D.M. performed stem cell experiments. F.S. R.S. K.-i.I. G.K. N.K. S.T. T.Z. E.T. C.C.B. R.T. R.J.I. J.E.O. S.M. R.M. O.D.K.M. A.S. S. Sarkar, and V.I.K. performed experiments, provided tools, or analyzed data. T.K. K.-i.I. M.L. R.J. M.I. S. Saiki, M.P.-C. O.D.K.M. A.S. S. Sarkar, and V.I.K. acquired funding; S. Sarkar and V.I.K. conceptualized and administered the project and wrote the manuscript with help from all authors. C.C.B. R.T. R.J.I. and J.E.O. are employees of The Procter & Gamble Company, USA. R.J. is the cofounder of Fate Therapeutics, Fulcrum Therapeutics, and Omega Therapeutics and adviser to Dewpoint Therapeutics. E.S. is founder of NMN Bio. V.I.K. is a Scientific Advisor for Longaevus Technologies. We support inclusive, diverse, and equitable conduct of research. Funding Information: We are grateful to B. Carroll, Y. Rabanal-Ruiz, F. Urselli, E. Bennet, and A.M. Palhegyi for technical assistance; R. Roduit and A. Corsinotti for providing pSin-TRE-GW-3xHa-puroR-mRFP-GFP-LC3 construct; N. Watson for electron microscopy; G. Nelson and Newcastle Bioimaging Unit for imaging assistance; H. Salmonowicz for graphical design; M. Coleman and S. Chakrabortee for manuscript feedback; and ChromaDex, Inc. for providing NR. This study was supported by Fellowships from Uehara Memorial Foundation , the International Medical Research Foundation and JSPS ( 19J12969 ) to T.K.; Sir Henry Wellcome Postdoctoral Fellowship to R.S. ( 204715/Z/16/Z ); grants from NIH RF1 ( AG 55549-06 ) and UG3/UH3NS ( 113776-2 ) to E.T.; grants from NIH ( R37HD045022 , R01-NS088538 , and R01-MH104610 ), Emerald Foundation , LEO Foundation ( L18015 ), and St. Baldrick's Foundation to R.J.; CRUK Fellowship ( C53309/A19702 ) to O.D.K.M.; JSPS ( 18KK0242 ) to S. Saiki, K.-i.I., M.I., and V.I.K.; NHMRC ( GNT1106471 and GNT1160315 ) and Australian Research Council ( FT1601100063 , DP200100347 ) to M.L.; Wellcome Trust Senior Fellowship to A.S.; Wellcome Trust ( 109626/Z/15/Z , 1516ISSFFEL10 ), LifeArc ( P2019-0004 ), UKIERI ( 2016-17-0087 ), and Birmingham Fellowship to S. Sarkar; BBSRC ( BB/M023389/1 ) and MRC studentship ( BH174490 ) to V.I.K.; and BBSRC ( BB/R008167/2 ) to A.S. and V.I.K. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = nov,
day = "21",
doi = "10.1016/j.devcel.2022.10.008",
language = "English (US)",
volume = "57",
pages = "2584--2598.e11",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "22",
}