A hydride transfer complex reprograms NAD metabolism and bypasses senescence
Open accessAbstract
Metabolic rewiring and redox balance play pivotal roles in cancer. Cellular senescence is a barrier for tumorigenesis circumvented in cancer cells by poorly understood mechanisms. We report a multi-enzymatic complex that reprograms NAD metabolism by transferring reducing equivalents from NADH to NADP+. This hydride transfer complex (HTC) is assembled by malate dehydrogenase 1, malic enzyme 1, and cytosolic pyruvate carboxylase. HTC is found in phase-separated bodies in the cytosol of cancer or hypoxic cells and can be assembled in vitro with recombinant proteins. HTC is repressed in senescent cells but induced by p53 inactivation. HTC enzymes are highly expressed in mouse and human prostate cancer models, and their inactivation triggers senescence. Exogenous expression of HTC is sufficient to bypass senescence, rescue cells from complex I inhibitors, and cooperate with oncogenic RAS to transform primary cells. Altogether, we provide evidence for a new multi-enzymatic complex that reprograms metabolism and overcomes cellular senescence.
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Mitochondrial dysfunction can be a direct inducer of senescence.
“mitochondrial dysfunction can be a direct inducer of senescence 51,52 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [52]
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References 77 · Cited by 60
- Authors
- Igelmann, S., Lessard, F., Uchenunu, O., Bouchard, J., Fernandez-Ruiz, A., Rowell, M.-C., Lopes-Paciencia, S., Papadopoli, D., Fouillen, A., Ponce, K. J., Huot, G., Mignacca, L., Benfdil, M., Kalegari, P., Wahba, H. M., Pencik, J., Vuong, N., Quenneville, J., Guillon, J., Bourdeau, V., Hulea, L., Gagnon, E., Kenner, L., Moriggl, R., Nanci, A., Pollak, M. N., Omichinski, J. G., Topisirovic, I., & Ferbeyre, G.
- Affiliations
- Université de Montréal (CA)
- Jewish General Hospital (CA)
- Beni-Suef University (EG)
- Institute for Research in Immunology and Cancer (CA)
- Hôpital Maisonneuve-Rosemont (CA)
- University of Veterinary Medicine Vienna (AT)
- Centre Hospitalier de l’Université de Montréal (CA)
- Corresponding author
- Ferbeyre, Gerardo
- ORCID
- Igelmann, Sebastian
- Lessard, Frédéric
- Uchenunu, Oro
- Bouchard, Jacob
- Papadopoli, David
- Fouillen, Aurélien
- Mignacca, Lian
- Benfdil, Mehdi
- Wahba, Haytham M.
- Vuong, Nhung
- Quenneville, Jordan
- Guillon, Jordan
- Bourdeau, Véronique
- Hulea, Laura
- Kenner, Lukas
- Moriggl, Richard
- Nanci, Antonio
- Omichinski, James G.
- Ferbeyre, Gerardo
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 81
- Issue
- 18
- Pages
- 3848-3865.e19
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W3199921626
- Cited by
- 60
- References
- 77
- Citations by year
- 2026: 13 · 2025: 8 · 2024: 16 · 2023: 12 · 2022: 8 · 2021: 3
- FWCI
- 6.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 380 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bundesministerium für Digitalisierung und Wirtschaftsstandort
- Terry Fox Research Institute (239585)
- Canadian Cancer Society Research Institute (706773)
- FRQS
- Institut Du Cancer de Montréal
- Bundesministerium für Verkehr, Innovation und Technologie
- Canadian Imperial Bank of Commerce
- Steirische Wirtschaftsförderungsgesellschaft
- National Foundation for Science and Technology Development
- NSERC
- Canadian Institutes of Health Research (MOP-133726, CIHR MOP-110972, MOP11151, PJT-153217, MFE-171312, MOP130414)
- Österreichischen Akademie der Wissenschaften
- Austrian Science Fund (P26011, SFB-F06107, SFB-F4707)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- NAD+ metabolism, cellular senescence, MDH1, ME1, p53 inactivation, prostate cancer, complex I inhibitors, cancer metabolism, metabolic reprogramming, redox homeostasis
- MeSH terms
- Aging, Animals, Cytosol, Glucose, Humans, Hydrogen, Malate Dehydrogenase, Male, Mice, Transgenic, NAD, Oxidation-Reduction, Pyruvate Carboxylase, Mice, Inbred NOD, Cellular Senescence, Pyruvic Acid, Cell Line, Tumor, Mice
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