A hydride transfer complex reprograms NAD metabolism and bypasses senescence

Mol Cell. 2021 Sep 16;81(18):3848-3865.e19. doi: 10.1016/j.molcel.2021.08.028.

Authors

Sebastian Igelmann¹, Frédéric Lessard², Oro Uchenunu³, Jacob Bouchard², Ana Fernandez-Ruiz⁴, Marie-Camille Rowell⁴, Stéphane Lopes-Paciencia⁴, David Papadopoli⁵, Aurélien Fouillen⁶, Katia Julissa Ponce⁷, Geneviève Huot², Lian Mignacca², Mehdi Benfdil², Paloma Kalegari¹, Haytham M Wahba⁸, Jan Pencik⁹, Nhung Vuong⁴, Jordan Quenneville¹⁰, Jordan Guillon⁴, Véronique Bourdeau², Laura Hulea¹¹, Etienne Gagnon¹², Lukas Kenner¹³, Richard Moriggl¹⁴, Antonio Nanci⁷, Michael N Pollak¹⁵, James G Omichinski², Ivan Topisirovic¹⁶, Gerardo Ferbeyre¹⁷

Affiliations

¹ CRCHUM, 900 Saint-Denis St, Montréal, QC H2X 0A9, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.
² Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.
³ Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC H3T1E2, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H4A3T2, Canada.
⁴ CRCHUM, 900 Saint-Denis St, Montréal, QC H2X 0A9, Canada.
⁵ Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC H3T1E2, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A3T2, Canada.
⁶ Faculté de médecine dentaire, Université de Montréal, Montréal, QC H3C 3J7, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.
⁷ Faculté de médecine dentaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.
⁸ Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62521, Egypt; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.
⁹ Department of Pathology, Medical University of Vienna, Vienna, Austria; Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Center for Biomarker Research in Medicine, 8010 Graz, Austria.
¹⁰ Institut de recherche en immunologie et en cancérologie (IRIC), Université de Montréal, Montréal, QC H3C 3J7, Canada.
¹¹ Maisonneuve-Rosemont Hospital Research Centre, Montréal, QC H1T 2M4, Canada, Département de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
¹² Institut de recherche en immunologie et en cancérologie (IRIC), Université de Montréal, Montréal, QC H3C 3J7, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H3C 3J7, Canada.
¹³ Department of Pathology, Medical University of Vienna, Vienna, Austria; Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria; Christian Doppler Laboratory for Applied Metabolomics, Vienna, Austria; CBmed GmbH - Center for Biomarker Research in Medicine, Graz, Styria, Austria.
¹⁴ Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
¹⁵ Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC H3T1E2, Canada.
¹⁶ Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC H3T1E2, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H4A3T2, Canada; Department of Biochemistry, McGill University, Montreal, QC H4A 3T2, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A3T2, Canada. Electronic address: ivan.topisirovic@mcgill.ca.
¹⁷ CRCHUM, 900 Saint-Denis St, Montréal, QC H2X 0A9, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada. Electronic address: g.ferbeyre@umontreal.ca.

PMID: 34547241
DOI: 10.1016/j.molcel.2021.08.028

Abstract

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.

Keywords: MDH1; ME1; NAD; NADPH; PC; cellular senescence; hypoxia; metabolon; mitochondrial dysfunction; p53.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging / metabolism
Aging / physiology
Animals
Cell Line, Tumor
Cellular Senescence / genetics
Cellular Senescence / physiology*
Cytosol
Glucose / metabolism
Humans
Hydrogen / chemistry
Hydrogen / metabolism
Malate Dehydrogenase / metabolism
Male
Mice
Mice, Inbred NOD
Mice, Transgenic
NAD / metabolism*
NAD / physiology
Oxidation-Reduction
Pyruvate Carboxylase / metabolism
Pyruvic Acid / metabolism

Substances

NAD
Hydrogen
Pyruvic Acid
Malate Dehydrogenase
malate dehydrogenase (decarboxylating)
Pyruvate Carboxylase
Glucose

Grants and funding

I 4157/FWF_/Austrian Science Fund FWF/Austria