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 novel 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 enzymes are found in phase-separated bodies in the cytosol of cancer cells and can be assembled in vitro from purified proteins. They are 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. We provide evidence for a new multi-enzymatic complex that reprograms metabolism and prevents cellular senescence.
Igelmann, Sebastian and Lessard, Frédéric and Fernandez-Ruiz, Ana and Bouchard, Jacob and Uchenunu, Oro and Rowell, Marie-Camille and Lopes-Paciência, Stéphane and Papadopoli, David and Fouillen, Aurélien and Ponce, Katja Julissa and Huot, Geneviève and Mignacca, Lian and Benfdil, Mehdi and Kalegari, Paloma and Wahba, Haytham M and Pencik, Jan and Vuong, Nhung and Quenneville, Jordan and Bourdeau, Véronique and Hulea, Laura and Gagnon, Etienne and Kenner, Lukas and Moriggl, Richard and Nanci, Antonio and Pollak, Michael and Omichinski, James and Topisitrovic, Ivan and Ferbeyre, Gerardo, A Hydride Transfer Complex Reprograms NAD Metabolism Preventing Senescence. Available at SSRN: https://ssrn.com/abstract=3753808 or http://dx.doi.org/10.2139/ssrn.3753808
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