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Gewählte Publikation:

Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2021

AutorInnen: Igelmann, S; Lessard, F; Uchenunu, O; Bouchard, J; Fernandez-Ruiz, A; Rowell, MC; Lopes-Paciencia, S; Papadopoli, D; Fouillen, A; Ponce, KJ; Huot, G; Mignacca, L; Benfdil, M; Kalegari, P; Wahba, HM; Pencik, J; Vuong, N; Quenneville, J; Guillon, J; Bourdeau, V; Hulea, L; Gagnon, E; Kenner, L; Moriggl, R; Nanci, A; Pollak, MN; Omichinski, JG; Topisirovic, I; Ferbeyre, G

Titel: A hydride transfer complex reprograms NAD metabolism and bypasses senescence.

Quelle: Mol Cell. 2021; 81(18):3848-3865.e19



Autor/innen der Vetmeduni Vienna:

Kenner Lukas
Moriggl Richard

Beteiligte Vetmed-Organisationseinheiten
Institut für Tierzucht und Genetik, Abteilung für Funktionelle Krebsgenomik
Institut für Pathologie, Abteilung für Labortierpathologie


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.Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.


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