Résumé
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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•PC, MDH1, and ME1 form a hydride transfer complex (HTC) in the cytoplasm•HTC transfers reducing equivalents from NADH to NADP+•HTC promotes tumor formation by bypassing senescence•HTC confers fitness to cells under hypoxia or mitochondrial dysfunction
Igelmann et al. identified a hydride transfer complex (HTC) that drives metabolic reprogramming to overcome senescence and induces tumorigenesis. HTC consists of pyruvate carboxylase, malate dehydrogenase 1 and malic enzyme 1 and catalyzes a metabolic cycle whose net effect is to supply NAD+ and NADPH, which are key cofactors for many essential metabolic reactions.