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.

代谢重连和氧化还原平衡在癌症中发挥着关键作用。细胞衰老是癌细胞发生肿瘤的一个障碍，但其机制尚不清楚。我们报告了一种多酶复合物，它通过将还原当量从 NADH 转移到 NADP ⁺来重新编程 NAD 代谢。该氢化物转移复合物 (HTC) 由苹果酸脱氢酶 1、苹果酸酶 1 和胞质丙酮酸羧化酶组装而成。HTC 存在于癌细胞或缺氧细胞的细胞质中的相分离体中，并且可以在体外与重组蛋白组装。HTC 在衰老细胞中受到抑制，但由 p53 失活诱导。HTC 酶在小鼠和人类前列腺癌模型中高度表达，它们的失活会引发衰老。HTC 的外源表达足以绕过衰老，从复合物 I 抑制剂中拯救细胞，并与致癌 RAS 合作转化原代细胞。总而言之，我们为一种新的多酶复合物提供了证据，该复合物可以重新编程新陈代谢并克服细胞衰老。