Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation.

长期以来，乳酸一直被认为是一种细胞废物。然而，我们发现，随着细胞外乳酸的积累，它也进入线粒体基质并刺激线粒体电子传递链 （ETC） 活性。由此产生的线粒体 ATP 合成增加抑制了糖酵解并增加了丙酮酸和/或其他呼吸底物的利用率。乳酸增加氧化磷酸化的能力不取决于其代谢。L-和 D-乳酸均能有效增强 ETC 活性和抑制糖酵解。此外，未代谢的 D-乳酸选择性诱导线粒体氧化磷酸化以 ATP 依赖性方式可逆地抑制癌细胞系和增殖原代细胞中的有氧糖酵解，并使细胞能够在呼吸依赖性生物能量底物上生长。在原代 T 细胞中，D-乳酸增强了细胞增殖和效应功能。总之，这些发现表明乳酸是线粒体氧化磷酸化抑制葡萄糖发酵能力的关键调节因子。