Direct mitochondrial import of lactate supports resilient carbohydrate oxidation

Lactate is the most abundant circulating metabolic intermediate in mammals and an important energy source for many organs. To use lactate as a fuel, it must be oxidized to pyruvate for entry into the TCA cycle. It is usually described that this reaction occurs in the cytosol and requires the mitochondrial pyruvate carrier (MPC) for pyruvate transport into the mitochondria. Here, using 13C stable isotope tracing, we report that lactate can be oxidized in the heart tissue of mice even when the MPC is genetically deleted. MPC-independent lactate import and oxidation within mitochondria is dependent upon the monocarboxylate transporter 1 (MCT1/ Slc16a1). Mitochondria isolated from Mct1iCKO hearts have impaired respiration on lactate but not pyruvate. Lactate import coupled to mitochondrial lactate dehydrogenase activity functions as an electron shuttle which can produce NADH sufficient for respiration even when the TCA cycle is blocked. Cardiac-specific loss of MCT1 leads to rapid decompensation into heart failure with reduced ejection fraction in response to diverse cardiac injuries. Thus, we identify a new mitochondrial electron shuttle that enables the oxidation of lactate and is required to support cardiac energetics under stress conditions. Overall design: To understand the mechanisms of lactate metabolism during cardiac hypertrophy we subjected control and MCT1-KO mice to Ang/PE neurohormonal agonists causing myocardial hypertrophy.

乳酸（Lactate）是哺乳动物体内丰度最高的循环代谢中间产物，亦是诸多器官的重要能量来源。若要将乳酸作为燃料利用，需先将其氧化为丙酮酸，方可进入三羧酸（TCA）循环。既往研究普遍认为，该反应发生于胞质溶胶中，且需要线粒体丙酮酸载体（mitochondrial pyruvate carrier, MPC）介导丙酮酸向线粒体内的转运。本研究借助13C稳定同位素示踪技术，发现即使在基因敲除MPC的小鼠心脏组织中，乳酸仍可被氧化。不依赖MPC的乳酸线粒体摄取与氧化过程，依赖于单羧酸转运蛋白1（monocarboxylate transporter 1, MCT1/Slc16a1）。从Mct1条件性敲除（Mct1iCKO）小鼠心脏分离的线粒体，在以乳酸为底物时呼吸功能受损，但以丙酮酸为底物时则无此异常。与线粒体乳酸脱氢酶活性偶联的乳酸摄取过程可作为电子穿梭系统，即便三羧酸循环被阻断，该系统仍可产生足量NADH以支持呼吸作用。心脏特异性缺失MCT1的小鼠，在遭遇多种心脏损伤时会快速出现射血分数降低型心力衰竭失代偿。综上，本研究鉴定出一种全新的线粒体电子穿梭系统，该系统可介导乳酸氧化，并在应激条件下为心脏能量代谢提供支持。整体实验设计：为阐明心肌肥厚过程中的乳酸代谢机制，我们将对照组与MCT1基因敲除（MCT1-KO）小鼠暴露于Ang/PE神经激素激动剂中，以诱导心肌肥厚。