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. 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，同时亦是多种器官的重要能量供体。若要将乳酸作为燃料加以利用，需先将其氧化为丙酮酸以进入三羧酸循环（TCA cycle）。既往主流观点认为，该反应发生于细胞质中，且需要依赖线粒体丙酮酸载体（MPC）将丙酮酸转运至线粒体。本研究借助13C稳定同位素示踪技术证实，即便在基因层面敲除MPC的小鼠心肌组织中，乳酸仍可发生氧化反应。线粒体中不依赖MPC的乳酸摄取与氧化过程，依赖于单羧酸转运蛋白1（MCT1/Slc16a1）。从Mct1iCKO小鼠心脏分离得到的线粒体，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，该系统仍可产生足够支撑呼吸作用的还原型烟酰胺腺嘌呤二核苷酸（NADH）。心肌特异性缺失MCT1会导致小鼠在遭遇多种心脏损伤时，快速进展为射血分数降低型心力衰竭。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，并在应激状态下维持心脏能量代谢稳态。为阐明心肌肥厚过程中的乳酸代谢机制，本研究将野生型对照与MCT1-KO小鼠暴露于血管紧张素/苯肾上腺素（Ang/PE）神经激素激动剂以诱导心肌肥厚。