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.