MCT1-dependent mitochondrial lactate import sustains cardiac metabolism

The heart possesses a dynamic capacity to oxidize a variety of fuels, including glucose and lactate, to meet its energetic demands under diverse dietary, exertion and injury stressors 1 . Oxidation of carbohydrate substrates is thought to converge on the cytosolic generation of pyruvate, which is transported by the mitochondrial pyruvate carrier (MPC) for entry into the tricarboxylic acid cycle 2 . Here we find that glucose-derived carbon is oxidized in mouse myocardium even when the MPC is genetically ablated. Using genetic and pharmacological tools, we demonstrate that lactate monocarboxylate transporter 1 (MCT1, encoded by Slc16a1 ) is required for the oxidation of glucose carbon by MPC-deficient myocardium. We further observe that MCT1, traditionally localized to the plasma membrane, also resides in the inner mitochondrial membrane of mouse and human cardiomyocytes. Together with matrix-localized LDHB, MCT1 enables mitochondrial lactate conversion to pyruvate and NADH, directly fueling the electron transport chain. Loss of MCT1 impairs lactate oxidation, disrupts metabolic flexibility and accelerates the development of heart failure with increased mortality after hyperactivation of the neurohormonal axis or ischemia–reperfusion injury. Thus, the existence of a parallel lactate-based pathway for carbohydrate oxidation can sustain cardiac energetics and maintain myocardial structure and function under diverse stress conditions.