MCT1-dependent mitochondrial lactate import sustains cardiac metabolism
Year: 2026
Type: article
Abstract: Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC). Using 13 C stable isotope tracing, we demonstrated that lactate is oxidized in the myocardial tissue of mice even when the MPC is genetically deleted. This MPC-independent lactate import and mitochondrial oxidation is dependent upon the monocarboxylate transporter 1 (MCT1/ Slc16a1 ). Mitochondria isolated from the myocardium without MCT1 exhibit a specific defect in mitochondrial lactate, but not pyruvate, metabolism. The import and subsequent mitochondrial oxidation of lactate by mitochondrial lactate dehydrogenase (LDH) acts as an electron shuttle, generating sufficient NADH to support respiration even when the TCA cycle is disrupted. In response to diverse cardiac insults, animals with hearts lacking MCT1 undergo rapid progression to heart failure with reduced ejection fraction. Thus, the mitochondrial import and oxidation of lactate enables carbohydrate entry into the TCA cycle to sustain cardiac energetics and maintain myocardial structure and function under stress conditions.
Source: Nature
Authors: Ahmad A. Cluntun, Joseph R. Visker, Jesse N. Velasco-Silva, James Carrington, Luis Cedeño-Rosario, Giulia C. Napoli, Ji Eon Kim, Thirupura S. Shankar, Marisa J. Brothwell, Rana Hamouche, Álvaro J. Narbona-Pérez, Jing Ling, Ashish G. Toshniwal, Hayden K. Low, Corey N. Cunningham, David R. Eberhardt, Jing Li, Claire E. Stanley, Queren A. Alcantara, Tarun Yadav, Ryan L. Maves, Wojciech I. Swiatek, Nicholas A. Offei, Bhavya Blaze, Sumangala P. Shetty, Dipayan Chaudhuri, Tingting Hong, Jeffery D. Rothstein, Deborah M. Muoio, Joao A. Paulo, Steven P. Gygi, Eleni Tseliou, Sutip Navankasattusas, James E. Cox, Katsuhiko Funai, Stavros G. Drakos, Jared Rutter, Gregory S. Ducker
Institutions: Rutgers, The State University of New Jersey, University of Utah, Wake Forest University Health Sciences, Wake Forest University, Sejong University, Huntsman Cancer Institute, Johns Hopkins University, Duke University, Harvard University, Intermountain Medical Center, VA Salt Lake City Healthcare System, University of Utah Health Care, Howard Hughes Medical Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Awards: Impact and regulation of lactate metabolism in the heart, Clinical and Metabolic Signature of Recovered Myocardium in Human Heart Failure, PE in modulation of energy flux through OXPHOS, Lands cycle and skeletal muscle insulin action, Mechanisms of metabolite signaling, Mitochondrial membrane lipids and respiratory efficiency, Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Mitral Regurgitation, Impact and regulation of lactate metabolism in the heart, Regulation of the mitochondrial calcium uniporter, Interdisciplinary Training Program in Metabolism, Metabolic Impact and Mechanism of Enhanced Mitochondrial Calcium Uptake in Mitochondrial Cardiomyopathies, LOOH-induced muscle atrophy with age, Cancer Center Support Grant, Training in Cardiovascular Research, Metabolite Transport Modulation to Mitigate Ischemic-Reperfusion Injury
OpenAlex ID: W4403257866