Cell Metab. 2021 Mar 2;33(3):629-648.e10. doi: 10.1016/j.cmet.2020.12.003. | PubMed

Ahmad A Cluntun¹, Rachit Badolia², Sandra Lettlova¹, K Mark Parnell³, Thirupura S Shankar², Nikolaos A Diakos², Kristofor A Olson¹, Iosif Taleb², Sean M Tatum⁴, Jordan A Berg¹, Corey N Cunningham¹, Tyler Van Ry⁵, Alex J Bott¹, Aspasia Thodou Krokidi², Sarah Fogarty⁶, Sophia Skedros², Wojciech I Swiatek¹, Xuejing Yu⁷, Bai Luo⁸, Shannon Merx³, Sutip Navankasattusas², James E Cox⁵, Gregory S Ducker¹, William L Holland⁴, Stephen H McKellar⁹, Jared Rutter¹⁰, Stavros G Drakos¹¹

1. Department of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA.
2. Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA.
3. Vettore Biosciences, 1700 Owens Street Suite 515, San Francisco, CA 94158, USA.
4. Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT 84112, USA.
5. Department of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA; Metabolomics, Proteomics and Mass Spectrometry Core Facility, University of Utah, Salt Lake City, UT 84112, USA.
6. Department of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA; Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
7. University of Utah, School of Medicine, Salt Lake City, UT 84132, USA; Division of Cardiothoracic Surgery, Department of Surgery, Salt Lake City, UT 84132, USA.
8. Drug Discovery Core Facility, University of Utah, Salt Lake City, UT 84112, USA.
9. University of Utah, School of Medicine, Salt Lake City, UT 84132, USA; Division of Cardiothoracic Surgery, Department of Surgery, Salt Lake City, UT 84132, USA; U.T.A.H. (Utah Transplant Affiliated Hospitals) Cardiac Transplant Program: University of Utah Healthcare and School of Medicine, Intermountain Medical Center, Salt Lake VA (Veterans Affairs) Health Care System, Salt Lake City, UT, USA.
10. Department of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA; Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. Electronic address: rutter@biochem.utah.edu.
11. Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA; U.T.A.H. (Utah Transplant Affiliated Hospitals) Cardiac Transplant Program: University of Utah Healthcare and School of Medicine, Intermountain Medical Center, Salt Lake VA (Veterans Affairs) Health Care System, Salt Lake City, UT, USA. Electronic address: stavros.drakos@hsc.utah.edu.

Abstract

The metabolic rewiring of cardiomyocytes is a widely accepted hallmark of heart failure (HF). These metabolic changes include a decrease in mitochondrial pyruvate oxidation and an increased export of lactate. We identify the mitochondrial pyruvate carrier (MPC) and the cellular lactate exporter monocarboxylate transporter 4 (MCT4) as pivotal nodes in this metabolic axis. We observed that cardiac assist device-induced myocardial recovery in chronic HF patients was coincident with increased myocardial expression of the MPC. Moreover, the genetic ablation of the MPC in cultured cardiomyocytes and in adult murine hearts was sufficient to induce hypertrophy and HF. Conversely, MPC overexpression attenuated drug-induced hypertrophy in a cell-autonomous manner. We also introduced a novel, highly potent MCT4 inhibitor that mitigated hypertrophy in cultured cardiomyocytes and in mice. Together, we find that alteration of the pyruvate-lactate axis is a fundamental and early feature of cardiac hypertrophy and failure.

Presented By Ahmad Cluntun | ORCID iD