Mitochondrial pyruvate carriers are required for myocardial stress adaptation
| Autor: | Shannon Hitchcock, Alvin D. Pewa, Eric B. Taylor, Lawrence R. Gray, Jonas Maximilian Marx, Isabelle Robillard-Frayne, Thomas Cassier, Rose McGlauflin, Fariba Tayyari, Paul V. Taufalele, Lauren Haff, Lynn M. Teesch, Jamie Soto, Peter A. Crawford, Kathy Zimmerman, Trevor Funari, Jennifer L. Stueve, Robert M. Weiss, Christine Des Rosiers, E. Douglas Lewandowski, E. Dale Abel, Yuan Zhang, James E. Cox, Adam J. Rauckhorst, Kevin D. Lin, William J. Kutschke, Patrycja Puchalska, Jared Rutter, Jesse D. Cochran, Kevin M. Kato |
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| Rok vydání: | 2020 |
| Předmět: |
Cardiomyopathy
Dilated medicine.medical_specialty Endocrinology Diabetes and Metabolism Anion Transport Proteins Cardiomegaly Constriction Pathologic In Vitro Techniques Mitochondrion Diet High-Fat Mitochondrial Membrane Transport Proteins Mitochondria Heart Article Mice chemistry.chemical_compound Cytosol Stress Physiological Physiology (medical) Internal medicine Pyruvic Acid Internal Medicine medicine Animals Myocytes Cardiac Glycolysis Heart metabolism Mice Knockout Pressure overload Glycogen Chemistry Myocardium Cell Biology Metabolism Adaptation Physiological Citric acid cycle Endocrinology Echocardiography Diet Ketogenic Homeostasis |
| Zdroj: | Nature metabolism |
| ISSN: | 2522-5812 |
| DOI: | 10.1038/s42255-020-00288-1 |
| Popis: | In addition to fatty acids, glucose and lactate are important myocardial substrates under physiologic and stress conditions. They are metabolized to pyruvate, which enters mitochondria via the mitochondrial pyruvate carrier (MPC) for citric acid cycle metabolism. In the present study, we show that MPC-mediated mitochondrial pyruvate utilization is essential for the partitioning of glucose-derived cytosolic metabolic intermediates, which modulate myocardial stress adaptation. Mice with cardiomyocyte-restricted deletion of subunit 1 of MPC (cMPC1−/−) developed age-dependent pathologic cardiac hypertrophy, transitioning to a dilated cardiomyopathy and premature death. Hypertrophied hearts accumulated lactate, pyruvate and glycogen, and displayed increased protein O-linked N-acetylglucosamine, which was prevented by increasing availability of non-glucose substrates in vivo by a ketogenic diet (KD) or a high-fat diet, which reversed the structural, metabolic and functional remodelling of non-stressed cMPC1−/− hearts. Although concurrent short-term KDs did not rescue cMPC1−/− hearts from rapid decompensation and early mortality after pressure overload, 3 weeks of a KD before transverse aortic constriction was sufficient to rescue this phenotype. Together, our results highlight the centrality of pyruvate metabolism to myocardial metabolism and function. Metabolic substrate partitioning underlies myocardial homeostatic capacity and adaptation to stress. Zhang et al. show that decreasing mitochondrial pyruvate carrier expression redirects glycolytic intermediates and leads to heart failure, which is prevented or reversed with a high-fat or ketogenic diet. |
| Databáze: | OpenAIRE |
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