Mitochondrial pyruvate carrier abundance mediates pathological cardiac hypertrophy
Mariana Fernandez-Caggiano,Alisa Kamynina,Asvi A. Francois,Oleksandra Prysyazhna,Thomas R. Eykyn,Susanne Krasemann,María G. Crespo-Leiro,Maria Garcia Vieites,Katiuscia Bianchi,Valle Morales,Nieves Doménech,Philip Eaton +11 more
- Vol. 2, Iss: 11, pp 1223-1231
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TLDR
It is demonstrated that loss of the MPC1/2 causally mediates adverse cardiac remodelling and protects against cardiac hypertrophy and failure.Abstract:
Cardiomyocytes rely on metabolic substrates, not only to fuel cardiac output, but also for growth and remodelling during stress. Here we show that mitochondrial pyruvate carrier (MPC) abundance mediates pathological cardiac hypertrophy. MPC abundance was reduced in failing hypertrophic human hearts, as well as in the myocardium of mice induced to fail by angiotensin II or through transverse aortic constriction. Constitutive knockout of cardiomyocyte MPC1/2 in mice resulted in cardiac hypertrophy and reduced survival, while tamoxifen-induced cardiomyocyte-specific reduction of MPC1/2 to the attenuated levels observed during pressure overload was sufficient to induce hypertrophy with impaired cardiac function. Failing hearts from cardiomyocyte-restricted knockout mice displayed increased abundance of anabolic metabolites, including amino acids and pentose phosphate pathway intermediates and reducing cofactors. These hearts showed a concomitant decrease in carbon flux into mitochondrial tricarboxylic acid cycle intermediates, as corroborated by complementary 1,2-[13C2]glucose tracer studies. In contrast, inducible cardiomyocyte overexpression of MPC1/2 resulted in increased tricarboxylic acid cycle intermediates, and sustained carrier expression during transverse aortic constriction protected against cardiac hypertrophy and failure. Collectively, our findings demonstrate that loss of the MPC1/2 causally mediates adverse cardiac remodelling.read more
Citations
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Cardiac Energy Metabolism in Heart Failure
TL;DR: In this paper, the effects of metabolic changes that occur in heart failure are complex and are dependent not only on the severity and type of heart failure present but also on the co-existence of common comorbidities such as obesity and type 2 diabetes.
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The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure.
Ahmad A. Cluntun,Rachit Badolia,Sandra Lettlova,K. Mark Parnell,Thirupura S. Shankar,Nikolaos A. Diakos,Kristofor A. Olson,Iosif Taleb,Sean M. Tatum,Jordan A. Berg,Corey N. Cunningham,Tyler Van Ry,Alex J. Bott,Aspasia Thodou Krokidi,Sarah Fogarty,Sophia Skedros,Wojciech I. Swiatek,Xuejing Yu,Bai Luo,Shannon Merx,Sutip Navankasattusas,James E. Cox,Gregory S. Ducker,William L. Holland,Stephen H. McKellar,Stephen H. McKellar,Jared Rutter,Stavros G. Drakos,Stavros G. Drakos +28 more
TL;DR: It is found that alteration of the pyruvate-lactate axis is a fundamental and early feature of cardiac hypertrophy and failure.
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Spatial multi-omic map of human myocardial infarction
Rafael Kramann,Alick Simmons +1 more
TL;DR: In this paper , a high-resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium was generated.
Journal ArticleDOI
Mitochondrial pyruvate carriers are required for myocardial stress adaptation.
Yuan Zhang,Paul V. Taufalele,Jesse D. Cochran,Isabelle Robillard-Frayne,Jonas Maximilian Marx,Jonas Maximilian Marx,Jamie Soto,Adam J. Rauckhorst,Fariba Tayyari,Alvin D. Pewa,Lawrence R. Gray,Lynn M. Teesch,Patrycja Puchalska,Patrycja Puchalska,Trevor Funari,Rose McGlauflin,Kathy Zimmerman,William J. Kutschke,Thomas Cassier,Shannon Hitchcock,Kevin D. Lin,Kevin M. Kato,Jennifer L. Stueve,Lauren Haff,Robert M. Weiss,James E. Cox,Jared Rutter,Jared Rutter,Eric B. Taylor,Peter A. Crawford,Peter A. Crawford,E. Douglas Lewandowski,E. Douglas Lewandowski,Christine Des Rosiers,E. Dale Abel +34 more
TL;DR: It is shown that MPC-mediated mitochondrial pyruvate utilization is essential for the partitioning of glucose-derived cytosolic metabolic intermediates, which modulate myocardial stress adaptation and highlight the centrality of pyruVate metabolism to myocardian metabolism and function.
Journal ArticleDOI
Nutritional modulation of heart failure in mitochondrial pyruvate carrier-deficient mice
Kyle S. McCommis,Kyle S. McCommis,Attila Kovacs,Carla J. Weinheimer,Trevor M. Shew,Timothy R. Koves,Olga Ilkayeva,Dakota R. Kamm,Kelly D. Pyles,M. Todd King,Richard L. Veech,Brian J. DeBosch,Deborah M. Muoio,Richard W. Gross,Brian N. Finck +14 more
TL;DR: It is shown that MPC1 and MPC2 expression is downregulated in failing human and mouse hearts, revealing a critical role for mitochondrial pyruvate use in cardiac function and highlighting the potential of dietary interventions to enhance cardiac fat metabolism to prevent or reverse cardiac dysfunction and remodelling in the setting of MPC deficiency.
References
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A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans.
Daniel K. Bricker,Eric B. Taylor,John C. Schell,Thomas Orsak,Audrey Boutron,Yu-Chan Chen,James E. Cox,Caleb M. Cardon,Jonathan G. Van Vranken,Noah Dephoure,Claire Redin,Sihem Boudina,Steven P. Gygi,Michèle Brivet,Carl S. Thummel,Jared Rutter +15 more
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Journal ArticleDOI
Identification and Functional Expression of the Mitochondrial Pyruvate Carrier
Sébastien Herzig,Etienne Raemy,Sylvie Montessuit,Jean-Luc Veuthey,Nicola Zamboni,Benedikt Westermann,Edmund R.S. Kunji,Jean-Claude Martinou +7 more
TL;DR: The existence of a specific mitochondrial pyruvate carrier (MPC) has been anticipated, but its molecular identity remained unknown and it is reported that MPC is a heterocomplex formed by two members of a family of previously uncharacterized membrane proteins that are conserved from yeast to mammals.
Journal ArticleDOI
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Peter Razeghi,Martin E. Young,Joseph L. Alcorn,Christine S. Moravec,O.H. Frazier,Heinrich Taegtmeyer,Heinrich Taegtmeyer,Heinrich Taegtmeyer +7 more
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