Mitochondrial pyruvate carrier abundance mediates pathological cardiac hypertrophy.

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.

• Authors: Mariana Fernandez-Caggiano, Alisa Kamynina, Asvi A Francois, Oleksandra Prysyazhna, Thomas R Eykyn, Susanne Krasemann, Maria G Crespo-Leiro, Maria Garcia Vieites, Katiuscia Bianchi, Valle Morales, Nieves Domenech, Philip Eaton
• Journal: Nature metabolism (Nat Metab) Vol. 2 Issue 11 Pg. 1223-1231 (11 2020) ISSN: 2522-5812 [Electronic] Germany
• PMID: 33106688 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anion Transport Proteins
• MPC1 pyruvate carrier protein, mouse
• MPC2 pyruvate carrier protein, mouse
• Mitochondrial Membrane Transport Proteins
• Monocarboxylic Acid Transporters
• Angiotensin II
• Pyruvic Acid

Topics

• Angiotensin II
• Animals
• Anion Transport Proteins (biosynthesis, genetics, metabolism)
• Cardiomegaly (metabolism, pathology)
• Cell Proliferation
• Citric Acid Cycle
• Constriction, Pathologic
• Female
• Heart Failure (chemically induced, metabolism, pathology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Mitochondria, Heart (metabolism)
• Mitochondrial Membrane Transport Proteins (biosynthesis, genetics, metabolism)
• Monocarboxylic Acid Transporters (biosynthesis, genetics, metabolism)
• Myocardium (metabolism)
• Myocytes, Cardiac (metabolism, pathology)
• Pyruvic Acid (metabolism)