Decreased Mitochondrial Pyruvate Transport Activity in the Diabetic Heart: ROLE OF MITOCHONDRIAL PYRUVATE CARRIER 2 (MPC2) ACETYLATION

J Biol Chem. 2017 Mar 17;292(11):4423-4433. doi: 10.1074/jbc.M116.753509. Epub 2017 Feb 1.


Alterations in mitochondrial function contribute to diabetic cardiomyopathy. We have previously shown that heart mitochondrial proteins are hyperacetylated in OVE26 mice, a transgenic model of type 1 diabetes. However, the universality of this modification and its functional consequences are not well established. In this study, we demonstrate that Akita type 1 diabetic mice exhibit hyperacetylation. Functionally, isolated Akita heart mitochondria have significantly impaired maximal (state 3) respiration with physiological pyruvate (0.1 mm) but not with 1.0 mm pyruvate. In contrast, pyruvate dehydrogenase activity is significantly decreased regardless of the pyruvate concentration. We found that there is a 70% decrease in the rate of pyruvate transport in Akita heart mitochondria but no decrease in the mitochondrial pyruvate carriers 1 and 2 (MPC1 and MPC2). The potential role of hyperacetylation in mediating this impaired pyruvate uptake was examined. The treatment of control mitochondria with the acetylating agent acetic anhydride inhibits pyruvate uptake and pyruvate-supported respiration in a similar manner to the pyruvate transport inhibitor α-cyano-4-hydroxycinnamate. A mass spectrometry selective reactive monitoring assay was developed and used to determine that acetylation of lysines 19 and 26 of MPC2 is enhanced in Akita heart mitochondria. Expression of a double acetylation mimic of MPC2 (K19Q/K26Q) in H9c2 cells was sufficient to decrease the maximal cellular oxygen consumption rate. This study supports the conclusion that deficient pyruvate transport activity, mediated in part by acetylation of MPC2, is a contributor to metabolic inflexibility in the diabetic heart.

Keywords: acetylation; bioenergetics; diabetes; heart; mitochondria; mitochondrial pyruvate carrier; mitochondrial transport; pyruvate dehydrogenase complex (PDC).

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Animals
  • Anion Transport Proteins / analysis
  • Anion Transport Proteins / metabolism*
  • Diabetes Mellitus, Type 1 / complications*
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetic Cardiomyopathies / metabolism*
  • Diabetic Cardiomyopathies / pathology
  • Fatty Acids / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria, Heart / metabolism
  • Mitochondria, Heart / pathology
  • Mitochondrial Membrane Transport Proteins / analysis
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Myocardium / metabolism
  • Myocardium / pathology*
  • Oxidation-Reduction
  • Oxygen Consumption
  • Pyruvic Acid / metabolism*


  • Anion Transport Proteins
  • Fatty Acids
  • MPC2 pyruvate carrier protein, mouse
  • Mitochondrial Membrane Transport Proteins
  • Pyruvic Acid