Decreased Mitochondrial Pyruvate Transport Activity in the Diabetic Heart: ROLE OF MITOCHONDRIAL PYRUVATE CARRIER 2 (MPC2) ACETYLATION.
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.
From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 and.
Shraddha S
SS
Vadvalkar
From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 and.
Satoshi
S
Matsuzaki
From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 and.
Craig A
CA
Eyster
From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 and.
Jennifer R
JR
Giorgione
From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 and.|the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
Lee B
LB
Bockus
From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 and.
Caroline S
CS
Kinter
From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 and.
Michael
M
Kinter
From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 and kenneth-humphries@omrf.org.|the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
Kenneth M
0000-0002-6167-3175
KM
Humphries
D000107:Acetylation; D000818:Animals; D027321:Anion Transport Proteins / Q000032:analysis / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D005227:Fatty Acids / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000378:metabolism / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000032:analysis / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D019289:Pyruvic Acid / Q000378:metabolism*
D027321:Anion Transport Proteins; D005227:Fatty Acids; C000595574:MPC2 pyruvate carrier protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; D019289:Pyruvic Acid
acetylation; bioenergetics; diabetes; heart; mitochondria; mitochondrial pyruvate carrier; mitochondrial transport; pyruvate dehydrogenase complex (PDC)