Functional deficiencies of subsarcolemmal mitochondria in the type 2 diabetic human heart.
The mitochondrion has been implicated in the development of diabetic cardiomyopathy. Examination of cardiac mitochondria is complicated by the existence of spatially distinct subpopulations including subsarcolemmal (SSM) and interfibrillar (IFM). Dysfunction to cardiac SSM has been reported in murine models of type 2 diabetes mellitus; however, subpopulation-based mitochondrial analyses have not been explored in type 2 diabetic human heart. The goal of this study was to determine the impact of type 2 diabetes mellitus on cardiac mitochondrial function in the human patient. Mitochondrial subpopulations from atrial appendages of patients with and without type 2 diabetes were examined. Complex I- and fatty acid-mediated mitochondrial respiration rates were decreased in diabetic SSM compared with nondiabetic (P ≤ 0.05 for both), with no change in IFM. Electron transport chain (ETC) complexes I and IV activities were decreased in diabetic SSM compared with nondiabetic (P ≤ 0.05 for both), with a concomitant decline in their levels (P ≤ 0.05 for both). Regression analyses comparing comorbidities determined that diabetes mellitus was the primary factor accounting for mitochondrial dysfunction. Linear spline models examining correlative risk for mitochondrial dysfunction indicated that patients with diabetes display the same degree of state 3 and electron transport chain complex I dysfunction in SSM regardless of the extent of glycated hemoglobin (HbA1c) and hyperglycemia. Overall, the results suggest that independent of other pathologies, mitochondrial dysfunction is present in cardiac SSM of patients with type 2 diabetes and the degree of dysfunction is consistent regardless of the extent of elevated HbA1c or blood glucose levels.
Division of Exercise Physiology and Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, West Virginia;
Tara L
TL
Croston
Division of Exercise Physiology and Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, West Virginia;
Dharendra
D
Thapa
West Virginia University School of Medicine, Department of Surgery, Morgantown, West Virginia;
Anthony A
AA
Holden
West Virginia University School of Medicine, Department of Surgery, Morgantown, West Virginia;
Kevin J
KJ
Tveter
Division of Exercise Physiology and Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, West Virginia;
Sara E
SE
Lewis
Division of Exercise Physiology and Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, West Virginia;
Danielle L
DL
Shepherd
Division of Exercise Physiology and Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, West Virginia;
Cody E
CE
Nichols
West Virginia University School of Public Health, Department of Biostatistics, Morgantown, West Virginia.
Dustin M
DM
Long
Division of Exercise Physiology and Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, West Virginia;
I Mark
IM
Olfert
Division of Exercise Physiology and Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, West Virginia;
Rajaganapathi
R
Jagannathan
Division of Exercise Physiology and Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, West Virginia; jhollander@hsc.wvu.edu.
John M
JM
Hollander
D019069:Cell Respiration; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology*; D058065:Diabetic Cardiomyopathies / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology*; D012508:Sarcolemma / Q000378:metabolism* / Q000473:pathology
diabetes mellitus; diabetic cardiomyopathy; mitochondria