Functional deficiencies of subsarcolemmal mitochondria in the type 2 diabetic human heart
Tara L Croston1, Dharendra Thapa1, Anthony A Holden2
1Division of Exercise Physiology and Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, West Virginia;
Abstract:
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.
Insights
Type 2 diabetes causes mitochondrial dysfunction in subsarcolemmal cardiac mitochondria in humans. This impairment occurs independently of other conditions and HbA1c levels, highlighting a specific cellular defect in diabetic cardiomyopathy.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Diabetology
Background:
- Mitochondria are crucial for cardiac function, but their role in diabetic cardiomyopathy is complex.
- Cardiac mitochondria exist in distinct subpopulations (subsarcolemmal and interfibrillar), with differing functions.
- Previous studies in animal models suggest subsarcolemmal mitochondrial dysfunction in diabetes, but human data are lacking.
Purpose of the Study:
- To investigate the impact of type 2 diabetes mellitus on human cardiac mitochondrial function.
- To analyze mitochondrial subpopulations (SSM and IFM) separately in diabetic and non-diabetic human hearts.
Main Methods:
- Mitochondrial subpopulations (SSM and IFM) were isolated from atrial appendages of type 2 diabetic and non-diabetic human patients.
- Mitochondrial respiration (Complex I and fatty acid-mediated) and electron transport chain (ETC) complex activities and levels were assessed.
- Statistical analyses, including regression and linear spline models, were used to determine the impact of diabetes and comorbidities.
Main Results:
- Diabetic subsarcolemmal mitochondria (SSM) exhibited reduced Complex I and fatty acid-mediated respiration rates compared to non-diabetic SSM.
- Electron transport chain complexes I and IV activities and levels were significantly decreased in diabetic SSM.
- No significant changes in mitochondrial function were observed in the interfibrillar mitochondrial subpopulation (IFM).
- Diabetes mellitus was identified as the primary driver of mitochondrial dysfunction, independent of other comorbidities.
- Mitochondrial dysfunction in SSM was consistent across varying levels of glycated hemoglobin (HbA1c) and hyperglycemia.
Conclusions:
- Cardiac subsarcolemmal mitochondria are functionally impaired in patients with type 2 diabetes.
- This mitochondrial dysfunction is specific to the SSM subpopulation and occurs independently of disease severity (HbA1c) or hyperglycemia.
- Findings suggest a direct link between type 2 diabetes and cardiac mitochondrial dysfunction, contributing to diabetic cardiomyopathy.
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