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TNF-alpha and IL-1 alpha inhibit both pyruvate dehydrogenase activity and mitochondrial function in cardiomyocytes:
1Department of Internal Medicine I, Klinikum Grosshadern, University of Munich, Germany.
Abstract:
Cytokines such as tumor necrosis factor alpha (TNF alpha) and Interleukin-1alpha (IL1alpha) are known to influence energy metabolism and mitochondrial function in tumor and vascular smooth muscle cells. The aim of the present study was to investigate whether in cardiomyocytes mitochondrial function and PDH activity may also be impaired by TNF alpha and IL1alpha. Pyruvate dehydrogenase (PDH) activity and mitochondrial oxygen consumption of cultured cardiomyocytes were determined after subchronic exposure (24 h) to TNF alpha (1, 10, 100, 1000 I.U./ml) and IL1alpha (0.1, 1, 10, 100 I.U./ml). TNF alpha- and IL1alpha- exposure of the cardiomyocytes resulted in a concentration dependent decrease of PDH activity up to 38%. In parallel, selective oxygen consumption of the respiratory chain complexes I (NADH:ubiquinone oxidoreductase) and II (succinate:ubiquinone oxidoreductase) decreased by up to 45%. Addition of the PDH activator dichloracetate (0.01 M) resulted in complete restoration of PDH activity but not of mitochondrial function. The results suggest a primary inhibition of the mitochondrial respiratory chain by TNF alpha and IL1alpha and a subsequent down regulation of PDH activity.
Insights
Tumor necrosis factor alpha (TNF alpha) and Interleukin-1alpha (IL1alpha) impair cardiomyocyte mitochondrial function and pyruvate dehydrogenase (PDH) activity. These cytokines primarily inhibit the mitochondrial respiratory chain, leading to reduced PDH activity.
Area of Science:
- Cardiovascular Biology
- Cellular Metabolism
- Mitochondrial Physiology
Background:
- Cytokines like TNF alpha and IL1alpha affect cellular energy metabolism.
- Previous studies linked these cytokines to mitochondrial dysfunction in tumor and vascular cells.
Purpose of the Study:
- To investigate the impact of TNF alpha and IL1alpha on cardiomyocyte mitochondrial function.
- To determine if these cytokines impair pyruvate dehydrogenase (PDH) activity in heart cells.
Main Methods:
- Cultured cardiomyocytes were exposed to varying concentrations of TNF alpha and IL1alpha for 24 hours.
- Assessed PDH activity and mitochondrial oxygen consumption using specific assays.
- Investigated the effect of a PDH activator (dichloracetate) on restored activity.
Main Results:
- TNF alpha and IL1alpha exposure caused a concentration-dependent decrease in PDH activity (up to 38%).
- Mitochondrial oxygen consumption by respiratory chain complexes I and II decreased by up to 45%.
- Dichloracetate restored PDH activity but not mitochondrial function.
Conclusions:
- TNF alpha and IL1alpha primarily inhibit the mitochondrial respiratory chain in cardiomyocytes.
- This inhibition leads to a subsequent downregulation of PDH activity.
- Suggests a novel mechanism of cytokine-induced cardiac metabolic dysfunction.