TNF-alpha and IL-1 alpha inhibit both pyruvate dehydrogenase activity and mitochondrial function in cardiomyocytes: evidence for primary impairment of mitochondrial function.
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.
Zell
R
R
Department of Internal Medicine I, Klinikum Grosshadern, University of Munich, Germany.
Geck
P
P
Werdan
K
K
Boekstegers
P
P
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000378:metabolism / Q000494:pharmacology; D000968:Antimycin A / Q000494:pharmacology; D003999:Dichloroacetic Acid / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*
D000906:Antibodies; D007375:Interleukin-1; D011768:Pyruvate Dehydrogenase Complex; D014409:Tumor Necrosis Factor-alpha; D000968:Antimycin A; D003999:Dichloroacetic Acid