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CELLULAR AND MOLECULAR

Fenofibrate Impairs Rat Mitochondrial Function by Inhibition of Respiratory Complex I

Department of Medicine III, Division of Endocrinology & Metabolism, Medical University of Vienna, Austria (B.B., A.L., F.G., N.S., M.R., W.W., C.F.); and Basic Research in Pharmacology and Toxicology, Veterinary University Vienna, Austria (K.S., H.N.)

Fibrates are used for the treatment of dyslipidemia and known to affect mitochondrial function in vitro. To better understand the mechanisms underlying their mitochondrial effects, fibrate actions on complex I of the respiratory chain and cell respiration were studied in vitro. In homogenates of rat skeletal muscle, fenofibrate, and to a lesser extent clofibrate, reduced the activity of complex I (10, 30, and 100 µM fenofibrate: –41 ± 7%, –70 ± 2%, and –78 ± 4%; 100 µM clofibrate: –27 ± 7%; p < 0.005 each). Inhibition of complex I by fenofibrate (100 µM) was confirmed by reduced state 3 respiration of isolated mitochondria consuming glutamate + malate as substrates for complex I (–33 ± 4%; p < 0.0005), but not of such consuming succinate as substrate for complex II (–8 ± 4%; NS). In isolated rat muscle, 24-h fenofibrate exposure (25, 50, and 100 µM) decreased CO₂ production from palmitate (–15 ± 7%, –23 ± 8%, and –22 ± 7%; p < 0.05 each) and increased lactate release (+15 ± 5%, +14 ± 5%, and + 17 ± 6%; p < 0.02 each) indicating impaired cell respiration. Ciprofibrate and gemfibrocil (but not bezafibrate) impaired cell respiration without any inhibition of complex I. Our findings support the notion that individual fibrates induce mitochondrial dysfunction via different molecular mechanisms and show that fenofibrate predominantly acts by inhibition of complex I of the respiratory chain.

Address correspondence to: Dr. Clemens Fürnsinn, Department of Medicine III, Division of Endocrinology and Metabolism, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail: clemens.fuernsinn{at}meduniwien.ac.at

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