Fenofibrate impairs rat mitochondrial function by inhibition of respiratory complex I.
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 microM fenofibrate: -41 +/- 7%, -70 +/- 2%, and -78 +/- 4%; 100 microM clofibrate: -27 +/- 7%; p < 0.005 each). Inhibition of complex I by fenofibrate (100 microM) 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 microM) decreased CO(2) 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.
Brunmair
Barbara
B
Department of Medicine III, Division of Endocrinology and Metabolism, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
Lest
Andrea
A
Staniek
Katrin
K
Gras
Florian
F
Scharf
Nicole
N
Roden
Michael
M
Nohl
Hans
H
Waldhäusl
Werner
W
Fürnsinn
Clemens
C
D000818:Animals; D042967:Electron Transport Complex I / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects; D011345:Fenofibrate / Q000494:pharmacology* / Q000633:toxicity; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000139:chemically induced*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000960:Hypolipidemic Agents; D042967:Electron Transport Complex I; D011345:Fenofibrate