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Research ArticleCELLULAR AND MOLECULAR

Fenofibrate Impairs Rat Mitochondrial Function by Inhibition of Respiratory Complex I

Barbara Brunmair, Andrea Lest, Katrin Staniek, Florian Gras, Nicole Scharf, Michael Roden, Hans Nohl, Werner Waldhäusl and Clemens Fürnsinn
Journal of Pharmacology and Experimental Therapeutics October 2004, 311 (1) 109-114; DOI: https://doi.org/10.1124/jpet.104.068312
Barbara Brunmair
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Andrea Lest
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Katrin Staniek
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Florian Gras
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Nicole Scharf
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Michael Roden
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Hans Nohl
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Werner Waldhäusl
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Clemens Fürnsinn
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Abstract

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.

Footnotes

  • Financial support was provided by the Austrian Science Fund (Grant P16352-B08).

  • doi:10.1124/jpet.104.068312.

  • ABBREVIATIONS: PPARα, peroxisome proliferator-activated receptor-α; BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; P/O, ADP added/amount of oxygen consumed during state 3 respiration.

    • Received March 29, 2004.
    • Accepted May 26, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 311 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 311, Issue 1
1 Oct 2004
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Research ArticleCELLULAR AND MOLECULAR

Fenofibrate Impairs Rat Mitochondrial Function by Inhibition of Respiratory Complex I

Barbara Brunmair, Andrea Lest, Katrin Staniek, Florian Gras, Nicole Scharf, Michael Roden, Hans Nohl, Werner Waldhäusl and Clemens Fürnsinn
Journal of Pharmacology and Experimental Therapeutics October 1, 2004, 311 (1) 109-114; DOI: https://doi.org/10.1124/jpet.104.068312

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Research ArticleCELLULAR AND MOLECULAR

Fenofibrate Impairs Rat Mitochondrial Function by Inhibition of Respiratory Complex I

Barbara Brunmair, Andrea Lest, Katrin Staniek, Florian Gras, Nicole Scharf, Michael Roden, Hans Nohl, Werner Waldhäusl and Clemens Fürnsinn
Journal of Pharmacology and Experimental Therapeutics October 1, 2004, 311 (1) 109-114; DOI: https://doi.org/10.1124/jpet.104.068312
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