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J Biol Chem, Vol. 275, Issue 1, 223-228, January 7, 2000
From the Laboratoire de Bioénergétique Fondamentale et
Appliquée, Université Joseph Fourier, F-38041
Grenoble-Cedex 09, France and § the Institut de Biochimie et
de Génétique Cellulaires du CNRS, Université de
Bordeaux II, F-33077 Bordeaux-Cedex, France
We report here a new mitochondrial regulation
occurring only in intact cells. We have investigated the effects of
dimethylbiguanide on isolated rat hepatocytes, permeabilized
hepatocytes, and isolated liver mitochondria. Addition of
dimethylbiguanide decreased oxygen consumption and mitochondrial
membrane potential only in intact cells but not in permeabilized
hepatocytes or isolated mitochondria. Permeabilized hepatocytes after
dimethylbiguanide exposure and mitochondria isolated from
dimethylbiguanide pretreated livers or animals were characterized by a
significant inhibition of oxygen consumption with complex I substrates
(glutamate and malate) but not with complex II (succinate) or complex
IV
(N,N,N',N'-tetramethyl-1,4-phenylenediamine dihydrochloride (TMPD)/ascorbate) substrates. Studies using
functionally isolated complex I obtained from mitochondria isolated
from dimethylbiguanide-pretreated livers or rats further confirmed that
dimethylbiguanide action was located on the respiratory chain complex
I. The dimethylbiguanide effect was temperature-dependent,
oxygen consumption decreasing by 50, 20, and 0% at 37, 25, and
15 °C, respectively. This effect was not affected by
insulin-signaling pathway inhibitors, nitric oxide precursor or
inhibitors, oxygen radical scavengers, ceramide synthesis inhibitors,
or chelation of intra- or extracellular Ca2+. Because it is
established that dimethylbiguanide is not metabolized, these results
suggest the existence of a new cell-signaling pathway targeted to the
respiratory chain complex I with a persistent effect after cessation of
the signaling process.
Dimethylbiguanide Inhibits Cell Respiration via an Indirect
Effect Targeted on the Respiratory Chain Complex I*
,
*
This work was supported by the Grant EP000983-01 from the
Fondation pour la Recherche Médicale, France (to M.-Y. El-Mir) and by the Ministère de l'Enseignement, de la Recherche et de la
Technologie.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
On leave from the Departamento de Fisiologia y Farmacologia,
Facultad de Farmacia, Universidad de Salamanca-E-37007, Spain.
¶
To whom correspondence should be addressed: Laboratoire de
Bioénergétique Fondamentale et Appliquée,
Université Joseph Fourier, B. P. 53X, F-38041 Grenoble-Cedex 09, France. Fax: 33-4-76-51-42-18; E-mail:
xavier.leverve@ujf-grenoble.fr.
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