This Article Full Text Full Text (PDF) Supplemental Data Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bastin, J. Articles by Djouadi, F. Search for Related Content PubMed PubMed Citation Articles by Bastin, J. Articles by Djouadi, F. Related Collections Metabolism

Activation of Peroxisome Proliferator-Activated Receptor Pathway Stimulates the Mitochondrial Respiratory Chain and Can Correct Deficiencies in Patients’ Cells Lacking Its Components

Université Paris Descartes (J.B., F.A., F.D.), Centre National de la Recherche Scientifique Unité Propre de Recherche 9078, Faculté Necker-Enfants Malades, 75015 Paris, France; and Institut National de la Santé et de la Recherche Médicale U781 (A.R., A.M.), Hôpital Necker-Enfants Malades, 75015 Paris, France

Address all correspondence and requests for reprints to: Fatima Djouadi, Ph.D., Centre National de la Recherche Scientifique Unité Propre de Recherche 9078, Faculté Necker-Enfants Malades, 156 rue de Vaugirard, 75015 Paris, France. E-mail: djouadi{at}necker.fr.

Context: The mitochondrial respiratory chain (RC) disorders are the largest group of inborn errors of metabolism and still remain without treatment in most cases.

Objective: We tested whether bezafibrate, a drug acting as a peroxisome proliferator-activated receptor (PPAR) agonist, could stimulate RC capacities.

Design: Fibroblasts or myoblasts from controls or patients deficient in complex I (CI), complex III (CIII), or complex IV (CIV) were cultured with or without bezafibrate.

Main Outcome Measures: Enzyme activities, mRNA and protein expression, and respiration rates were measured.

Results: In control cells, bezafibrate increased the CI, CIII, and CIV enzyme activities (+42 to +52%), as well as RC mRNAs (+40 to +120%) and RC protein levels (+50 to +150%). Nine of 14 patient cell lines tested exhibited a significant increase in the activity of the deficient RC complex after bezafibrate treatment (+46 to +133%), and full pharmacological correction could be achieved in seven cell lines. Similar effects were obtained using a PPAR agonist. These changes were related to a drug-induced increase in the mutated mRNAs and RC protein levels. Finally, the molecular mechanisms by which the PPAR pathway could induce the expression of genes encoding structural subunits or ancillary proteins of the RC apparatus, leading to stimulate the activity and protein levels of RC complex, likely involved the PPAR coactivator-1.

Conclusions: This study suggests a rationale for a possible correction of moderate RC disorders due to mutations in nuclear genes, using existing drugs, and brings new insights into the role of PPAR in the regulation of the mitochondrial RC in human cells.

This article has been cited by other articles:

				S Rahman and M G Hanna Diagnosis and therapy in neuromuscular disorders: diagnosis and new treatments in mitochondrial diseases J. Neurol. Neurosurg. Psychiatry, September 1, 2009; 80(9): 943 - 953. [Abstract] [Full Text] [PDF]

				S. Srivastava, F. Diaz, L. Iommarini, K. Aure, A. Lombes, and C. T. Moraes PGC-1{alpha}/{beta} induced expression partially compensates for respiratory chain defects in cells from patients with mitochondrial disorders Hum. Mol. Genet., May 15, 2009; 18(10): 1805 - 1812. [Abstract] [Full Text] [PDF]