Inborn enzyme defects of the mitochondrial respiratory chain (RC) or of fatty acid ß-oxidation (FAO) form a large family of rare genetic disorders that are associated with life-threatening pediatric presentations or with milder phenotypes. The patients have variable ages of onset and severity of disease, which may include myopathy and neuro-metabolic disorders. Advances in diagnosis have revealed a large number of disease-causing genes and associated mutations and have led to a continuous increase in the number of patients. However, little progress has been made in treatment, and the majority of these diseases are incurable.
For many years, our group has been dedicated to the screening of candidate molecules, drugs or natural compounds, based on their presumed mechanism of action, that might correct FAO or RC disorders. The development of new therapeutic strategies also involves the identification of new therapeutic targets, in diverse signaling pathways, which are known as regulators of energy metabolism. Thus, our group has demonstrated, using bezafibrate or resveratrol, that a target-based pharmacological strategy can result in the up-regulation of the residual mutated protein and can be successful in the correction of some inborn FAO or RC mitochondrial disorders.
Our research is performed mainly ex vivo on panels of FAO- or RC-deficient patients’ fibroblasts which harbor known mutations. This approach allows the pre-clinical evaluation of the compounds tested in a context of personalized medicine.
- Jean BASTIN, INSERM researcher, DR- INSERM, Inborn mitochondrial diseases : pharmacological therapy and metabolic signalingjean.bastin@-Code to remove to avoid SPAM-inserm.fr, +33 1 42 86 22 19, room P470
- Fatima DJOUADI, INSERM researcher, DR-INSERM, Inborn mitochondrial diseases : pharmacological therapy and metabolic signalingfatima.djouadi@-Code to remove to avoid SPAM-inserm.fr, +33 1 42 86 22 19, room P470
- Jean-Louis BRESSON, University Professor, Inborn mitochondrial diseases : pharmacological therapy and metabolic signalingjean-louis.bresson@-Code to remove to avoid SPAM-nck.aphp.fr
- Beneficial effects of Resveratrol on respiratory chain defects in patients’ fibroblasts involve estrogen receptor and estrogen-related receptor a signaling.
Lopes Costa A, Le Bachelier C, Mathieu L, Rotig A, Boneh A, De Lonlay P, Tarnopolsky MA, Thorburn David R, Bastin , Djouadi F : Hum. Mol. Genet, 2014
- Exposure to resveratrol triggers pharmacological correction of fatty acid utilization in human fatty acid oxidation-deficient fibroblasts.
Bastin J, Lopes Costa A, Djouadi F : Hum. Mol. Genet, 2011
- Long term follow-up of bezafibrate treatment in the myopathic form of Carnitine-PalmitoyI Transferase 2 deficiency.
Bonnefont JP, Bastin J, Laforêt P, Aubey F, Mogenet A, Romano S, Ricquier D, Gobin-Limballe S, Vassault A, Behin A, Eymard B, Bresson JL, Djouadi F : Clin Pharmacol Ther, 2010
- Compared effects of missense mutations in Very Long Chain Acyl-CoA Dehydrogenase deficiency: combined analysis by structural, functional and pharmacological approaches.
Gobin-Limballe S, McAndrew R, Djouadi F, Kim JJ, Bastin J : BBA-Molecular Basis of Disease, 2010
- Bezafibrate for treatment on an inborn mitochondrial ß-oxidation defect.
Bonnefont JP, Bastin J, Behin A, Djouadi F : N. Engl. J. Med., 2009
Bastin J, Djouadi F : Nutrients, 2016
Mathieu L, Costa AL, Le Bachelier C, Slama A, Lebre AS, Taylor RW, Bastin J, Djouadi F : Free Radic Biol Med, 2016