title: Pharmacological inhibition of carnitine palmitoyltransferase 1 restores mitochondrial oxidative phosphorylation in human trifunctional protein deficient fibroblasts.
abstract: Mitochondrial Trifunctional Protein deficiency (TFPD) is a severe genetic disease characterized by altered energy metabolism and accumulation of long-chain (LC) acylcarnitines in blood and tissues. This accumulation could impair the mitochondrial oxidative phosphorylation (OxPhos), contributing to the non-optimal outcome despite conventional diet therapy with medium-chain triglycerides (MCT).
  
  
  
  Acylcarnitine and OxPhos parameters were measured in TFPD-fibroblasts obtained from 8 children and cultured in medium mimicking fasting (LCFA) or conventional treatment (MCT), with or without Etomoxir (ETX) an inhibitor of carnitine palmitoyltransferase 1 (CPT1) activity, and were compared to results obtained with fibroblasts from 5 healthy-control children. The effects of various acylcarnitines were also tested on control fibroblasts.
  
  
  
  In the LCFA-condition, TFPD-fibroblasts demonstrated a large accumulation of LC-acylcarnitines associated with decreased O2-consumption (63±3% of control, P<0.001) and ATP production (67±5%, P<0.001) without modification of coupling efficiency. A dose-dependent decrease in O2-consumption was reproduced in control fibroblasts by addition of increasing dose of LC-acylcarnitines, while it was almost preserved with MC-acylcarnitines. The MCT-condition reduced LC-acylcarnitine accumulation and partially improved O2-consumption (80±3%, P<0.01) in TFPD-fibroblasts. The addition of ETX in both LCFA- and MCT-conditions normalized acylcarnitine profiles and restored O2-consumption and ATP production at the same levels than control.
  
  
  
  Accumulation of LC-acylcarnitines plays a major role in the pathophysiology of TFPD, reducing OxPhos capacities. These deleterious effects could be partially prevented by MCT-therapy and totally corrected by ETX. Inhibition of CPT1 may be view as a new therapeutic target for patients with a severe form of TFPD.
authors.affiliation: CHU de Tours, Médecine Pédiatrique, Tours, France, and INSERM U1069, Université François Rabelais, Tours, France. Electronic address: bruno.lefort@univ-tours.fr.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lefort
authors.affiliation: CHU de Tours, Médecine Pédiatrique, Tours, France, and INSERM U1069, Université François Rabelais, Tours, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Gouache
authors.affiliation: CHU de Lyon, Maladies Héréditaires du Métabolisme, Lyon, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Acquaviva
authors.affiliation: CHU de Tours, Médecine Pédiatrique, Tours, France, and INSERM U1069, Université François Rabelais, Tours, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Tardieu
authors.affiliation: CHU Robert Debré, Biochimie, Paris, France.
authors.forename: Jean François
authors.initials: JF
authors.lastname: Benoist
authors.affiliation: INSERM U1069, Université François Rabelais, Tours, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dumas
authors.affiliation: INSERM U1069, Université François Rabelais, Tours, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Servais
authors.affiliation: INSERM U1069, Université François Rabelais, Tours, France.
authors.forename: Stéphan
authors.initials: S
authors.lastname: Chevalier
authors.affiliation: CHU de Lyon, Maladies Héréditaires du Métabolisme, Lyon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Vianey-Saban
authors.affiliation: CHU de Tours, Médecine Pédiatrique, Tours, France, and Inserm U1069, Université François Rabelais de Tours, PRES Centre-Val de Loire Universités, Tours, France.
authors.forename: François
authors.initials: F
authors.lastname: Labarthe
mesh_terms: D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D017240:Mitochondrial Myopathies / Q000378:metabolism* / Q000473:pathology; D063991:Mitochondrial Trifunctional Protein / Q000172:deficiency* / Q000187:drug effects / Q000378:metabolism; D009422:Nervous System Diseases / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D012206:Rhabdomyolysis / Q000378:metabolism* / Q000473:pathology
chemical_list: D004852:Epoxy Compounds; D063991:Mitochondrial Trifunctional Protein; D002334:Carnitine O-Palmitoyltransferase; C054207:etomoxir
keywords: Acylcarnitines; Etomoxir; Long-chain 3-hydroxyacyl-CoA dehydrogenase; Mitochondria; Mitochondrial trifunctional protein deficiency; Oxidative phosphorylation