title: Regulation of mitochondrial fatty acid β-oxidation in human: what can we learn from inborn fatty acid β-oxidation deficiencies?
abstract: The mitochondrial fatty acid β-oxidation (FAO) pathway plays a crucial role in ATP production in many tissues with high-energy demand. This is highlighted by the diverse and possibly severe clinical manifestations of inborn fatty acid β-oxidation deficiencies. More than fifteen genetic FAO enzyme defects have been described to date, forming a large group of rare diseases. Inborn FAO disorders are characterized by a high genetic heterogeneity, with a variety of gene mutations resulting in complete or partial loss-of-function of the corresponding enzyme. The panel of observed phenotypes varies from multi-organ failure in the neonate with fatal outcome, up to milder late onset manifestations associated with significant disabilities. Diagnosis of FAO disorders has markedly improved over the last decades, but few treatments are available. The clinical, biochemical, and molecular analysis of these disorders provided new, and sometimes unexpected, data on the organization and regulation of mitochondrial FAO in humans, in various tissues, and at various stages of development. This will be illustrated by examples of FAO defects affecting enzymes of long-chain fatty acid import into the mitochondria, or Lynen helix enzymes. The involvement of the transcriptional network regulating FAO gene expression, in particular the PGC-1α/PPAR axis, as a target for pharmacological therapy of these genetic disorders, will also be discussed.
authors.affiliation: INSERM U747, Université Paris Descartes, UFR Biomédicale des Saints-Pères, 45, rue des Saints-Pères, 75270 Paris Cedex 06, France. Electronic address: jean.bastin@inserm.fr.
authors.forename: Jean
authors.initials: J
authors.lastname: Bastin
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000188:drug therapy / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D010084:Oxidation-Reduction
chemical_list: D005227:Fatty Acids; D042964:Acyl-CoA Dehydrogenase
keywords: Fibrates; Inborn enzyme defects; Mitochondrial fatty acid β-oxidation; Newborn screening; PPAR; Pharmacological therapy