Abstract
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid β-oxidation in humans. To better understand the pathogenesis of this disease, we developed a mouse model for MCAD deficiency (MCAD−/−) by gene targeting in embryonic stem (ES) cells. The MCAD−/− mice developed an organic aciduria and fatty liver, and showed profound cold intolerance at 4 °C with prior fasting. The sporadic cardiac lesions seen in MCAD−/− mice have not been reported in human MCAD patients. There was significant neonatal mortality of MCAD−/− pups demonstrating similarities to patterns of clinical episodes and mortality in MCAD-deficient patients. The MCAD-deficient mouse reproduced important aspects of human MCAD deficiency and is a valuable model for further analysis of the roles of fatty acid oxidation and pathogenesis of human diseases involving fatty acid oxidation.
Highlights
Mitochondrial b-oxidation of fatty acids provides energy, especially during fasting conditions
Targeting Acadm produced a mouse model for Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency with features that mimic the clinical, biochemical, and pathologic phenotype found in human patients
MCAD-deficient patients have abnormal plasma and urine metabolites associated with the medium chain–length enzyme specificity
Summary
Mitochondrial b-oxidation of fatty acids provides energy, especially during fasting conditions. Fatty acid oxidation occurs in mitochondria and consists of a repeating circuit of four sequential steps. There are four straight-chain acyl-CoA dehydrogenases involved in the initial step. Medium-chain acyl-CoA dehydrogenase (MCAD) (the mouse gene is Acadm, whereas the protein is MCAD), is responsible for catalyzing the dehydrogenation of medium-chain length (C6– C12) fatty acid thioesters [1]. Acadm is transcribed in the nucleus, translated in the cytosol, and translocated into the mitochondrial matrix [2,3,4]. Once inside the mitochondrial matrix, the MCAD monomers are assembled into homotetramers to gain enzymatic activity [4]
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