Fatty acid metabolism in mitochondria: defects and genetics.

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Inherited disorders of mitochondrial fatty acid β-oxidation have emerged as relatively common causes of metabolic derangement in brain, muscle, and liver. Mitochondrial β-oxidation is a complex pathway of energy production that has become increasingly understood in the last decade, in large part because of the delineation of these clinically important disorders. Of the 20 or so integrated steps involved in mitochondrial energy production from long-chain fatty acids, single-gene abnormalities affecting half of them have been described. Fatty acids are activated to their acyl-CoA derivatives in the cytoplasm and then require carnitine for their transport into mitochondria. Once inside the mitochondrial matrix, they are sequentially broken down in a series of four enzyme-mediated steps, but as the chain length of the fatty acid becomes smaller and smaller, different enzymes that exhibit chain-length specificity carry out some of these steps. In addition, there are enzymes required for handling the double bonds that occur in unsaturated fatty acids. Energy produced from β-oxidation is realized through links to the electron transport chain, to the tricarboxylic acid cycle, and (in the liver) to ketogenesis. The disorders of this pathway (see Table 1) share some clinical and biochemical features that have been valuable in their diagnosis. There is a primarily hepatic presentation (steatosis, hypoketotic hypoglycemia) in some (e.g., MCAD deficiency, CPT I deficiency), a primarily muscular presentation (myopathy, myoglobinuria) in others (e.g., muscular CPT II deficiency), and a combination of these