Fig. 1: A simplified scheme of mitochondrial fatty acid oxidation.

Most fatty acid oxidation occurs in the mitochondria. Medium- and short-chain fatty acids directly enter the mitochondria. Long-chain fatty acids (LCFA) circulate in plasma bound to albumin. They are carried across the plasma membrane via several LCFA transport systems, CD36 (cluster of differentiation 36) being probably the most important. LCFA must be activated to coenzyme A and transferred to carnitine (CPT IA) to cross the inner mitochondrial membrane (CACT). They are then transferred back to CoA esters in the mitochondrial matrix (CPT II). Beta-oxidation is catalysed by enzymes with different fatty acid chain length specificity (VLCAD, MTP, MCAD, SCAD, crotonase, SCHAD, and SC-thiolase). Electrons (e⁻) are passed to the respiratory chain either directly or via transfer proteins (ETF, ETF-QO). Acetyl-CoA can be oxidised in the tricarboxylic acid (Krebs) cycle or, in the liver, used to synthetize ketone bodies. Fatty acid oxidation disorders mentioned in this manuscript are labelled in red. Crotonase (also named short-chain enoyl-CoA hydratase) deficiency has a different clinical presentation, like mitochondrial cytopathies. No deficiency of LCFA transporter(s) and SC-thiolase has been identified so far. CACT carnitine acylcarnitine translocase, CPT IA carnitine palmitoyl transferase IA, CPT II carnitine palmitoyl transferase II, ETF electron transfer flavoprotein, ETF-QO electron transfer flavoprotein ubiquinone oxidoreductase, LC long-chain, LCFA long-chain fatty acids, LCHAD long-chain 3-hydroxyacyl-CoA dehydrogenase, MC-acyl-CoA medium-chain acyl-CoA, MCAD medium-chain acyl-CoA dehydrogenase, MTP mitochondrial trifunctional protein, OCTN2 high affinity sodium-dependent carnitine transporter, SCAD short-chain acyl-CoA dehydrogenase, SCHAD short-chain 3-hydroxyacyl-CoA dehydrogenase, SC-thiolase short-chain acyl-CoA thiolase, VLCAD very long-chain acyl-CoA dehydrogenase.