betaOxidation

Beta-oxidation is the catabolic process by which fatty acids are broken down into acetyl-CoA units, with the concomitant production of NADH and FADH2 that feed the mitochondrial respiratory chain for ATP generation. It occurs mainly in the mitochondrial matrix; very-long-chain fatty acids are initially shortened in peroxisomes, and the resulting shorter acyl-CoAs are transported to mitochondria for completion.

Activation and transport: Fatty acids are activated to fatty acyl-CoA in the cytosol by fatty acyl-CoA synthetases. Long-chain acyl-CoAs enter the mitochondria via the carnitine shuttle, involving CPT1 on the outer membrane, the CACT translocase, and CPT2 on the inner membrane.

Cycle: Each round shortens the acyl-CoA by two carbons, yielding one acetyl-CoA, one FADH2, and one NADH. The steps are: oxidation to enoyl-CoA by acyl-CoA dehydrogenase (FADH2); hydration to 3-hydroxyacyl-CoA; oxidation to 3-ketoacyl-CoA (NADH); thiolysis by beta-ketothiolase to release acetyl-CoA and a shortened acyl-CoA. Repetition continues until the fatty acyl-CoA is reduced to acetyl-CoA units.

Even- versus odd-numbered chains: Even-numbered fatty acids yield only acetyl-CoA units along with reduced cofactors. Odd-numbered chains generate one propionyl-CoA per cycle, which is converted to succinyl-CoA and enters the TCA cycle after appropriate remodeling.

Peroxisomal beta-oxidation: Very-long-chain and certain branched substrates are partly oxidized in peroxisomes, where electrons are transferred to O2 (producing H2O2, neutralized by catalase). Shortened products are then transferred to mitochondria for final oxidation.

Clinical significance: Defects in beta-oxidation enzymes or transport (eg, MCAD deficiency, CPT deficiencies) cause metabolic disorders such as hypoketotic hypoglycemia during fasting.