Mitochondrial β-oxidation

Long-chain fatty acids cannot freely cross the inner mitochondrial membrane: they require the carnitine shuttle. The enzyme CPT1 (carnitine palmitoyltransferase 1), on the outer membrane, transfers the acyl group to carnitine to form acylcarnitine; a translocase moves it into the matrix and CPT2 regenerates acyl-CoA for oxidation. CPT1 is the rate-limiting step of the entire pathway and is inhibited by malonyl-CoA, the product of acetyl-CoA carboxylase (ACC). When energy is abundant, malonyl-CoA rises and suppresses fat burning; when AMPK is activated (fasting, exercise, caloric restriction), malonyl-CoA falls and β-oxidation accelerates.

Each turn of the cycle yields one FADH₂, one NADH and one molecule of acetyl-CoA, shortening the chain by two carbons until it is fully consumed. Acetyl-CoA enters the Krebs cycle and the reducing equivalents drive oxidative phosphorylation. Efficient β-oxidation reduces the ectopic lipid accumulation linked to insulin resistance and visceral fat. Its decline with age and mitochondrial dysfunction contributes to metabolic fatigue, making it a central target of longevity interventions that optimize mitochondrial function.