Mitochondrial fatty acid beta-oxidation (mFAO) (mFAO)

Mitochondrial beta-oxidation is the primary metabolic pathway for the catabolism of fatty acids into acetyl-CoA, which then enters the tricarboxylic acid (TCA) cycle to generate ATP [15, 17]. This multi-step process occurs within the mitochondrial matrix and involves four recurring enzymatic reactions: oxidation, hydration, oxidation, and thiolysis, catalyzed by enzymes such as acyl-CoA dehydrogenases and the mitochondrial trifunctional protein [2, 7]. The pathway is critical for energy homeostasis, particularly in high-demand tissues like the heart and skeletal muscle during periods of fasting or metabolic stress [1, 16]. Genetic deficiencies in pathway enzymes lead to fatty acid oxidation disorders (FAODs), characterized by life-threatening hypoketotic hypoglycemia and cardiac dysfunction [1, 12]. Pharmacologically, the pathway is targeted for inhibition in ischemic heart disease to shift myocardial fuel preference from fatty acids to more oxygen-efficient glucose oxidation, or activated via regulatory proteins like ACC2 to treat obesity and metabolic syndrome [3, 11, 20].

Other names

Mitochondrial fatty acid oxidationFatty acid beta-oxidationBeta-oxidation pathwayFAOFatty acid beta-oxidation spiral

Inhibition of carnitine palmitoyltransferase 1 (CPT1) to prevent fatty acid entry into mitochondria, or inhibition of 3-ketoacyl-CoA thiolase (3-KAT) to halt the final step of the beta-oxidation spiral, thereby shifting metabolism toward glucose oxidation.