Mitochondrial fatty acid oxidation pathway and carnitine-dependent transport system (mFAO/Carnitine shuttle)

The mitochondrial fatty acid oxidation (mFAO) pathway and the carnitine-dependent transport system (carnitine shuttle) are essential for the catabolism of long-chain fatty acids to produce energy [1]. The process begins with the transport of fatty acids across the mitochondrial membranes via carnitine palmitoyltransferase 1 (CPT1), carnitine-acylcarnitine translocase (CACT), and carnitine palmitoyltransferase 2 (CPT2) [2]. Once inside the matrix, fatty acids undergo beta-oxidation, a four-step enzymatic cycle (dehydrogenation, hydration, dehydrogenation, and thiolysis) that yields acetyl-CoA, NADH, and FADH2 [1]. This pathway is a major therapeutic target in ischemic heart disease, where drugs like trimetazidine and ranolazine inhibit FAO to promote glucose oxidation, which is more oxygen-efficient [3]. Conversely, genetic deficiencies in mFAO enzymes lead to metabolic crises characterized by hypoglycemia and cardiomyopathy, while certain cancers upregulate this pathway to support rapid proliferation and survival under stress [4, 5].

Other names

Beta-oxidation pathwayCarnitine palmitoyltransferase systemFatty acid beta-oxidationCarnitine shuttle

Inhibition of carnitine palmitoyltransferase 1 (CPT1) to reduce fatty acid entry into mitochondria; inhibition of long-chain 3-ketoacyl-CoA thiolase (3-KAT) to suppress beta-oxidation; or supplementation of carnitine/substrates to bypass metabolic blocks.