Mitochondrial fatty acid beta-oxidation pathway (mFAO)

The mitochondrial fatty acid beta-oxidation (FAO) pathway is a fundamental metabolic process that breaks down long-chain fatty acids to generate acetyl-CoA, NADH, and FADH2, which are essential for ATP production via the citric acid cycle and oxidative phosphorylation [1]. The pathway involves the activation of fatty acids in the cytosol, their transport across the mitochondrial membranes via the carnitine shuttle (facilitated by CPT1 and CPT2), and a four-step recurring enzymatic cycle of oxidation, hydration, and thiolysis [2]. In clinical medicine, this pathway is a significant therapeutic target for ischemic heart diseases and heart failure; by pharmacologically inhibiting FAO, the heart is forced to shift its metabolism toward glucose oxidation, which requires less oxygen per mole of ATP produced [3]. Beyond cardiology, the pathway is implicated in the metabolic reprogramming of cancer cells, which often upregulate FAO to survive under stress, and in genetic disorders such as Medium-Chain Acyl-CoA Dehydrogenase (MCAD) deficiency [4]. Drugs like trimetazidine and ranolazine are used to modulate this pathway to provide anti-anginal effects, while research continues into its role in metabolic syndrome and oncology [5]. [1] Houten, S. M., & Wanders, R. J. (2010). J Inherit Metab Dis. [2] Longo, N., et al. (2016). Am J Med Genet. [3] Lopaschuk, G. D., et al. (2010). Physiol Rev. [4] Knottnerus, S. J., et al. (2018). Semin Cell Dev Biol. [5] Carracedo, A., et al. (2013). Nat Rev Cancer.

Other names

Fatty acid oxidationBeta-oxidationMitochondrial fatty acid import and oxidationFAO pathwayCarnitine shuttle and beta-oxidation

Inhibition of key enzymes (e.g., 3-ketoacyl-CoA thiolase) or transporters (e.g., Carnitine palmitoyltransferase 1) within the pathway to reduce fatty acid utilization and promote glucose oxidation, which improves oxygen efficiency in ischemic tissues.