Mitochondrial fatty acid synthesis: The physiopathological role in cellular processes and human diseases

The cytosolic fatty acid synthesis (FAS) type I pathway is widely recognized as the "classical" system in mammals. However, recent investigations have identified another highly conserved de novo fatty acid synthesis pathway, the mitochondrial fatty acid synthesis (mtFAS) pathway, or FAS II. This pathway operates within mitochondria and relies on malonyl-CoA/acyl carrier protein (ACP). Experimental evidence has underscored the pivotal role of mtFAS in mitochondrial respiratory function, biogenesis, cell growth, cell differentiation, and immune-inflammatory responses. The primary product of this pathway, octanoyl-ACP, is a vital substrate for lipoic acid in mitochondria. Subsequent studies indicate that the mtFAS pathway can also generate long-chain fatty acids with lengths up to 16 carbons, which attach to mitochondrial ACP. These longer acyl chains are known to modulate mitochondrial translation, protein acylation, and mitochondrial oxidative phosphorylation. Nonetheless, the specific role and fate of these longer fatty acids remain an enigma. Deficiencies in the mtFAS pathway are correlated with altered mitochondrial physiology and various human diseases. This underscores the nexus between mtFAS and pathological conditions. This review provides a comprehensive overview of the enzymes and products involved in the mtFAS pathway, elucidates the potential mechanisms through which mtFAS influences cellular processes, and explores its association with human disease. Collectively, these findings contribute to a deeper understanding of the physiopathological significance of the mtFAS pathway.