Enzymes of the outer mitochondrial membrane regulating cholesterol and fatty acid metabolism in cancer

Abstract

Mitochondria are major sites of ATP production, also serving as metabolic and biosynthetic hubs. The structure of mitochondria comprises a matrix enclosed by an inner membrane which is separated from the outer mitochondrial membrane (OMM) by the intermembrane space. The OMM is a lipid bilayer that forms an interphase between mitochondria and the surrounding cytosol. While its primary function is to act as a selective barrier, controlling the exchange of molecules between these two cellular compartments, the OMM also plays a crucial role in various metabolic and regulatory processes. It is home to 114 distinct proteins, including transporters, signaling molecules, and structural components. Among these, approximately 30 are enzymes that actively participate in the regulation of lipid metabolism, amino acid processing, calcium homeostasis, and heme biosynthesis. These enzymatic functions highlight the OMM’s significance beyond its structural role, positioning it as a key player in cellular energy balance, apoptosis, and intracellular signaling pathways. Here, we focus on OMM proteins involved in the synthesis and utilization of cholesterol and fatty acids. We describe the mechanisms of action, effects, regulation, association with cancer progression, and their potential as pharmacological targets of the steroid acute regulatory protein (StAR), translocator protein (TSPO), acetyl-CoA carboxylase β (ACCβ), acyl-CoA synthetases long chain family member 1 and 6 (ACSL1 and ACSL6), and carnitine palmitoyl transferases 1A and 1B (CPT1A and CPT1B). Overall, we provide a comprehensive view of these OMM enzymes in non-cancerous and cancer cells as well as their potential as targets for developing novel chemotherapies.