Crosstalk between Succinate and Fatty Acid Metabolism

Fatty acid biosynthesis is mainly known as a cytosolic process carried out by the fatty acid synthase (FASN). FASN is a very large enzyme with several catalytic subunits that perform sequential enzymatic reactions to produce palmitic acid (PA) from Malony CoA. Malonyl CoA itself is produced from acetyl CoA, which originates from the mitochondria. PA serves for generating membranes or steroids and hormones. Additionally, PA can be used for lipid storage or as a signal molecule or can be converted back into citrate, which is transported to the mitochondria for ATP production via ß oxidation. The mitochondrial production of fatty acids however is less well appreciated. Several independent mitochondrial proteins, each having homologies with one of the FASN subunits, synthetise lipoic acid from malonyl CoA. Unlike PA, lipoic acid is not used for the formation of membranes. Lipoic acid is a crucial regulatory cofactor of mitochondrial metabolic enzymes, the dehydrogenases, and plays an important role in regulating the biogenesis of the respiratory chain according to the available acetyl CoA pools. We found that a new FASN inhibitor inhibits not only FASN but also the succinate dehydrogenase (SDH)/respiratory chain complex II, and induces cell death in cancer cells through this dual inhibition. However, it is mechanistically not clear how pharmacological inhibition of cytosolic FASN inhibits mitochondrial SDH. Our hypothesis is that the cytosolic and the mitochondrial fatty acid synthesis interact with each other and that this interaction regulates the SDH activity. The aim of the project is therefore to investigate whether the FASN inhibitor also suppresses the mitochondrial fatty acid biogenesis and whether mitochondrial fatty acid biogenesis coordinates the assembly of SDH, which consists of four subunits. An additional aim is to identify which proteins or metabolites of cytosolic and mitochondrial fatty acid biosynthesis communicate with each other. So far, only cytosolic fatty acid synthesis has been attributed a role in cancer because FASN is upregulated in cancer cells. The discovery of interorganellar communication between the two fatty acid biosynthesis systems would be completely new and possibly reveal a new role of mitochondrial fatty acid synthesis in tumors.

Cells possess two distinct systems for fatty acid synthesis. The first operates in the cytosol and is carried out by the enzyme fatty acid synthase (FASN), which produces palmitic acid. Palmitic acid is essential for building cell membranes and hormones, storing energy, and supporting cellular signaling. Because FASN activity is often increased in cancer cells, it represents an attractive therapeutic target. Far less is known about mitochondrial fatty acid synthesis (mtFAS). In mitochondria, a set of enzymes produces octanoic acid, which is further converted into lipoic acid. Unlike palmitic acid, lipoic acid does not serve for membrane formation but is an essential cofactor for key mitochondrial enzymes that support cellular energy metabolism. We discovered that a novel FASN inhibitor, originally developed as an anticancer drug, not only blocks FASN but also inhibits succinate dehydrogenase (SDH), a central enzyme of mitochondrial energy metabolism. This unexpected dual targeting explains the strong cytotoxic effect of the compound. We further demonstrated a synthetic lethal interaction between FASN and SDHB, meaning that cancer cells lacking SDH activity critically depend on FASN for survival. This finding opens new therapeutic perspectives for tumors caused by SDH mutations. To understand the mechanism underlying this dual inhibition, we investigated whether cytosolic and mitochondrial fatty acid synthesis are functionally connected. Our results indicate that the two systems operate independently. Instead, we identified the mitochondrial enzyme LIAS, which converts octanoic acid into lipoic acid, as an additional drug target. Our data show that the iron-sulfur protein LIAS is indispensable for SDHB stability and function and consequently for the assembly of a functional SDH complex. Together, our findings uncover a previously unrecognized link between fatty acid metabolism and SDH function in cancer cells, providing a new mechanistic basis for targeting metabolic vulnerabilities. Central to our findings is the identification of LIAS as a key determinant of SDH biogenesis and function.