Ferredoxin 2 is critical for tumor suppression and lipid homeostasis but dispensable for embryonic development.

Abstract

Ferredoxin 1 and 2 (FDX1/2) constitute an evolutionarily conserved FDX family of iron-sulfur cluster (ISC) containing proteins. FDX1/2 are cognate substrates of ferredoxin reductase (FDXR) and serve as conduits for electron transfer from NADPH to a set of proteins involved in biogenesis of steroids, hemes, ISC and lipoylated proteins. Recently, we showed that Fdx1 is essential for embryonic development and lipid homeostasis. To explore the physiological role of FDX2, we generated Fdx2-deficient mice. Interestingly, we found that unlike Fdx1-null embryos, which were dead at embryonic day 10.5 to 13.5, Fdx2-null mice were viable. We also found that both Fdx2-null and Fdx2-heterozygous mice had a short lifespan and were susceptible to spontaneous tumors and steatohepatitis. Moreover, we found that FDX2-deficiency increased whereas overexpression of FDX2 decreased cytoplasmic accumulation of lipid droplets. Consistently, we found that FDX2 deficiency led to accumulation of cholesterol and triglycerides. Mechanistically, we found that FDX2 deficiency suppressed expression of cholesterol transporter ABCA1 and activated master lipid transcription regulators SREBP1/2, thus leading to altered lipid metabolism. Untargeted lipidomic analysis showed that FDX2 deficiency led to altered biosynthesis of various lipid classes, including cardiolipins, cholesterol, ceramides, triglycerides, and fatty acids. In summary, our findings underscore an indispensable role of FDX2 in tumor suppression and lipid homeostasis at both cellular and organismal levels without being a prerequisite for embryonic development.