Ferredoxin 1 is essential for embryonic development and lipid homeostasis.

Abstract

Mammalian ferredoxin 1 and 2 (FDX1/2) belong to an evolutionary conserved family of iron-sulfur cluster containing proteins and act as electron shutters between ferredoxin reductase (FDXR) and numerous proteins involved in critical biological pathways. FDX1 is involved in biogenesis of steroids and bile acids, Vitamin A/D metabolism, and lipoylation of tricarboxylic acid (TCA) cycle enzymes. FDX1 has been extensively characterized biochemically but its role in physiology and lipid metabolism has not been explored. In this study, we generated <i>Fdx1</i>-deficient mice and showed that knockout of both alleles of the <i>Fdx1</i> gene led to embryonic lethality. We also showed that like <i>Fdxr^+/-</i>+/-, <i>Fdx1^+/-</i>+/- had a shorter life span and were prone to steatohepatitis. However, unlike <i>Fdxr^+/-</i>+/-, <i>Fdx1^+/-</i>+/- were not prone to spontaneous tumors. Additionally, we showed that FDX1 deficiency led to lipid droplet accumulation possibly via the ABCA1-SREBP1/2 pathway. Specifically, untargeted lipidomic analysis showed that FDX1 deficiency led to alterations in several classes of lipids, including cholesterol, triacylglycerides, acylcarnitines, ceramides, phospholipids and lysophospholipids. Taken together, our data indicate that FDX1 is essential for mammalian embryonic development and lipid homeostasis at both cellular and organismal levels.