Nuclear translocation of mitochondrial ferredoxin reductase is regulated by AKT-mediated phosphorylation

Ferredoxin reductase (FDXR) is the sole ferredoxin reductase in humans and plays an essential role for steroidogenesis and biosynthesis of heme and iron-sulfur cluster (ISC) by transferring electrons from NADPH to ISC-containing ferredoxin 1 (FDX1) and FDX2. In this study, we found that while FDXR is classified as a mitochondria-localized flavoprotein, it can be translocated into the nucleus, especially in response to various stress signals. Next, we identified a bipartite nuclear localization signal within amino acids 271-299 of FDXR, the disruption of which impairs its nuclear translocation. Further, we found that AKT can phosphorylate threonine 277 adjacent to the NLS in FDXR and subsequently enhances its nuclear translocation. Consistent with this, mutant FDXR(T277A), in which threonine 277 was substituted with alanine, impaired FDXR nuclear translocation. Together, our data provide evidence that the mitochondrial FDXR can be translocated to the nucleus, which is regulated by AKT-mediated phosphorylation, especially in response to cellular stress. Our data suggest that FDXR plays a role in the mitochondria-nucleus communication and stress responses.