Liver specific disruption of Glutaredoxin 3 leads to iron accumulation and impaired cellular iron homeostasis

Authors: CHENG, NINGHUI - Children'S Nutrition Research Center (CNRC); DONELSON, JIMMONIQUE - Children'S Nutrition Research Center (CNRC); BRETON, GHISLAIN - University Of Texas Health Science Center; Nakata, Paul

Submitted to: Biochemical and Biophysical Research Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/28/2023
Publication Date: 1/30/2023
Citation: Cheng, N., Donelson, J., Breton, G., Nakata, P.A. 2023. Liver specific disruption of Glutaredoxin 3 leads to iron accumulation and impaired cellular iron homeostasis. Biochemical and Biophysical Research Communications. 649:39-46. https://doi.org/10.1016/j.bbrc.2023.01.095.
DOI: https://doi.org/10.1016/j.bbrc.2023.01.095

Interpretive Summary: The failure to regulate tissue iron concentrations can have a negative impact on animal health and lead to disease. Glutaredoxin 3 (Grx3) plays a role in regulating tissue iron concentrations but just how it does this remains unknown. As a step toward a better understanding of Grx3's role, we generated and characterized mice that lack Grx3 in their livers. These mice that lacked Grx3 looked and grew just like control mice. But upon closer inspection, mice that lacked Grx3 were found to have enlarged livers. Biochemical measurements using these enlarged livers revealed elevated concentrations of iron and impaired function. Protein measurements revealed an increase in the proteins encoded by iron regulatory genes such as ferritin H. Interestingly, as the amount of ferritin H increased the accumulation of degradation proteins decreased. Overall, our findings suggest a crucial role for Grx3 in regulating iron concentrations in the liver through the control of protein degradation. It is our hope that by conducting these studies and gaining a better understanding of how iron accumulation is controlled in the body, new strategies can be developed that promote better animal health.

Technical Abstract: Iron is an essential mineral nutrient that is tightly regulated through mechanisms encoded by iron sensing, storage, and recycling (e.g. autophagy) genes. Dysregulation of these mechanisms often results in either excess iron accumulation (overload) or iron deficiency (anemia). Recent studies indicate that mammalian glutaredoxin 3 (Grx3) may play a crucial role in iron homeostasis and hemoglobin maturation, but the underlying mechanism remains largely unknown. To study the function of Grx3 in iron regulation in vivo, a Grx3 liver specific deficient (LKO) mouse was generated. Mice with liver specific deletion of Grx3 were viable and grew indistinguishably from their wild-type (WT) littermates. The LKO mice were found to have livers larger than controls and with higher concentrations of iron. Grx3 LKO mice also displayed impaired liver function at the age of 8 months. Transcription profiling analysis revealed increased expression of iron homeostasis genes in LKO mice compared to controls. In addition, we observed altered mitochondrial and nuclear Fe-S cluster assembly. Among the many iron regulatory proteins present in the liver, ferritin H (FTH1) was increased in the LKO mice compared to controls displaying an inverse correlation with proteins of the autophagy pathway. Our data suggests that the Grx3-mediated ferritin H increase may be dependent on cellular iron status. Overall, our findings suggest a crucial role for Grx3 in regulating iron homeostasis in hepatocytes through the control of cellular storage protein turnover and recycling via the autophagy pathway.