Ferritin regulates organismal energy balanceand thermogenesis

Abstract

[ENG]Objective:The ferritin heavy/heart chain (FTH) gene encodes the ferroxidase component of the iron (Fe) sequestering ferritin complex, whichplays a central role in the regulation of cellular Fe metabolism. Here we tested the hypothesis that ferritin regulates organismal Fe metabolism in amanner that impacts energy balance and thermal homeostasis.Methods:We developed a mouse strain, referred herein asFthR26fl/fl, expressing a tamoxifen-inducible Cre recombinase under the control of theRosa26(R26) promoter and carrying two LoxP (fl) sites: one at the 50end of theFthpromoter and another the 3’end of thefirstFthexon.Tamoxifen administration induces global deletion ofFthin adultFthR26D/Dmice, testing whether FTH is required for maintenance of organismalhomeostasis.Results:Under standard nutritional Fe supply,Fthdeletion in adultFthR26D/Dmice led to a profound deregulation of organismal Fe metabolism,oxidative stress, inflammation, and multi-organ damage, culminating in death. Unexpectedly,Fthdeletion was also associated with a profoundatrophy of white and brown adipose tissue as well as with collapse of energy expenditure and thermogenesis. This was attributed mechanisticallyto mitochondrial dysfunction, as assessed in the liver and in adipose tissue.Conclusion:The FTH component of ferritin acts as a master regulator of organismal Fe homeostasis, coupling nutritional Fe supply to organismalredox homeostasis, energy expenditure and thermoregulation