Ferritin regulates organismal energy balance and thermogenesis

Birte Blankenhaus, Faouzi Braza, Rui Martins, Patricia Bastos-Amador, Ismael González-García, Ana Rita Carlos, Inês Mahu, Pedro Faisca, Jose Moura Nunes, Pedro Ventura, Verena Hoerr, Sebastian Weis, Joel Guerra, Silvia Cardoso, Ana Domingos, Miguel López, Miguel P. Soares

Intracellular Fe redox activity is controlled by ferritin, a multimeric protein complex composed of variable ratios of ferritin light chain (FTL) and ferritin heavy chain (FTH). Blankenhaus, Braza, et al. report that global Fth deletion in adult mice leads to a profound disruption of organismal Fe metabolism and redox homeostasis, associated with failure to sustain energy expenditure and thermal homeostasis. Ferritin acts as a gatekeeper of organismal Fe metabolism, coupling nutritional Fe supply to organismal energy expenditure and thermoregulation.

Objective: The ferritin heavy/heart chain (FTH) gene encodes the ferroxidase component of the iron (Fe) sequestering ferritin complex, which plays a central role in the regulation of cellular Fe metabolism. Here we tested the hypothesis that ferritin regulates organismal Fe metabolism in a manner that impacts energy balance and thermal homeostasis.

Methods: We developed a mouse strain, referred herein as Fth^R26 fl/fl, expressing a tamoxifen-inducible Cre recombinase under the control of the Rosa26 (R26) promoter and carrying two LoxP (fl) sites: one at the 5′end of the Fth promoter and another the 3' end of the first Fth exon. Tamoxifen administration induces global deletion of Fth in adult Fth^R26Δ/Δ mice, testing whether FTH is required for maintenance of organismal homeostasis.

Results: Under standard nutritional Fe supply, Fth deletion in adult Fth^R26Δ/Δ mice led to a profound deregulation of organismal Fe metabolism, oxidative stress, inflammation, and multi-organ damage, culminating in death. Unexpectedly, Fth deletion was also associated with a profound atrophy of white and brown adipose tissue as well as with collapse of energy expenditure and thermogenesis. This was attributed mechanistically to mitochondrial dysfunction, as assessed in the liver and in adipose tissue.

Conclusions: The FTH component of ferritin acts as a master regulator of organismal Fe homeostasis, coupling nutritional Fe supply to organismal redox homeostasis, energy expenditure and thermoregulation.

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