mRNA-binding protein tristetraprolin is essential for cardiac response to iron deficiency by regulating mitochondrial function

Abstract

Significance Iron deficiency is the most common nutrient deficiency, yet cardiomyopathy rarely develops in these patients. We solved this paradox and identified a protective mechanism involving the mRNA-binding protein tristetraprolin (TTP), which adjusts mitochondrial function in response to iron deficiency. Mice lacking TTP in their hearts were phenotypically normal at baseline but developed spontaneous cardiomyopathy under iron deficiency and exhibited increased reactive oxygen species (ROS)-mediated damage in their hearts. We further demonstrate that down-regulation of specific iron-containing mitochondrial complexes by TTP is the mechanism preventing the formation of dysfunctional mitochondria, subsequent ROS production, and cellular damage. In summary, we show that activation of TTP is part of a required pathway protecting critical organ function when iron becomes scarce.