Lack of Transferrin Receptor 1 in the Heart Causes Lethal Cardiomyopathy and Disruption of Mitophagy in Mice

Iron is an essential nutrient involved in numerous cellular functions and tightly regulated within cells. It is extremely important to maintain both systemic and intracellular iron homeostasis by orchestrating iron uptake, storage, utilization and export. Many human diseases are associated with disruption of iron homeostasis. Both iron overload and iron deficiency have been associated with cardiomyopathy and heart failure, but the molecular details of cardiac iron utilization are incompletely understood. Although it was known that transferrin receptor 1 (Tfr1) is responsible for iron uptake in erythroid precursors, its role in other tissues, and other possible roles, have not been studied in detail. We hypothesized that Tfr1 might play a role in cardiac iron uptake and used gene targeting to examine the role of Tfr1 in the heart in vivo. Tfr1 was deleted specifically in cardiomyocytes, and loss of Tfr1 caused iron deficiency in the heart. Surprisingly, we found that decreased iron was associated with severe cardiac metabolic consequences. Mice lacking Tfr1 in the heart died in the second week of life, with cardiomegaly, poor cardiac function, failure of mitochondrial respiration and ineffective mitophagy. The phenotype could only be rescued by aggressive and ongoing iron therapy, but it was ameliorated by either a mutant Tfr1 allele that does not bind transferrin or administration of nicotinamide riboside, an NAD precursor.

In summary, our study found that Tfr1 plays a primary role in uptake of Tf-bound iron in the heart, and yet may have other iron-independent functions in autophagy. Our results showed that iron is critical for the normal cellular metabolism, mitochondrial respiration and mitophagy in the heart. Our findings underscore the importance of both Tfr1 and iron in the heart and provide mechanistic evidence for iron therapy in heart failure patients. By elucidating the processes iron participates in the heart and the consequences of cardiac iron deficiency, our study may inform the identification of new therapeutic targets for heart failure. Finally, we found that NR prolonged the lifespan of mice with cardiac iron deficiency, suggesting possible benefit in treating heart failure accompanied by iron deficiency.