Mitochondrial
ferritin (MtFt) is a mitochondrial
iron-storage
protein whose function and regulation is largely unknown. Our previous results have shown that MtFt overexpression markedly affects intracellular
iron homeostasis in mammalian cells. Using
tumor xenografts, we examined the effects of MtFt overexpression on
tumor iron metabolism and growth. The expression of MtFt dramatically reduced implanted
tumor growth in nude mice. Mitochondrial
iron deposition in MtFt-expressing
tumors was directly observed by transmission electron microscopy. A cytosolic
iron starvation phenotype in MtFt-expressing
tumors was revealed by increased
RNA-binding activity of
iron regulatory proteins, and concomitantly both an increase in
transferrin receptor levels and a decrease in cytosolic
ferritin. MtFt overexpression also led to decreases in total cellular
heme content and
heme oxygenase-1 levels. In addition, elevated MtFt in
tumors was also associated with a decrease in total
aconitase activity and lower
frataxin protein level. In conclusion, our study shows that high MtFt levels can significantly affect
tumor iron homeostasis by shunting
iron into mitochondria;
iron scarcity resulted in partially deficient
heme and
iron-
sulfur cluster synthesis. It is likely that deprivation of
iron in the cytosol is the cause for the significant inhibition of xenograft
tumor growth.