Submitted April 24, 2006
Accepted May 18, 2006
In vivo tumor growth is inhibited by cytosolic iron
deprivation caused by the expression of mitochondrial
ferritin
Guangjun Nie, Guohua Chen, Alex D Sheftel, Kostas Pantopoulos, and Prem Ponka*
Lady Davis Institute for Medical Research, Dept. of Physiology, McGill University, Quebec, Canada
Lady Davis Institute for Medical Research, Dept. of Medicine, McGill University, Quebec, Canada
* Corresponding author; email: prem.ponka{at}mcgill.ca.
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.
