Human Molecular Genetics Advance Access published online on September 24, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn308
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MITOCHONDRIAL FERRITIN LIMITS OXIDATIVE DAMAGE REGULATING MITOCHONDRIAL IRON AVAILABILITY: HYPOTHESIS FOR A PROTECTIVE ROLE IN FRIEDREICH ATAXIA
1 IIT Network, Research Unit of Molecular Neuroscience, Via Olgettina 58, 20132, Milano, Italy 2 Vita-Salute San Raffaele University, Via Olgettina 58, 20132, Milano, Italy 3 San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milano, Italy 4 Division of Biochemistry and Genetics, Fondazione IRCCS-Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy
* Correspondence: Prof. Sonia Levi Vita-Salute San Raffaele University and San Raffaele Scientific Institute Via Olgettina 58 20132 Milano ITALY tel:39-02-26434755 Fax:39-02-26434844 e-mail: levi.sonia{at}hsr.it
Received July 30, 2008; Revised September 22, 2008; Accepted September 22, 2008
Mitochondrial ferritin (FtMt) is a nuclear-encoded iron-sequestering protein that specifically localizes in mitochondria. In mice it is highly expressed in cells characterized by high-energy consumption, while is undetectable in iron storage tissues like liver and spleen. FtMt expression in mammalian cells was shown to cause a shift of iron from cytosol to mitochondria, and in yeast it rescued the defects associated with frataxin deficiency. To study FtMt role in oxidative damage we analysed the effect of its expression in HeLa cells after incubation with H2O2 and Antimicyn A, and after long-term growth in glucose-free media that enhance mitochondrial respiratory activity. FtMt reduced Reactive Oxygen Species (ROS) level, increased ATP level and the activity of mitochondrial Fe-S enzymes, and had positive effect on cell viability. Furthermore, FtMt expression reduced the size of cytosolic and mitochondrial labile iron pools. In cells grown in glucose-free media, FtMt level was reduced due to faster degradation rate, however it still protected the activity of mitochondrial Fe-S enzymes without affecting cytosolic iron status. In addition, FtMt expression in fibroblasts from Fredreich ataxia (FRDA) patients prevented ROS formation and partially rescued the impaired activity of mitochondrial Fe-S enzymes, caused by frataxin deficiency. These results indicate that the primary function of FtMt consists in the control of ROS formation through the regulation of mitochondrial iron availability. They are consistent with the FtMt expression pattern observed in mouse tissues, suggesting a FtMt protective role in cells characterized by defective iron homeostasis and respiration, such as in FRDA.