Abstract
Mitochondrial ferritin (FtMt) is an iron-sequestering protein that specifically localizes into mitochondria and whose physiological role is only partly characterized. It was first identified in humans and subsequently described in mice, Drosophila, and plant. FtMt is a 24-homo-polymeric shell protein, with structure and function similar to those of cytosolic H-ferritin. Different from cytosolic ferritins, FtMt does not show ubiquitous distribution, and its expression is not iron-dependent. Studies on mice revealed that the protein has a tight tissue-specific expression pattern; it is preferentially expressed in cells characterized by high-energy consumption, like spermatozoa, neurons, and cardiomyocytes, while it is not present in iron storage tissues. In humans, the protein is also highly expressed in sideroblasts of patients affected by sideroblastic anemia (SA), and data on patients with myelodysplastic syndromes has provided evidence that FtMt represents a specific marker of SA. In refractory anemia with ringed sideroblasts, FtMt expression occurred in CD34+ cells before any morphological sign of maturation and iron accumulation appeared. This argues for a complex mechanism of gene regulation that remains to be elucidated. Previous studies on HeLa and yeast cells showed that FtMt expression affected cellular iron homeostasis, driving iron into mitochondria and inducing cytosolic iron starvation; however, FtMt is also able to reduce mitochondrial iron accumulation and improve iron-sulphur cluster (Fe/S) enzymes activity. Thus, it remains to be established under which conditions the presence of FtMt could be either helpful or detrimental to the cells. To clarify the physiological role of human FtMt, we tested its properties on a HeLa-tTa inducible clone. Expression of FtMt in cells was associated with a protective effect against oxidative damage promoted by hydrogen peroxide or Antimycin A insults, and against oxidative stress occurring under increased mitochondrial respiratory metabolism. The FtMt expression reduced the Reactive Oxygen Species (ROS) level and preserved ATP production and mitochondrial Fe/S enzymes activity, with a consequent positive effect on cell viability. FtMt reduced cytosolic and mitochondrial labile iron pools during glycolytic cellular growth, where FtMt was slowly degraded. In cells grown in glucose-free media, FtMt was degraded faster, determining iron redistribution among cellular compartments, which promoted mitochondrial enzymes activity without affecting cytosolic iron status. However, even under enhanced respiratory condition, FtMt maintained ROS buffering properties, indicating that the primary function of FtMt consists of the control of ROS formation through the regulation of mitochondrial iron availability. This FtMt protective effect might be particularly important in iron-overloaded mitochondria, as in SA. We produced FtMt-lentivirus vectors to transduce human CD34+ cells, and preliminary results indicate that they can be effectively employed to clarify the role of FtMt in pathophysiology of SA.
Role of cation gradients in hypercontracture of myocytes during simulated ischemia and reperfusion
