Patients with primary or secondary hemochromatosis are liable to cardiac and hepatic failure, and type II diabetes. Despite the (highly likely) conjecture that iron-mediated tissue damage involves the conspiracy of cellular oxidizing and reducing equivalents, the pathophysiologic events have not been fully elucidated. The present investigations represent an attempt to define the toxic effects of iron on intracellular organelles, in particular, mitochondria and lysosomes. The tissues at risk- heart, liver and pancreatic beta cells - all have highly active mitochondria which incidentally generate activated oxygen species capable of causing synergistic toxicity with intracellular iron. Our investigations center about three specific hypotheses: (1) Iron is more toxic to cells with active mitochondria. (2) The mitochondrial genome is preferentially damaged by iron-mediated oxidative reactions and accumulation of mutational events leads to mitochondrial dysfunction. (3) 'Loose' intracellular iron also causes the oxidative destabilization of lysosomes, causing leak of digestive enzymes into the cell cytoplasm and eventuating in apoptotic or necrotic cell death. These hypotheses will be tested by: (1) Determining whether cultured myeloid cells and myoblasts with active mitochondria are more readily damaged by iron loading than are cells depleted in mitochondrial function (via long-term culture in ethidium bromide or treatment with selected inhibitors). (2) Using full-length quantitative polymerase chain reaction, we will determine whether the mitochondrial genome in iron-loaded cultured myoblasts accumulates modification which prevent read-through by the polymerase compared with similar lengths of genes within the nuclear genome. In these experiments, several techniques will also be used to estimate the state of 'intactness' of cellular lysosomes. (3) Similar investigations of mitochondrial vs. nuclear DNA damage and lysosomal integrity will also be conducted on mice with congenital or acquired iron-overload, mice expressing 50 percent of normal manganese superoxide dismutase (the mitochondrial form of the enzyme), sickle hemoglobin and thalassemia. The resulting information will be used to help probe the efficiency of presently available and experimental chelators, not only in promoting iron excretion but also in the prevention of defined types of cellular damage.
| Campian, Jian Li; Gao, Xueshan; Qian, Mingwei et al. (2007) Cytochrome C oxidase activity and oxygen tolerance. J Biol Chem 282:12430-8 |
| Gao, Xueshan; Qian, Mingwei; Campian, Jian Li et al. (2006) Cytotoxic and mutagenic effects of tobacco-borne free fatty acids. Free Radic Biol Med 40:165-72 |
| Ujhelyi, L; Balla, G; Jeney, V et al. (2006) Hemodialysis reduces inhibitory effect of plasma ultrafiltrate on LDL oxidation and subsequent endothelial reactions. Kidney Int 69:144-51 |
| Persson, H Lennart; Kurz, Tino; Eaton, John W et al. (2005) Radiation-induced cell death: importance of lysosomal destabilization. Biochem J 389:877-84 |
| Nagy, E; Jeney, V; Yachie, A et al. (2005) Oxidation of hemoglobin by lipid hydroperoxide associated with low-density lipoprotein (LDL) and increased cytotoxic effect by LDL oxidation in heme oxygenase-1 (HO-1) deficiency. Cell Mol Biol (Noisy-le-grand) 51:377-85 |
| Campian, Jian Li; Qian, Mingwei; Gao, Xueshan et al. (2004) Oxygen tolerance and coupling of mitochondrial electron transport. J Biol Chem 279:46580-7 |
| Li, Jian; Gao, Xueshan; Qian, Mingwei et al. (2004) Mitochondrial metabolism underlies hyperoxic cell damage. Free Radic Biol Med 36:1460-70 |
| Balla, Jozsef; Vercellotti, Gregory M; Nath, Karl et al. (2003) Haem, haem oxygenase and ferritin in vascular endothelial cell injury. Nephrol Dial Transplant 18 Suppl 5:v8-12 |
| Persson, Hans L; Yu, Zhengquan; Tirosh, Oren et al. (2003) Prevention of oxidant-induced cell death by lysosomotropic iron chelators. Free Radic Biol Med 34:1295-305 |
| Yu, Zhengquan; Persson, H Lennart; Eaton, John W et al. (2003) Intralysosomal iron: a major determinant of oxidant-induced cell death. Free Radic Biol Med 34:1243-52 |
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