title: Mitochondrial superoxide mediates labile iron level: evidence from Mn-SOD-transgenic mice and heterozygous knockout mice and isolated rat liver mitochondria.
abstract: Superoxide is the main reactive oxygen species (ROS) generated by aerobic cells primarily in mitochondria. It is also capable of producing other ROS and reactive nitrogen species (RNS). Moreover, superoxide has the potential to release iron from its protein complexes. Unbound or loosely bound cellular iron, known as labile iron, can catalyze the formation of the highly reactive hydroxyl radical. ROS/RNS can cause mitochondrial dysfunction and damage. Manganese superoxide dismutase (Mn-SOD) is the chief ROS-scavenging enzyme and thereby the primary antioxidant involved in protecting mitochondria from oxidative damage. To investigate whether mitochondrial superoxide mediates labile iron in vivo, the levels of labile iron were determined in the tissues of mice overexpressing Mn-SOD and heterozygous Mn-SOD-knockout mice. Furthermore, the effect of increased mitochondrial superoxide generation on labile iron levels was determined in isolated rat liver mitochondria exposed to various electron transport inhibitors. The results clearly showed that increased expression of Mn-SOD significantly lowered the levels of labile iron in heart, liver, kidney, and skeletal muscle, whereas decreased expression of Mn-SOD significantly increased the levels of labile iron in the same organs. In addition, the data showed that peroxidative damage to membrane lipids closely correlated with the levels of labile iron in various tissues and that altering the status of Mn-SOD did not alter the status of other antioxidant systems. Results also showed that increased ROS production in isolated liver mitochondria significantly increased the levels of mitochondrial labile iron. These findings constitute the first evidence suggesting that mitochondrial superoxide is capable of releasing iron from its protein complexes in vivo and that it could also release iron from protein complexes contained within the organelle.
authors.affiliation: Department of Nutrition and Health, College of Food and Agriculture, United Arab Emirates University, Al Ain, United Arab Emirates. Electronic address: wibrahim@uaeu.ac.ae.
authors.forename: Wissam H
authors.initials: WH
authors.lastname: Ibrahim
authors.affiliation: Department of Nutrition and Health, College of Food and Agriculture, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Hosam M
authors.initials: HM
authors.lastname: Habib
authors.affiliation: Department of Nutrition and Health, College of Food and Agriculture, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Hina
authors.initials: H
authors.lastname: Kamal
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Daret K
authors.initials: DK
authors.lastname: St Clair
authors.affiliation: Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Ching K
authors.initials: CK
authors.lastname: Chow
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D006801:Humans; D007501:Iron / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D013481:Superoxides; D007501:Iron; D013482:Superoxide Dismutase
keywords: Antioxidant status; Cu-Zn-SOD; Free radicals; GSH; Heterozygous Mn-SOD-knockout mice; Labile iron; Lipid peroxidation; Mitochondria; Mn-SOD; Mn-SOD-transgenic mice; RNS; ROS; Superoxide; TBARS; copper-zinc superoxide dismutase; manganese superoxide dismutase; reactive nitrogen species; reactive oxygen species; reduced glutathione; thiobarbituric acid reactants