Oxidants in mitochondria: from physiology to diseases

Abstract

Reactive oxygen species (ROS: superoxide radical, O2.-; hydrogen peroxide, H2O2; hydroxyl radical, OH.), which arise from the univalent reduction of dioxygen are formed in mitochondria. We summarize here results which indicate that ROS, and also the radical nitrogen monoxide ('nitric oxide', NO), act as physiological modulators of some mitochondrial functions, but may also damage mitochondria. Hydrogen peroxide, which originates in mitochondria predominantly from the dismutation of superoxide, causes oxidation of mitochondrial pyridine nucleotides and thereby stimulates a specific Ca2+ release from intact mitochondria. This release is prevented by cyclosporin A (CSA). Hydrogen peroxide thus contributes to the maintenance of cellular Ca2+ homeostasis. A stimulation of mitochondrial ROS production followed by an enhanced Ca2+ release and re uptake (Ca2+ 'cycling') by mitochondria causes apoptosis and necrosis, and contributes to hypoxia/reperfusion injury. These kinds of cell injury can be attenuated at the mitochondrial level by CSA. When ROS are produced in excessive amounts in mitochondria nucleic acids, proteins, and lipids are extensively modified by oxidation. Physiological (sub-micromolar) concentrations of NO potently and reversibly deenergize mitochondria at oxygen tensions that prevail in cells by transiently binding to cytochrome oxidase. This is paralleled by mitochondrial Ca2+ release and uptake. Higher NO concentrations or prolonged exposure of cells to NO causes their death. It is concluded that ROS and NO are important physiological reactants in mitochondria and become toxic only when present in excessive amounts.

Role of Ca(2+) in diallyl disulfide-induced apoptotic cell death of HCT-15 cells

“…In a wide variety of multicellular organisms, ROIs production, in conjunction with changes in Ca 2+ homeostasis, is a common feature of apoptosis and necrosis (Nicotera and Orrenius, 1992;Richter et al, 1995;Lipton and Nicotera, 1998). We demonstrated the increase of DCF fluorescence correlating with the production of H 2 O 2 in the cells treated with DADS.…”

Purification, molecular cloning, and some properties of a manganese-containing superoxide dismutase from Japanese flounder (Paralichthys olivaceus)

“…Inefficient targeting of Mn-SOD caused mitochondria without their full defense system against superoxide radicals, leading to protein oxidation as well as mitochondrial DNA mutations (Rosenblum et al, 1996;Ambrosone et al, 1999). Thus, it is becoming increasingly clear that the mitochondria-targeting signal plays a crucial role in terms of Mn-SOD controlling dioxygen toxicity in the mitochondria (Fridovich, 1995;Richter et al, 1995). According to some reports, the mitochondria-targeting signal is characterized by the existence of some common basic amino acids and the insertion of several hydrophobic amino acids into these basic amino acids (Roise and Schatz, 1988;Wispe et al, 1989).…”

Biochemistry and pathology of radical-mediated protein oxidation

“…Mitochondria exposed to exogenous radicals lose control of ion balance, notably of calcium transport ; protein oxidation as well as proteolysis may be important in such changes [145,155,156]. Leakage of electrons from the chains, leading to radical fluxes and self-inactivation, may also be important, especially as mitochondria seem to be a major radical-generating site and contain more oxidized DNA than nuclei [157,158]. Again, this may be associated with alterations in enzymic proteolysis as well as protein oxidation [159,160].…”