Oxidants in mitochondria: from physiology to diseases.
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.
Richter
C
C
Laboratory of Biochemistry I, Swiss Federal Institute of Technology (ETH), Zürich.
Gogvadze
V
V
Laffranchi
R
R
Schlapbach
R
R
Schweizer
M
M
Suter
M
M
Walter
P
P
Yaffee
M
M
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004194:Disease; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D009603:Nitroso Compounds / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012016:Reference Values; D026422:S-Nitrosoglutathione
D009603:Nitroso Compounds; D016877:Oxidants; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D005978:Glutathione; D002118:Calcium