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Abstract: Carbon monoxide (CO) toxicity is the result of a combination of tissue hypoxia and direct CO-mediated damage at a cellular level, since not all the signs and symptoms presented can be explained only by the formation of carboxyhaemoglobin. Mitochondria, specially the electron transport chain, seem to be the target for CO at a subcellular level. However, the direct effect of CO in individual complexes of the human mitochondrial respiratory chain has not been completely elucidated. We here studied the in vitro effect of CO on individual complexes of the mitochondrial respiratory chain of human mitochondria. We obtained muscle tissue from 10 healthy people who underwent orthopaedic surgery for hip replacement. Isolated mitochondria were incubated for 5 min. under CO concentrations of 50, 100 and 500 ppm. Afterwards, enzymatic activities of individual complexes of the mitochondrial respiratory chain were assessed in vitro and compared with those obtained in basal (synthetic air without CO) conditions. Cytochrome c oxidase (complex IV of the mitochondrial respiratory chain) activity showed a decrease from 836±439 nmol/min./mg of mitochondrial protein after air incubation to 670±401, 483±182, and 379±131 nmol/min./mg after 50, 100 and 500 ppm of CO incubation, respectively (20%, 42% and 55% decrease in cytochrome c oxidase activity). This gradual decrease in cytochrome c oxidase was found to be statistically significant (P<0.001). Other complex activities showed no any significant variation. Carbon monoxide is toxic for mitochondria in man, altering the mitochondrial respiratory chain at the cytochrome c oxidase level. This inhibition in cytochrome c oxidase may play a role in the development of the symptoms observed in acute CO poisoning, and in some diseases related to smoking.