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Article Dans Une Revue Biochimica et Biophysica Acta - Molecular Basis of Disease Année : 2009

Myoglobin causes oxidative stress, increase of NO production and dysfunction of kidney's mitochondria

Résumé

Rhabdomyolysis or crush syndrome is a pathology caused by muscle injury resulting in acute renal failure. The latest data give strong evidence that this syndrome caused by accumulation of muscle breakdown products in the blood stream is associated with oxidative stress with primary role of mitochondria. In order to evaluate the significance of oxidative stress under rhabdomyolysis we explored the direct effect of myoglobin on renal tubules and isolated kidney mitochondria while measuring mitochondrial respiratory control, production of reactive oxygen and nitrogen species and lipid peroxidation. In parallel, we evaluated mitochondrial damage under myoglobinurea in vivo. An increase of lipid peroxidation products in kidney mitochondria and release of cytochrome c was detected on the first day of myoglobinuria. In mitochondria incubated with myoglobin we detected respiratory control drop, uncoupling of oxidative phosphorylation, an increase of lipid peroxidation products and stimulated NO synthesis. Mitochondrial pore inhibitor, cyclosporine A, mitochondria-targeted antioxidant (SkQ1) and deferoxamine (Fe-chelator and ferryl-myoglobin reducer) abrogated these events. Similar effects (oxidative stress and mitochondrial disfunction) were revealed when myoglobin was added to isolated renal tubules. Thus, rhabdomyolysis can be considered as oxidative stress-mediated pathology with mitochondria to be the primary target and possibly the source of reactive oxygen and nitrogen species. We speculate that rhabdomyolysis-induced kidney damage involves direct interaction of myoglobin with mitochondria possibly resulting in iron ions released from myoglobin's heme, which promotes the peroxidation of mitochondrial membranes. Usage of mitochondrial permeability transition blockers, Fe-chelators or mitochondria-targeted antioxidants, may bring salvage from this pathology.

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Dates et versions

hal-00562908 , version 1 (04-02-2011)

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Egor Y. Plotnikov, Anastasia A. Chupyrkina, Irina B. Pevzner, Nickolaj K. Isaev, Dmitry B. Zorov. Myoglobin causes oxidative stress, increase of NO production and dysfunction of kidney's mitochondria. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2009, 1792 (8), pp.796. ⟨10.1016/j.bbadis.2009.06.005⟩. ⟨hal-00562908⟩

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