Mild Uncoupling of Respiration and Phosphorylation as a Mechanism Providing Nephro- and Neuroprotective Effects of Penetrating Cations of the SkQ Family

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E. Y. Plotnikov^1,2*, D. N. Silachev^1,2, S. S. Jankauskas^2,3, T. I. Rokitskaya^1,2, A. A. Chupyrkina^1,2, I. B. Pevzner^2,3, L. D. Zorova^2,4, N. K. Isaev^1,2, Y. N. Antonenko^1,2, V. P. Skulachev^1,2,3, and D. B. Zorov^1,2*

¹Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; fax: (495) 939-3181; E-mail: plotnikov@genebee.msu.su; zorov@genebee.msu.ru

²Mitoengeneering Institute, Lomonosov Moscow State University, 119991 Moscow, Russia

³Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia

⁴International Laser Center, Lomonosov Moscow State University, 119991 Moscow, Russia

^* To whom correspondence should be addressed.

Received May 15, 2012; Revision received May 21, 2012

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It is generally accepted that mitochondrial production of reactive oxygen species is nonlinearly related to the value of the mitochondrial membrane potential with significant increment at values exceeding 150 mV. Due to this, high values of the membrane potential are highly dangerous, specifically under pathological conditions associated with oxidative stress. Mild uncoupling of oxidative phosphorylation is an approach to preventing hyperpolarization of the mitochondrial membrane. We confirmed data obtained earlier in our group that dodecylrhodamine 19 (C₁₂R1) (a penetrating cation from SkQ family not possessing a plastoquinone group) has uncoupling properties, this fact making it highly potent for use in prevention of pathologies associated with oxidative stress induced by mitochondrial hyperpolarization. Further experiments showed that C₁₂R1 provided nephroprotection under ischemia/reperfusion of the kidney as well as under rhabdomyolysis through diminishing of renal dysfunction manifested by elevated level of blood creatinine and urea. Similar nephroprotective properties were observed for low doses (275 nmol/kg) of the conventional uncoupler 2,4-dinitrophenol. Another penetrating cation that did not demonstrate protonophorous activity (SkQR4) had no effect on renal dysfunction. In experiments with induced ischemic stroke, C₁₂R1 did not have any effect on the area of ischemic damage, but it significantly lowered neurological deficit. We conclude that beneficial effects of penetrating cation derivatives of rhodamine 19 in renal pathologies and brain ischemia may be at least partially explained by uncoupling of oxidation and phosphorylation.

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KEY WORDS: ischemia, rhabdomyolysis, kidney, brain, stroke, oxidative stress, mitochondria-targeted compounds, SkQ, mitochondria

DOI: 10.1134/S0006297912090106

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