Mild uncoupling of respiration and phosphorylation as a mechanism providing nephro- and neuroprotective effects of penetrating cations of the SkQ family

Abstract

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 (C(12)R1) (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 C(12)R1 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, C(12)R1 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.

Mitochondrial membrane potential

“…If a minor decline in the ΔΨm could lead to a significant decrease in harmful levels of ROS production [65], it is reasonable to hypothesize that the optimal values of ΔΨm, might be achieved by application of “mild uncouplers” which lower ΔΨm to a level still allowing both production of required amounts of ATP, and also of lower ROS levels that would be relatively harmless to the cells [72]. Consequently, under specific cases of poorly regulated ΔΨm and ROS elevations “mild uncouplers” could potentially have beneficial properties in limiting the ravages of a number of diseases, including those associated with aging [73], obesity [74,75] and pathologies accompanied by oxidative stress, such as stroke and heart attack [76–78]. Therefore, an extensive search has been initiated among the compounds with various chemical structures for new drugs which could potentially be tested therapeutically as “mild uncouplers” of oxidative phosphorylation [79–84].…”

The Emerging Role of Mitochondrial Targeting in Kidney Disease

“…Mitochondria-targeted antioxidants of the SkQ group such as plastoquinonyl-decyl-triphenylphosphonium (SkQ1) and plastoquinonyl decylrhodamine 19 (SkQR1) are positively charged compounds that prevent IRI-induced AKI (Plotnikov et al 2012) and ameliorate gentamicin-induced damage of rat kidney (Jankauskas et al 2012). Likewise, specific mitochondrially targeted heme oxygenase (HO)-1 protects against hypoxia-dependent renal epithelial cell death and loss of mitochondrial membrane potential (Bolisetty et al 2013).…”

Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium

“…In the current study, we used SkQ1 antioxidant, based on the plastoquinone moiety linked to dodecyltriphenylphosphonium cation that targets SkQ1 to mitochondria [26]. SkQ1 and its analogs are efficient in the prevention of some age-associated pathologies, and they have therapeutic effects in animal models of diseases associated with inflammatory response (heart, brain, and kidney ischemic injury [27, 28], pyelonephritis [29], eye diseases [30, 31], sarcopenia [32], and dermal wound healing [33]). SkQ1 delays the development of various markers of aging and prolongs the lifespan of various animals [20, 22, 34, 35].…”