Mitochondria as source of reactive oxygen species under oxidative stress. Study with novel mitochondria-targeted antioxidants — the “Skulachev-ion” derivatives

Abstract

Production of reactive oxygen species (ROS) in mitochondria was studied using the novel mitochondria-targeted antioxidants (SkQ) in cultures of human cells. It was shown that SkQ rapidly (1-2 h) and selectively accumulated in mitochondria and prevented oxidation of mitochondrial components under oxidative stress induced by hydrogen peroxide. At nanomolar concentrations, SkQ inhibited oxidation of glutathione, fragmentation of mitochondria, and translocation of Bax from cytosol into mitochondria. The last effect could be related to prevention of conformational change in the adenine nucleotide transporter, which depends on oxidation of critical thiols. Mitochondria-targeted antioxidants at nanomolar concentrations prevented accumulation of ROS and cell death under oxidative stress. These effects required 24 h or more (depending on the cell type) preincubation, and this was not related to slow induction of endogenous antioxidant systems. It is suggested that SkQ slowly accumulates in a small subpopulation of mitochondria that have decreased membrane potential and produce the major part of ROS under oxidative stress. This population was visualized in the cells using potential-sensitive dye. The possible role of the small fraction of "bad" mitochondria in cell physiology is discussed.

Prevention of export of anoxia/reoxygenation injury from ischemic to nonischemic cardiomyocytes via inhibition of endocytosis

“…The accumulation in the nucleus is likely due to the ability of this derivative of ethidium bromide to act as an intercalator. In fact, the fluorescence signal of MitoSOX increases when it interacts with DNA (16). It should also be noted that detection of ROS production using fluorescent probes is a methodologically thorny issue.…”

Mitochondrial reactive oxygen species and inflammation: Molecular mechanisms, diseases and promising therapies

“…This finding sustains not only the feasibility and safety of further investigations but also the possibility to widen the testing to other inflammation-related pathologies. The need to refine the approach to the mitochondria-targeted therapy has also led to the development of newer drugs, such as SkQ compounds, molecules that contain a quinone antioxidant moiety that is covalently conjugated to a lipophilic cation via alkyl chains (Izyumov et al, 2010). Among these drugs, SkQ1 (plastoquinonyl-decyltriphenylphosphonium) shows the highest membrane-penetrating capacity and potent antioxidant activity (Antonenko et al, 2008).…”

Novel Mitochondria-Targeted Antioxidants: Plastoquinone Conjugated with Cationic Plant Alkaloids Berberine and Palmatine

“…The possible explanation of delayed antioxidant and protective effects of mitochondria-targeted antioxidants suggests slow redistribution of this compound in the population of mitochondria in the cell. It was shown in various cell types, including fibroblasts, that the cells contain a fraction of mitochondria with low membrane potential that would accumulate cationic antioxidants only slowly (46). These same "impaired" mitochondria probably produced the major part of ROS under oxidative stress (as observed in other cell models (48,49).…”

“…Our earlier studies using mitochondria-targeted antioxidants demonstrated (9,44,46) that oxidative stress induced by exogenous H 2 O 2 results in an excessive production of endogenous ROS in mitochondria. That is why we have exploited this model in the following experiments.…”