Mitochondria-targeted antioxidants are known to alleviate mitochondrial oxidative damage that is associated with a variety of diseases. Here, we showed that SkQ1, a decyltriphenyl phosphonium cation conjugated to a quinone moiety, exhibited strong antibacterial activity towards Gram-positive Bacillus subtilis, Mycobacterium sp. and Staphylococcus aureus and Gram-negative Photobacterium phosphoreum and Rhodobacter sphaeroides in submicromolar and micromolar concentrations. SkQ1 exhibited less antibiotic activity towards Escherichia coli due to the presence of the highly effective multidrug resistance pump AcrAB-TolC. E. coli mutants lacking AcrAB-TolC showed similar SkQ1 sensitivity, as B. subtilis. Lowering of the bacterial membrane potential by SkQ1 might be involved in the mechanism of its bactericidal action. No significant cytotoxic effect on mammalian cells was observed at bacteriotoxic concentrations of SkQ1. Therefore, SkQ1 may be effective in protection of the infected mammals by killing invading bacteria.
Mitochondrial dysfunction plays a crucial role in the macroautophagy/autophagy cascade. In a recently published study Sun et al. described the induction of autophagy by the membranophilic triphenylphosphonium (TPP)-based cation 10-(6'-ubiquinonyl) decyltriphenylphosphonium (MitoQ) in HepG2 cells (Sun C, et al. "MitoQ regulates autophagy by inducing a pseudo-mitochondrial membrane potential [PMMP]", Autophagy 2017, 13:730-738.). Sun et al. suggested that MitoQ adsorbed to the inner mitochondrial membrane with its cationic moiety remaining in the intermembrane space, adding a large number of positive charges and establishing a "pseudo-mitochondrial membrane potential," which blocked the ATP synthase. Here we argue that the suggested mechanism for generation of the "pseudo-mitochondrial membrane potential" is physically implausible and contradicts earlier findings on the electrophoretic displacements of membranophilic cations within and through phospholipid membranes. We provide evidence that TPP-cations dissipated the mitochondrial membrane potential in HepG2 cells and that the induction of autophagy in carcinoma cells by TPP-cations correlated with the uncoupling of oxidative phosphorylation. The mild uncoupling of oxidative phosphorylation by various mitochondria-targeted penetrating cations may contribute to their reported therapeutic effects via inducing both autophagy and mitochondria-selective mitophagy.
In endothelial cells, mitochondria play an important regulatory role in physiology as well as in pathophysiology related to excessive inflammation. We have studied the effect of low doses of mitochondrial uncouplers on inflammatory activation of endothelial cells using the classic uncouplers 2,4-dinitrophenol and 4,5,6,7-tetrachloro-2-trifluoromethylbenzimidazole, as well as the mitochondria-targeted cationic uncoupler dodecyltriphenylphosphonium (C12TPP). All of these uncouplers suppressed the expression of E-selectin, adhesion molecules ICAM1 and VCAM1, as well as the adhesion of neutrophils to endothelium induced by tumor necrosis factor (TNF). The antiinflammatory action of the uncouplers was at least partially mediated by the inhibition of NFκB activation due to a decrease in phosphorylation of the inhibitory subunit IκBα. The dynamic concentration range for the inhibition of ICAM1 expression by C12TPP was three orders of magnitude higher compared to the classic uncouplers. Probably, the decrease in membrane potential inhibited the accumulation of penetrating cations into mitochondria, thus lowering the uncoupling activity and preventing further loss of mitochondrial potential. Membrane potential recovery after the removal of the uncouplers did not abolish its antiinflammatory action. Thus, mild uncoupling could induce TNF resistance in endothelial cells. We found no significant stimulation of mitochondrial biogenesis or autophagy by the uncouplers. However, we observed a decrease in the relative amount of fragmented mitochondria. The latter may significantly change the signaling properties of mitochondria. Earlier we showed that both classic and mitochondria-targeted antioxidants inhibited the TNF-induced NFκB-dependent activation of endothelium. The present data suggest that the antiinflammatory effect of mild uncoupling is related to its antioxidant action.
SESN2 is a member of the evolutionarily conserved sestrin protein family found in most of the Metazoa species. The SESN2 gene is transcriptionally activated by many stress factors, including metabolic derangements, reactive oxygen species (ROS), and DNA-damage. As a result, SESN2 controls ROS accumulation, metabolism, and cell viability. The best-known function of SESN2 is the inhibition of the mechanistic target of rapamycin complex 1 kinase (mTORC1) that plays a central role in support of cell growth and suppression of autophagy. SESN2 inhibits mTORC1 activity through interaction with the GATOR2 protein complex preventing an inhibitory effect of GATOR2 on the GATOR1 protein complex. GATOR1 stimulates GTPase activity of the RagA/B small GTPase, the component of RagA/B:RagC/D complex, preventing mTORC1 translocation to the lysosomes and its activation by the small GTPase Rheb. Despite the well-established role of SESN2 in mTORC1 inhibition, other SESN2 activities are not well-characterized. We recently showed that SESN2 could control mitochondrial function and cell death via mTORC1-independent mechanisms, and these activities might be explained by direct effects of SESN2 on mitochondria. In this work, we examined mitochondrial localization of SESN2 and demonstrated that SESN2 is located on mitochondria and can be directly involved in the regulation of mitochondrial functions. Project administration: Andrei V. Budanov. Resources: Andrei V. Budanov. Supervision: Andrei V. Budanov. Validation: Andrei V. Budanov. Visualization: Andrei V. Budanov. Writing -original draft: Andrei V. Budanov.
Leber's hereditary optic neuropathy (LHON) refers to a group of mitochondrial diseases and is characterized by defects of the mitochondrial electron transport chain and decreased level of oxidative phosphorylation. The list of LHON primary mtDNA mutations is regularly updated. In this study, we describe the homoplasmic nucleotide substitution m.3472T>C in the MT-ND1 (NADH-ubiquinone oxidoreductase chain 1) gene and specific changes in cell metabolism in a patient with LHON and his asymptomatic sister. To confirm the presence of mutation-related mitochondrial dysfunction, respiration of skin fibroblasts and platelets from the patient and his sister was studied, as well as the mitochondrial potential and production of reactive oxygen species in the skin fibroblasts. In addition, based on characteristics of the toxic effect of paraquat, a new approach was developed for detecting the functional activity of complex I of the mitochondrial respiratory chain.
The goal of this study was to understand the potential mechanisms responsible for the regulation of metabolism and mitochondrial functions by SESTRIN2 (SESN2) and other members of the SESTRIN protein family. Our studies are based on cell fractionation and microscopy analyses to determine the localization of SESN2 and on theC. elegans model to define the role of SESTRINs in mitochondrial respiration. SESN2 is a member of evolutionarily conserved SESTRIN protein family found in the majority of theMetazoa species. SESN2 is transcriptionally activated by many stress factors including metabolic derangements, oxidants, and DNA‐damage. As a result, SESN2 suppresses oxidative stress, tunes up metabolic pathways, and regulates cell viability. Many of the activities of SESN2 are linked to regulation of mechanistic target of rapamycin complex 1 kinase (mTORC1) that plays the central role in the regulation of cell growth, metabolism, and autophagy. SESN2 inhibits mTORC1 activity through the interaction with the GATOR2 protein complex that prevents the inhibitory effect of GATOR2 on the GATOR1 protein complex and relieves an inhibitory effect of GATOR1 towards RagA/B GTPases, the major activators of mTORC1. Despite the well‐established role of SESN2 in the mTORC1 inhibition, some other SESN2 activities are not well characterized. As established by us and other groups, SESN2 can control mitochondrial respiration and cell death via mTORC1‐independent mechanisms. We hypothesized that these processes can be explained by the direct effects of SESN2 on mitochondria. To study the potential localization of SESN2 on mitochondria we performed mitochondrial fractionation from different human cancer cell lines and observed that considerable amounts of SESN2 protein were co‐purified with mitochondria. According to the results of treatment with proteases, SESN2 was located on the outer mitochondrial membrane. While we observed no association of SESN2 with the AKAP1 protein, as was previously reported, we found that the mitochondrial localization of SESN2 depends on GATOR2. We determine that mitochondrial SESN2 might be responsible for the regulation of the accumulation of reactive oxygen species and respiration in mammalian cells andC. elegans. We have shown that SESN2 is associated with mitochondria and can be directly involved in direct regulation of mitochondria functions. Support or Funding Information This work was supported by Russian Science Foundation grant 17‐14‐01420.
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