Mitochondria‐Targeted Antioxidants in the Treatment of Disease

Smith, Robin A.J.; Adlam, Victoria J.; Blaikie, Frances H.; Manas, Abdul-Rahman B.; Porteous, Carolyn M.; James, Andrew M.; Ross, Meredith F.; Logan, Angela; Cochemé, Helena M.; Trnka, Ján; Prime, Tracy A.; Абакумова, Ирина; Jones, Bruce A.; Filipovska, Aleksandra; Murphy, Michael P.

doi:10.1196/annals.1427.003

Cited by 99 publications

(71 citation statements)

References 27 publications

(57 reference statements)

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“…We utilized mitoquinol (Mitq), a reduced form of the mitochondria‐targeted coenzyme Q (CoQ) analog, which is a well‐characterized mitochondria‐targeted antioxidant (mt‐antioxidant) 24. As expected, Mitq, but not CoQ, effectively decreased ROS levels in the MDA cells (Figs 6b, S4a).…”

Section: Resultsmentioning

confidence: 70%

Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

et al. 2016

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Mitochondria are multifunctional organelles; they have been implicated in various aspects of tumorigenesis. In this study, we investigated a novel role of the basal electron transport chain (ETC) activity in cell proliferation by inhibiting mitochondrial replication and transcription (mtR/T) using pharmacological and genetic interventions, which depleted mitochondrial DNA/RNA, thereby inducing ETC deficiency. Interestingly, mtR/T inhibition did not decrease ATP levels despite deficiency in ETC activity in different cell types, including MDA‐MB‐231 breast cancer cells, but it severely impeded cell cycle progression, specifically progression during G2 and/or M phases in the cancer cells. Under these conditions, the expression of a group of cell cycle regulators was downregulated without affecting the growth signaling pathway. Further analysis suggested that the transcriptional network organized by E2F1 was significantly affected because of the downregulation of E2F1 in response to ETC deficiency, which eventually resulted in the suppression of cell proliferation. Thus, in this study, the E2F1‐mediated ETC‐dependent mechanism has emerged as the regulatory mechanism of cell cycle progression. In addition to E2F1, FOXM1 and BMYB were also downregulated, which contributed specifically to the defects in G2 and/or M phase progression. Thus, ETC‐deficient cancer cells lost their growing ability, including their tumorigenic potential in vivo. ETC deficiency abolished the production of reactive oxygen species (ROS) from the mitochondria and a mitochondria‐targeted antioxidant mimicked the deficiency, thereby suggesting that ETC activity signaled through ROS production. In conclusion, this novel coupling between ETC activity and cell cycle progression may be an important mechanism for coordinating cell proliferation and metabolism.

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Section: Resultsmentioning

confidence: 70%

Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

et al. 2016

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“…Therefore, pharmacological agents that alleviate mitochondrial dysfunction could exert neuroprotective effects. Extremely promising in this respect are mitochondrial-targeted antioxidants including SkQ1, as well as mitochondrial MitoQ [50] which play an important role in modulating ROS-induced mitochondrial permeability transition and cell death, and were found to be protective in several models of ischemia, reperfusion injury, and oxidative stress. Favorable effects of SkQ1 were shown in animal models of some age-related pathologies, namely, heart and kidney infarction, heart arrhythmia, and stroke [51].…”

Section: Discussionmentioning

confidence: 99%

Behavioral Effects Induced by Mitochondria-Targeted Antioxidant SkQ1 in Wistar and Senescence-Accelerated OXYS Rats

Stefanova

Фурсова

Kolosova

2010

JAD

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Abstract. Mitochondrial dysfunction is involved in aging and in neurodegenerative diseases and, therefore, pharmacological agents that alleviate mitochondrial dysfunction are expected to have neuroprotective effects. Promising in this respect is mitochondrial-targeted antioxidant plastoquinonyl-decyl-triphenylphosphonium (SkQ1). We investigated the effects of SkQ1 (250 nmol SkQ1/kg × day with food) on behavior in the elevated plus-maze (EPM) and open field (OF) and on spatial memory in a Morris water maze (MWM) in middle-aged (12 mo) Wistar and senescence-accelerated OXYS rats. Given that changes in the behavior of OXYS rats may be associated with visual impairment, the condition of the retina and the lens was evaluated by ophthalmoscopy. 14-month-old as well as 3-month-old OXYS rats had considerably reduced activities in OF, increased anxiety in EPM, and manifested impaired learning abilities in the MWM in comparison with Wistar rats. SkQ1-treated rats of both strains displayed significantly higher locomotor and exploratory activity in the OF and less anxiety in the EPM compared to age-matched controls. SkQ1 significantly improved visual ability of the rats reducing the severity of the developed signs of retinopathy and cataract but had no impact on OXYS rat's spatial memory in the MWM. SkQ1-treated Wistar rats exhibited slower learning in the MWM task comparison to the control group. Thus, SkQ1 had beneficial effects on locomotor and exploratory functions of the rat brain. Nevertheless, SkQ1 did not alter learning performance in the MWM in OXYS rats and slightly reduced it in the Wistar strain, which may be associated with differences in redox homeostasis.

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“…Mitochondria and NADPH oxidases (19) are the two principle sources of ROS although their relative contribution to inflammatory pathologies is not well-defined. A new class of antioxidants that specifically target mitochondrial ROS (hereafter referred to as SkQ1 and SkQR1) have been recently developed and shown to have a beneficial effect in a number of cell pathologies (20)(21)(22)(23)(24)(25)(26)(27)(28).…”

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confidence: 99%

Protective effect of mitochondria-targeted antioxidants in an acute bacterial infection

Plotnikov

Morosanova

Pevzner

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Acute pyelonephritis is a potentially life-threatening infection of the upper urinary tract. Inflammatory response and the accompanying oxidative stress can contribute to kidney tissue damage, resulting in infection-induced intoxication that can become fatal in the absence of antibiotic therapy. Here, we show that pyelonephritis was associated with oxidative stress and renal cell death. Oxidative stress observed in pyelonephritic kidney was accompanied by a reduced level of mitochondrial B-cell lymphoma 2 (Bcl-2). Importantly, renal cell death and animal mortality were both alleviated by mitochondria-targeted antioxidant 10(6′-plastoquinonyl) decylrhodamine 19 (SkQR1). These findings suggest that pyelonephritis can be treated by reducing mitochondrial reactive oxygen species and thus by protecting mitochondrial integrity and lowering kidney damage.inflammation | phenoptosis | urological diseases | innate immunity | toll-like receptors

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Mitochondria‐Targeted Antioxidants in the Treatment of Disease

Cited by 99 publications

References 27 publications

Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

Behavioral Effects Induced by Mitochondria-Targeted Antioxidant SkQ1 in Wistar and Senescence-Accelerated OXYS Rats

Protective effect of mitochondria-targeted antioxidants in an acute bacterial infection

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