The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats

Kolosova, N. G.; Stefanova, Natalia A.; Muraleva, Natalia A.; Vp, Skulachev

doi:10.18632/aging.100493

Cited by 45 publications

(28 citation statements)

References 47 publications

(58 reference statements)

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“…Recently, Skulachev et al reported that mitochondrial ROS are especially important for progression of an aging phenotype, which was shown using the mitochondrial targeted antioxidant SkQ1 (24,44). In support of this notion, Mito-TEMPO efficiently suppressed CSE-induced HBEC senescence, suggesting that ROS in CSE is mainly involved in the initial step of mitochondrial fragmentation and that subsequent ROS release from fragmented mitochondria is the more crucial mechanism for CSEinduced HBEC senescence.…”

Section: L743mentioning

confidence: 85%

“…Although CSE contains a wide array of toxic components, including ROS, the precise source of ROS involved in progression of cellular senescence in response to CSE exposure remains to be clearly elucidated. Mitochondria are a major source of intrinsic ROS production, and mitochondrial ROS is considered to be associated with aging (24,44,52). Accordingly, we hypothesized that mitochondrial ROS production participates in the regulation of CSE-induced cellular senescence.…”

Section: Mitochondrial Ros Production Is Involved In Cse-induced Hbecmentioning

confidence: 99%

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Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence

Hara

Araya

Ito

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

161

153

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Mitochondria are dynamic organelles that continuously change their shape through fission and fusion. Disruption of mitochondrial dynamics is involved in disease pathology through excessive reactive oxygen species (ROS) production. Accelerated cellular senescence resulting from cigarette smoke exposure with excessive ROS production has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Hence, we investigated the involvement of mitochondrial dynamics and ROS production in terms of cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBEC). Mitochondrial morphology was examined by electron microscopy and fluorescence microscopy. Senescence-associated β-galactosidase staining and p21 Western blotting of primary HBEC were performed to evaluate cellular senescence. Mitochondrial-specific superoxide production was measured by MitoSOX staining. Mitochondrial fragmentation was induced by knockdown of mitochondrial fusion proteins (OPA1 or Mitofusins) by small-interfering RNA transfection. N-acetylcysteine and Mito-TEMPO were used as antioxidants. Mitochondria in bronchial epithelial cells were prone to be more fragmented in COPD lung tissues. CSE induced mitochondrial fragmentation and mitochondrial ROS production, which were responsible for acceleration of cellular senescence in HBEC. Mitochondrial fragmentation induced by knockdown of fusion proteins also increased mitochondrial ROS production and percentages of senescent cells. HBEC senescence and mitochondria fragmentation in response to CSE treatment were inhibited in the presence of antioxidants. CSE-induced mitochondrial fragmentation is involved in cellular senescence through the mechanism of mitochondrial ROS production. Hence, disruption of mitochondrial dynamics may be a part of the pathogenic sequence of COPD development.

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Section: L743mentioning

confidence: 85%

Section: Mitochondrial Ros Production Is Involved In Cse-induced Hbecmentioning

confidence: 99%

Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence

Hara

Araya

Ito

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

161

153

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“…Since there is evidence of mitochondrial oxidative stress in age-related diseases an intracellular antioxidant may be more useful. For example, the mitochondrial antioxidant SkQ1 reverses ageing-related biomarkers in rats, whereas N-acetyl cysteine is ineffective [143]. Nrf2 activators are of particular interest as Nrf2 may be defective in several diseases of accelerated ageing, including COPD, chronic kidney disease, neurodegeneration, cardiovascular disease and cancer [52,144].…”

Section: Pharmacological Therapiesmentioning

confidence: 99%

Mechanisms of development of multimorbidity in the elderly

2015

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In ageing populations many patients have multiple diseases characterised by acceleration of the normal ageing process. Better understanding of the signalling pathways and cellular events involved in ageing shows that these are characteristic of many chronic degenerative diseases, such as chronic obstructive pulmonary disease (COPD), chronic cardiovascular and metabolic diseases, and neurodegeneration. Common mechanisms have now been identified in these diseases, which show evidence of cellular senescence with telomere shortening, activation of PI3K-AKT-mTOR signalling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunosenescence and low grade chronic inflammation ("inflammaging"). Many of these pathways are driven by chronic oxidative stress. There is also a reduction in anti-ageing molecules, such as sirtuins and Klotho, which further accelerates the ageing process. Understanding these molecular mechanisms has identified several novel therapeutic targets and several drugs have already been developed that may slow the ageing process, as well as lifestyle interventions, such as diet and physical activity. This indicates that in the future new treatment approaches may target the common pathways involved in multimorbidity and this area of research should be given high priority. Thus, COPD should be considered as a component of multimorbidity and common disease pathways, particularly accelerated ageing, should be targeted. @ERSpublications Multimorbidities share many common underlying mechanisms that may be linked to common causes such as oxidative stress

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“…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]. The antiinflammatory and vasoprotective action of SkQ1 could underlie some of these effects.…”

Section: Introductionmentioning

confidence: 99%

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

Zinovkin

Romaschenko

Galkin

et al. 2014

Aging

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Vascular aging is accompanied by increases in circulatory proinflammatory cytokines leading to inflammatory endothelial response implicated in early atherogenesis. To study the possible role of mitochondria-derived reactive oxygen species (ROS) in this phenomenon, we applied the effective mitochondria-targeted antioxidant SkQ1, the conjugate of plastoquinone with dodecyltriphenylphosphonium. Eight months treatment of (CBAxC57BL/6) F1 mice with SkQ1 did not prevent age-related elevation of the major proinflammatory cytokines TNF and IL-6 in serum, but completely abrogated the increase in adhesion molecule ICAM1 expression in aortas of 24-month-old animals. In endothelial cell culture, SkQ1 also attenuated TNF-induced increase in ICAM1, VCAM, and E-selectin expression and secretion of IL-6 and IL-8, and prevented neutrophil adhesion to the endothelial monolayer. Using specific inhibitors to transcription factor NF-κB and stress-kinases p38 and JNK, we demonstrated that TNF-induced ICAM1 expression depends mainly on NF-κB activity and, to a lesser extent, on p38. SkQ1 had no effect on p38 phosphorylation (activation) but significantly reduced NF-κB activation by inhibiting phosphorylation and proteolytic cleavage of the inhibitory subunit IκBα. The data indicate an important role of mitochondrial reactive oxygen species in regulation of the NF-κB pathway and corresponding age-related inflammatory activation of endothelium.

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The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats

Cited by 45 publications

References 47 publications

Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence

Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence

Mechanisms of development of multimorbidity in the elderly

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

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