A mitochondria‐targeted antioxidant can inhibit peroxidase activity of cytochrome <i>c</i> by detachment of the protein from liposomes

Firsov, Alexander M.; Kotova, Еlena А.; Orlov, V. N.; Antonenko, Yuri N.; Vp, Skulachev

doi:10.1002/1873-3468.12319

Cited by 13 publications

(8 citation statements)

References 39 publications

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“…These were filled with the fluorescent dye Calcein, release and unquenching of which was then used as a readout of increase in membrane permeability (Firsov et al. ). We observed an abrupt increase in Calcein release with DTPP (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To investigate this, and exclude the potentially confounding effects of interactions with native mitochondrial proteins, we performed experiments using artificial liposomes containing 20% cardiolipin, to model the consistency of the IMM. These were filled with the fluorescent dye Calcein, release and unquenching of which was then used as a readout of increase in membrane permeability (Firsov et al 2016). We observed an abrupt increase in Calcein release with DTPP ( Fig.…”

Section: Dodecyltriphenylphosphomium Increases Mitochondrial Inner Mementioning

confidence: 87%

“…Liposomes were prepared according to a previously established protocol (Firsov et al. ). Excess Calcein was removed with dialysis (Slide‐A‐Lyzer MINI 7K, Thermo Fisher Scientific) at 4°C for 48 h against a buffer containing 100 mmol/L KCl, 10 mmol/L Tris, and 10 mmol/L MES, and adjusted to pH 7.4.…”

Section: Methodsmentioning

confidence: 99%

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The targeted anti-oxidant MitoQ causes mitochondrial swelling and depolarization in kidney tissue

et al. 2018

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Kidney proximal tubules (PTs) contain a high density of mitochondria, which are required to generate ATP to power solute transport. Mitochondrial dysfunction is implicated in the pathogenesis of numerous kidney diseases. Damaged mitochondria are thought to produce excess reactive oxygen species (ROS), which can lead to oxidative stress and activation of cell death pathways. MitoQ is a mitochondrial targeted anti‐oxidant that has shown promise in preclinical models of renal diseases. However, recent studies in nonkidney cells have suggested that MitoQ might also have adverse effects. Here, using a live imaging approach, and both in vitro and ex vivo models, we show that MitoQ induces rapid swelling and depolarization of mitochondria in PT cells, but these effects were not observed with SS‐31, another targeted anti‐oxidant. MitoQ consists of a lipophilic cation (Tetraphenylphosphonium [TPP]) joined to an anti‐oxidant component (quinone) by a 10‐carbon alkyl chain, which is thought to insert into the inner mitochondrial membrane (IMM). We found that mitochondrial swelling and depolarization was also induced by dodecyltriphenylphosphomium (DTPP), which consists of TPP and the alkyl chain, but not by TPP alone. Surprisingly, MitoQ‐induced mitochondrial swelling occurred in the absence of a decrease in oxygen consumption rate. We also found that DTPP directly increased the permeability of artificial liposomes with a cardiolipin content similar to that of the IMM. In summary, MitoQ causes mitochondrial swelling and depolarization in PT cells by a mechanism unrelated to anti‐oxidant activity, most likely because of increased IMM permeability due to insertion of the alkyl chain.

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Section: Resultsmentioning

confidence: 99%

Section: Dodecyltriphenylphosphomium Increases Mitochondrial Inner Mementioning

confidence: 87%

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The targeted anti-oxidant MitoQ causes mitochondrial swelling and depolarization in kidney tissue

et al. 2018

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“…MitoQ 10 can solve this problem; this antioxidant is composed of ubiquinone moieties attached to a TPP moiety by a 10-carbon alkyl chain. Lipophilic cations can readily move through phospholipid bilayers, therefore, MitoQ 10 can be taken up by mitochondria and be effective in combating ROS ( 25 , 26 ). Once within the mitochondria, almost all of the accumulated MitoQ 10 resides in the matrix surface of the inner-membrane and prevents OS and mitochondrial dysfunction ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

Mitochondria-targeted antioxidant therapy for an animal model of PCOS-IR

et al. 2018

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Polycystic ovary syndrome (PCOS) is a common endocrine disorder with unknown etiology and unsatisfactory clinical treatment. Considering the ethical limitations of studies involving humans, animal models that reflect features of PCOS and insulin resistance (IR) are crucial resources in investigating this syndrome. Our previous study showed that mitochondrial dysfunction resulted from pathogenic mutations of mitochondrial DNA (mtDNA), and that oxidative stress had an active role in the phenotypic manifestation of PCOS-IR. Therefore, it was hypothesized that limiting oxidative stress and mitochondrial damage may be useful and effective for the clinical treatment of PCOS-IR. For this purpose, the present study examined the therapeutic effects of the mitochondria-targeted antioxidant MitoQ10 for PCOS-IR. Furthermore, the histopathology was used to analysis the ovarian morphological changes. The endocrine and reproductive related parameters were analyzed by ELISA approach. A PCOS-IR model was successfully established by subcutaneous injection of rats with testosterone propionate and feeding a high-fat diet. The 30 female Sprague-Dawley rats were then divided into three groups, comprising a control (n=10), animal model (PCOS-IR, n=10) and MitoQ10 treatment (n=10) group. It was found that MitoQ10 significantly improved the IR condition and reversed the endocrine and reproductive conditions of PCOS. In addition, the impaired mitochondrial functions were improved following MitoQ10 administration. Notably, western blot results suggested that this antioxidant reduced the expression levels of apoptosis-related proteins cytochrome c and B-cell lymphoma-2 (Bcl-2)-associated X protein, whereas the anti-apoptotic protein Bcl-extra large was increased following MitoQ10 treatment. Taken together, the data indicated that the MitoQ10 may have a beneficial favorable therapeutic effect on animals with PCOS-IR, most likely via the protection of mitochondrial functions and regulation of programmed cell death-related proteins.

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“…Additionally, the NS1 protein together with STS was able to cause the release of cytochrome c from the mitochondria to the cytosol, and the change of MMP. During the intrinsic mitochondrial apoptosis process, the permeabilization of the mitochondrial outer membrane is the critical step, which results in the release of several apoptogenic factors from the intermembrane space of mitochondria ( 20 – 22 ). Cytochrome c is one of these factors, which binds to the adaptor apoptotic peptidase-activating factor 1 that subsequently recruits cytosolic pro-caspase-9 into a heptameric apoptosome ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Highly pathogenic avian influenza A virus H5N1 non‑structural protein 1 is associated with apoptotic activation of the intrinsic mitochondrial pathway

Bian

Zhang

et al. 2017

Exp Ther Med

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Outbreaks of avian influenza A (H5N1) virus infection have significant health and economic consequences. Non-structural protein 1 (NS1) is an essential virulence factor of the highly pathogenic H5N1 avian influenza virus and of the apoptosis associated with the pathogenesis of H5N1. Previous studies have revealed that the NS1 protein is able to induce apoptosis via an extrinsic pathway. However, it remains unclear whether the intrinsic pathway is also associated with this apoptosis. The present study used a clone of the NS1 gene from avian influenza A/Jiangsu/1/2007 and observed the localization of the NS1 protein and cytochrome c release from mitochondria and the change of mitochondrial membrane potential (MMP) in lung cancer cells. Cytotoxicity was detected using an MTT assay and the number of apoptotic cells was counted using a flow cytometer. Following the isolation of mitochondria, western blotting was performed to compare cytochrome c release from the mitochondria in cells before and after apoptosis. The change of MMP was detected using JC-1 staining. Furthermore, the results reveal that the majority of the NS1 protein was localized in the cell nucleus, and that it may induce apoptosis of human lung epithelial cells. The apoptosis occurred with marked cytochrome c release from mitochondria and a change of the MMP. This indicated that the NS1 protein may be associated with apoptosis induced by an intrinsic mitochondrial pathway.

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A mitochondria‐targeted antioxidant can inhibit peroxidase activity of cytochrome c by detachment of the protein from liposomes

Cited by 13 publications

References 39 publications

The targeted anti-oxidant MitoQ causes mitochondrial swelling and depolarization in kidney tissue

The targeted anti-oxidant MitoQ causes mitochondrial swelling and depolarization in kidney tissue

Mitochondria-targeted antioxidant therapy for an animal model of PCOS-IR

Highly pathogenic avian influenza A virus H5N1 non‑structural protein 1 is associated with apoptotic activation of the intrinsic mitochondrial pathway

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