Mitochondria transmit apoptosis signalling in cardiomyocyte-like cells and isolated hearts exposed to experimental ischemia-reperfusion injury

Neužil, Jiřı́; Widén, Cecilia; Gellert, Nina; Swettenham, Emma; Zobalova, Renata; Dong, Lan-Feng; Wang, Xiufang; Lidebjer, Caroline; Dalen, Helge; Headrick, John P.; Witting, Paul K.

doi:10.1179/135100007x200227

Cited by 75 publications

(53 citation statements)

References 64 publications

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“…One enzyme that may be up-regulated is manganese superoxide dismutase (MnSOD). This idea is consistent with reports showing that cells deficient in mtDNA are resistant to apoptosis and show increased expression of MnSOD (40)(41)(42). We have also found elevated expression of MnSOD in arrested endothelial cells, 7 possibly related to higher levels of p53 (43,44).…”

Section: Cancer Researchsupporting

confidence: 81%

Vitamin E Analogues Inhibit Angiogenesis by Selective Induction of Apoptosis in Proliferating Endothelial Cells: The Role of Oxidative Stress

Dong¹,

Swettenham²,

Eliasson³

et al. 2007

Cancer Research

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104

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Section: Cancer Researchsupporting

confidence: 81%

Vitamin E Analogues Inhibit Angiogenesis by Selective Induction of Apoptosis in Proliferating Endothelial Cells: The Role of Oxidative Stress

Dong¹,

Swettenham²,

Eliasson³

et al. 2007

Cancer Research

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104

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“…To achieve this, the strategy of Murphy and Smith (21), used previously to deliver antioxidants to the mitochondria of cultured cells and tissues in vivo was adapted here. For their studies, a lipophilic cationic group was used to tag and modify antioxidants (21,59), thereby endowing them with profound biological activity (60,61) while not jeopardizing the normal mitochondrial physiology (62). Further, incorporation of lipophilic cationic compounds inside tumor mitochondria is favored by the inherent nature of their much greater electrochemical gradient (by 20 -60 mV versus normal cell mitochondria).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Targeting of Vitamin E Succinate Enhances Its Pro-apoptotic and Anti-cancer Activity via Mitochondrial Complex II

Dong¹,

Jameson

Tilly

et al. 2011

Journal of Biological Chemistry

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188

189

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Mitochondrial complex II (CII) has been recently identified as a novel target for anti-cancer drugs. Mitochondrially targeted vitamin E succinate (MitoVES) is modified so that it is preferentially localized to mitochondria, greatly enhancing its pro-apoptotic and anti-cancer activity. Using genetically manipulated cells, MitoVES caused apoptosis and generation of reactive oxygen species (ROS) in CII-proficient malignant cells but not their CII-dysfunctional counterparts. MitoVES inhib-ited the succinate dehydrogenase (SDH) activity of CII with IC 50 of 80 M, whereas the electron transfer from CII to CIII was inhibited with IC 50 of 1.5 M. The agent had no effect either on the enzymatic activity of CI or on electron transfer from CI to CIII. Over 24 h, MitoVES caused stabilization of the oxygen-dependent destruction domain of HIF1␣ fused to GFP, indicating promotion of the state of pseudohypoxia. Molecular modeling predicted the succinyl group anchored into the proximal CII ubiquinone (UbQ)-binding site and successively reduced interaction energies for serially shorter phytyl chain homologs of MitoVES correlated with their lower effects on apoptosis induction, ROS generation, and SDH activity. Mutation of the UbQ-binding Ser 68 within the proximal site of the CII SDHC subunit (S68A or S68L) suppressed both ROS generation and apoptosis induction by MitoVES. In vivo studies indicated that MitoVES also acts by causing pseudohypoxia in the context of tumor suppression. We propose that mitochondrial targeting of VES with an 11-carbon chain localizes the agent into an ideal position across the interface of the mitochondrial inner membrane and matrix, optimizing its biological effects as an anti-cancer drug.Mitochondria are emerging as targets for a variety of anti-cancer drugs (1-5) that belong to a group of compounds termed "mitocans" (6, 7). Of these agents, we and others have been studying the group of vitamin E (VE) 2 analogs, epitomized by the "redox-silent" ␣-tocopheryl succinate (␣-TOS) and ␣-tocopheryl acetyl ether (8). Both of these agents proved to be selective inducers of apoptosis in cancer cells and efficient suppressors of tumors in experimental models (9 -16).VE analogs with anti-cancer activity have been classified as mitocans (i.e. small anti-cancer agents that act by selectively destabilizing mitochondria in cancer cells) (6 -8). Of the several groups of mitocans, the anti-cancer VE analogs belong to both the class of BH3 mimetics, which includes compounds interfering with the interactions of the Bcl-2 family proteins (17), as well as to the class of agents that interfere with the mitochondrial electron redox chain. The latter activity is probably the main reason for the strong apoptogenic efficacy of agents like ␣-TOS (18). More specifically, ␣-TOS interferes * This work was supported by grants from the Australian Research Council,

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“…Moreover, MitoQ has been investigated in clinical trials [20,37,38] and is expected to be promising candidate for a mitochondrial medicine. MitoQ was also investigated for protection of the liver and heart from I/R injury in in vivo experiments using I/R injury induced mice and rats [15,39,40].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial delivery of Coenzyme Q10 via systemic administration using a MITO-Porter prevents ischemia/reperfusion injury in the mouse liver

Yamada

Nakamura

Abe

et al. 2015

Journal of Controlled Release

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We herein report on a mitochondrial therapeutic effect based on the delivery of coenzyme Q10 (CoQ10), an anti-oxidant, to in vivo mitochondria using a MITO-Porter, a liposome-based mitochondrial delivery system that functions via membrane fusion. To evaluate the effects, we used a mouse liver ischemia/reperfusion injury (I/R injury) model, in which mitochondrial reactive oxygen species are overexpressed. We packaged CoQ10 in the lipid phase of a MITO-Porter and optimized the mitochondrial fusogenic activities to produce the CoQ10-MITO-Porter. A histological observation of the carriers in the liver by confocal laser scanning microscopy was done and the accumulation of the carrier labeled with a radio isotope in the liver confirmed that the CoQ10-MITO-Porter was delivered to liver mitochondria via systemic injection. These analytical results permitted us to optimize the compositions of the CoQ10-MITO-Porter so as to permit it to efficiently accumulate in mouse liver mitochondria.Finally, we applied the optimized CoQ10-MITO-Porter to mice via tail vein injection, and hepatic I/R injury was then induced, followed by measuring serum alanine aminotransferase (ALT) levels, a marker of liver injury. We confirmed that the use of the CoQ10-MITO-Porter resulted in a significant decrease in serum ALT levels, indicating that in vivo mitochondrial delivery of the CoQ10 via MITO-Porter prevents I/R injury in mice livers. This provides a demonstration of the potential use of such a delivery system in mitochondrial therapies.

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Mitochondria transmit apoptosis signalling in cardiomyocyte-like cells and isolated hearts exposed to experimental ischemia-reperfusion injury

Cited by 75 publications

References 64 publications

Vitamin E Analogues Inhibit Angiogenesis by Selective Induction of Apoptosis in Proliferating Endothelial Cells: The Role of Oxidative Stress

Vitamin E Analogues Inhibit Angiogenesis by Selective Induction of Apoptosis in Proliferating Endothelial Cells: The Role of Oxidative Stress

Mitochondrial Targeting of Vitamin E Succinate Enhances Its Pro-apoptotic and Anti-cancer Activity via Mitochondrial Complex II

Mitochondrial delivery of Coenzyme Q10 via systemic administration using a MITO-Porter prevents ischemia/reperfusion injury in the mouse liver

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