Diazoxide protects mitochondria from anoxic injury: Implications for myopreservation

Özcan, Cevher; Holmuhamedov, Ekhson; Jahangir, Arshad; Terzic, André

doi:10.1067/mtc.2001.111421

Cited by 76 publications

(55 citation statements)

References 47 publications

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“…In the first instance, the complexity of the biochemical profile of the mitochondria in response to the delayed preconditioning needs further characterization. However, our data and the studies performed in classic preconditioning 11,25 collectively suggest that energetic homeostasis controlled by the mitochondrion should be considered central in orchestrating the cardioprotective programs induced by preconditioning. In addition, the nuclear regulatory program identified in this study, ie, upregulation of NRF-1 and PGC-1␣, could be compatible with either the upregulation of the ETC machinery in individual mitochondria 20 or the initiation of mitochondrial biogenesis.…”

Section: Discussionmentioning

confidence: 91%

“…Also, this augmented respiratory capacity in response to anoxia has been shown to be present in diazoxide-induced classic preconditioning. 11,25 Figure 4. Steady-state mRNA and protein levels of ETC complex proteins after sham or ischemic preconditioning procedures.…”

Section: Discussionmentioning

confidence: 99%

“…10 Baseline respiration was measured polarographically at 25°C in response to ADP and glutamate, 10 and mitochondria were then exposed to a 25-minute anoxic insult in the oxygraph chamber, followed by reoxygenation. 11 Recovery of respiratory function was evaluated by expressing the state 3 respiration after anoxia over the state 3 respiration before anoxia. The activity of cytochrome oxidase (complex IV) was measured polarographically by a Clark-type electrode in the presence of 50 mmol/L potassium phosphate (pH 7.4), 40 mol/L cytochrome c, 12.5 mmol/L ascorbate, 0.63 mmol/L N,N,NЈ,NЈ-tetramethyl-p-phenylenediamine, and 0.03% Triton X-100.…”

Section: Biochemical Analysismentioning

confidence: 99%

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Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery

et al. 2004

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Background-Delayed ischemic preconditioning promotes cardioprotection via genomic reprogramming. We hypothesize that molecular regulation of mitochondrial energetics is integral to this cardioprotective program. Methods and Results-Preconditioning was induced by use of 3 episodes of 3-minute coronary artery occlusion separated by 5 minutes of reperfusion. Twenty-four hours later, infarct size was reduced by 58% after preconditioning compared with sham-operated controls (PϽ0.001). Cardiac mitochondria were isolated from sham and preconditioned rat hearts. Mitochondrial respiration and ATP production were similar between the groups; however, preconditioned mitochondria exhibit modest hyperpolarization of the inner mitochondrial membrane potential (Ն22% versus control, PϽ0.001).After 35-minute anoxia and reoxygenation, preconditioned mitochondria demonstrated a 191Ϯ12% improvement in ADP-sensitive respiration (Pϭ0.002) with preservation of electron-transfer-chain (ETC) activity versus controls. This augmented mitochondrial recovery was eradicated when preconditioning was abolished by the antioxidant 2-mercaptopropionyl glycine (2-MPG). These biochemical modulations appear to be regulated at the genomic level in that the expression of genes encoding rate-controlling complexes in the ETC was significantly upregulated in preconditioned myocardium, with a concordant induction of steady-state protein levels of cytochrome oxidase, cytochrome c, and adenine nucleotide translocase-1. 2-MPG abolished preconditioning induction of these transcripts. Moreover, transcripts of nuclear regulatory peptides known to orchestrate mitochondrial biogenesis, nuclear respiratory factor-1 and peroxisome-proliferator-activated receptor gamma coactivator 1␣, were significantly induced in preconditioned myocardium. Conclusions-Delayed preconditioned mitochondria display increased tolerance against anoxia-reoxygenation in association with modifications in mitochondrial bioenergetics, with concordant genomic induction of a mitochondrial energetic gene regulatory program. This program appears to be mediated by reactive oxygen species signaling.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Biochemical Analysismentioning

confidence: 99%

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Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery

et al. 2004

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“…The protective effect of diazoxide was demonstrated also by Wu et al (2006), who showed that diazoxide blocked hypoxic cell injury by preventing the induction of MPTP opening. Ozcan et al (2001) also showed that the activation of mitoK ATP -channels by diazoxide helps maintain normal mitochondrial morphology and physiology during anoxia/reoxygenation, and preserves the oxidative phosphorylation and ATP production in anoxic mitochondria, while the mitochondria of cells that underwent oxidative stress tend to lose the normal morphology (Wilson et al, 2005). Thus, if MPTP, in response to oxidants, may cause mitochondrial volume deregulation, rupture of the outer mitochondrial membrane, and release of cytochrome c, mitoK ATPchannels activation, unlike MPTP, has beneficial effects on mitochondrial bioenergetics.…”

Section: Resultsmentioning

confidence: 99%

“…Activation of the mitoK ATP has beneficial consequences on mitochondrial physiology under both normal and stress conditions. Ozcan et al provided direct evidence that diazoxide maintains the functional and structural integrity of isolated cardiac mitochondria exposed to anoxia/reoxygenation (Ozcan et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Diazoxide attenuates ROS generation and exerts cytoprotection underconditions of ROS overproduction in rat uterus cells

Vadzyuk¹,

Костерін²

2015

Turk J Biol

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Reactive oxygen species (ROS) overproduction may severely affect cell functions and even provoke cell death. Diazoxide, an opener of ATP-sensitive potassium channels, induces pharmacological preconditioning in different types of cells. However, the target of action of diazoxide is not clear enough because this substance can activate ATP-sensitive potassium channels localized in mitochondria (mitoK ATP ) as well as in plasma membranes (K ATP channels). It has not yet been established if diazoxide activates mitoK ATP in uterus cells. Our objective was to examine the influence of diazoxide on ROS production and on the viability of rat uterus cells under oxidative stress conditions. Using an ROS-sensitive fluorescent probe, we found that diazoxide enhances ROS production under normal conditions, but attenuates this process under conditions of ROS overproduction. Cells pretreated with diazoxide demonstrated lower levels of ROS production and of cell death under oxidative stress, in comparison with conditions where diazoxide was not present. The effects of diazoxide were eliminated by 5-hydroxydecanoate (5-HD), a blocker of mitoK ATP . The principal conclusion of the present study is that decreased ROS production and increased cell survival in the presence of diazoxide under oxidative stress conditions are mediated by the activation of mitoK ATP in rat uterus cells.

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PKCε promotes cardiac mitochondrial and metabolic adaptation to chronic hypobaric hypoxia by GSK3β inhibition

McCarthy

Lochner

Opie

et al. 2011

Journal Cellular Physiology

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PKCε is central to cardioprotection. Sub-proteome analysis demonstrated co-localization of activated cardiac PKCε (aPKCε) with metabolic, mitochondrial, and cardioprotective modulators like hypoxia-inducible factor 1α (HIF-1α). aPKCε relocates to the mitochondrion, inactivating glycogen synthase kinase 3β (GSK3β) to modulate glycogen metabolism, hypertrophy and HIF-1α. However, there is no established mechanistic link between PKCε, p-GSK3β and HIF1-α. Here we hypothesized that cardiac-restricted aPKCε improves mitochondrial response to hypobaric hypoxia by altered substrate fuel selection via a GSK3β/HIF-1α-dependent mechanism. aPKCε and wild-type (WT) mice were exposed to 14 days of hypobaric hypoxia (45 kPa, 11% O2) and cardiac metabolism, functional parameters, p-GSK3β/HIF-1α expression, mitochondrial function and ultrastructure analyzed versus normoxic controls. Mitochondrial ADP-dependent respiration, ATP production and membrane potential were attenuated in hypoxic WT but maintained in hypoxic aPKCε mitochondria (P< 0.005, n = 8). Electron microscopy revealed a hypoxia-associated increase in mitochondrial number with ultrastructural disarray in WT versus aPKCε hearts. Concordantly, left ventricular work was diminished in hypoxic WT but not aPKCε mice (glucose only perfusions). However, addition of palmitate abrogated this (P<0.05 vs. WT). aPKCε hearts displayed increased glucose utilization at baseline and with hypoxia. In parallel, p-GSK3β and HIF1-α peptide levels were increased in hypoxic aPKCε hearts versus WT. Our study demonstrates that modest, sustained PKCε activation blunts cardiac pathophysiologic responses usually observed in response to chronic hypoxia. Moreover, we propose that preferential glucose utilization by PKCε hearts is orchestrated by a p-GSK3β/HIF-1α-mediated mechanism, playing a crucial role to sustain contractile function in response to chronic hypobaric hypoxia.

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Diazoxide protects mitochondria from anoxic injury: Implications for myopreservation

Cited by 76 publications

References 47 publications

Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery

Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery

Diazoxide attenuates ROS generation and exerts cytoprotection underconditions of ROS overproduction in rat uterus cells

PKCε promotes cardiac mitochondrial and metabolic adaptation to chronic hypobaric hypoxia by GSK3β inhibition

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