Isoflurane preconditioning uncouples mitochondria and protects against hypoxia-reoxygenation

Ljubković, Marko; Mio, Yasushi; Marinović, Jasna; Stadnicka, Anna; Warltier, David C.; Bošnjak, Željko J.; Bienengraeber, Martin

doi:10.1152/ajpcell.00221.2006

Cited by 74 publications

(102 citation statements)

References 57 publications

(51 reference statements)

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“…These data suggest that oyster mitochondria undergo minimal functional alterations during the prolonged "shutdown" in anoxic tissues, and the only significant functionally relevant change is a reduction in mitochondrial RCR. A similar moderate decrease in RCR without a concomitant decline in oxidation capacity was found in mammalian mitochondria during hypoxia/reoxygenation-resistant states induced by ischemic preconditioning or by pharmacological agents and was interpreted as a sign of mild uncoupling that serves as a protection mechanism against elevated ROS formation and associated mitochondrial and tissue damage (44,48,52). Possibly a similar mechanism is involved in mitochondrial protection during postanoxic recovery in oysters.…”

Section: Discussionsupporting

confidence: 58%

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Kurochkin

Ivanina

Eilers

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Kurochkin IO, Ivanina AV, Eilers S, Downs CA, May LA, Sokolova IM. Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica). Am J Physiol Regul Integr Comp Physiol 297: R1262-R1272, 2009. First published September 2, 2009 doi:10.1152/ajpregu.00324.2009.-Benthic marine organisms such as mollusks are often exposed to periodic oxygen deficiency (due to the tidal exposure and/or seasonal expansion of the oxygen-deficient dead zones) and pollution by metals [e.g., cadmium, (Cd)]. These stressors can strongly affect mollusks' survival; however, physiological mechanisms of their combined effects are not fully understood. We studied the effects of Cd exposure on metabolic responses to prolonged anoxia and subsequent recovery in anoxia-tolerant intertidal mollusks Crassostrea virginica (eastern oysters). Anoxia led to an onset of anaerobiosis indicated by accumulation of L-alanine, acetate, and succinate. Prolonged anoxia (for 6 days) caused a decline in the maximum activity of electron transport chain and ADP-stimulated (state 3) oxygen uptake by mitochondria (MO 2), but no change in the resting (state 4) MO 2 of oyster mitochondria, along with a slight but significant reduction of mitochondrial respiratory control ratio. During reoxygenation, there was a significant overshoot of mitochondrial MO 2 (by up to 70% above the normoxic steady-state values) in control oysters. Mild mitochondrial uncoupling during prolonged shutdown in anoxic tissues and a subsequent strong stimulation of mitochondrial flux during recovery may help to rapidly restore redox status and protect against elevated reactive oxygen species formation in oysters. Exposure to Cd inhibits anaerobic metabolism, abolishes reoxygenation-induced stimulation of mitochondrial MO 2, and leads to oxidative stress (indicated by accumulation of DNA lesions) and a loss of mitochondrial capacity during postanoxic recovery. This may result in increased sensitivity to intermittent hypoxia and anoxia in Cd-exposed mollusks and will have implications for their survival in polluted estuaries and coastal zones. air exposure; recovery; mitochondrial function; oxidative damage; mollusks PERIODICAL OXYGEN DEFICIENCY is an important environmental stressor in intertidal and coastal habitats. Short-term intermittent hypoxia/anoxia (from several hours to several days, depending on the state of the tides) often occurs in intertidal invertebrates during the low tide, and may also occur in tidal pools and shallow lagoons with limited water exchange (8,36,49). Furthermore, long-term severe hypoxia and anoxia triggered by anthropogenic release of nutrients has become a serious issue in many estuaries and coastal zones rivaling the climate change (18,22). In the coastal dead zones, benthic invertebrates including mollusks can be exposed to severe hypoxia or anoxia for prolonged periods (from weeks to up to several months) (10,22,34,46). Long-term oxygen deficiency often leads to the massive die-offs in species with limited or...

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Section: Discussionsupporting

confidence: 58%

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Kurochkin

Ivanina

Eilers

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…However, it is unclear what mediates mitochondrial depolarization by APC. It is suggested that mitochondrial K ϩ channels, often identified as effectors of protection by preconditioning, could be these mediators (10,27,32,34). However, their role in this mechanism is questionable since their activation has been correlated with both increase and decrease in ROS production (20,49).…”

Section: Discussionmentioning

confidence: 99%

“…The ⌬⌿m-sensitive fluorescent dye tetramethylrhodamine ethyl ester (TMRE) (Invitrogen, Carlsbad, CA) and autofluorescence of mitochondrial flavoproteins (FPs) were used for the assessment of ⌬⌿ m in cardiomyocytes (Fig. 1A) as previously described (32). Excitation and emission Fig.…”

Section: Methodsmentioning

confidence: 99%

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Mitochondrial depolarization underlies delay in permeability transition by preconditioning with isoflurane: roles of ROS and Ca²⁺

Sedlić

Šepac²,

Pravdić³

et al. 2010

American Journal of Physiology-Cell Physiology

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-During reperfusion, the interplay between excess reactive oxygen species (ROS) production, mitochondrial Ca 2ϩ overload, and mitochondrial permeability transition pore (mPTP) opening, as the crucial mechanism of cardiomyocyte injury, remains intriguing. Here, we investigated whether an induction of a partial decrease in mitochondrial membrane potential (⌬⌿ m) is an underlying mechanism of protection by anesthetic-induced preconditioning (APC) with isoflurane, specifically addressing the interplay between ROS, Ca 2ϩ , and mPTP opening. The magnitude of APCinduced decrease in ⌬⌿m was mimicked with the protonophore 2,4-dinitrophenol (DNP), and the addition of pyruvate was used to reverse APC-and DNP-induced decrease in ⌬⌿ m. In cardiomyocytes, ⌬⌿ m, ROS, mPTP opening, and cytosolic and mitochondrial Ca 2ϩ were measured using confocal microscope, and cardiomyocyte survival was assessed by Trypan blue exclusion. In isolated cardiac mitochondria, antimycin A-induced ROS production and Ca 2ϩ uptake were determined spectrofluorometrically. In cells exposed to oxidative stress, APC and DNP increased cell survival, delayed mPTP opening, and attenuated ROS production, which was reversed by mitochondrial repolarization with pyruvate. In isolated mitochondria, depolarization by APC and DNP attenuated ROS production, but not Ca 2ϩ uptake. However, in stressed cardiomyocytes, a similar decrease in ⌬⌿m attenuated both cytosolic and mitochondrial Ca 2ϩ accumulation. In conclusion, a partial decrease in ⌬⌿m underlies cardioprotective effects of APC by attenuating excess ROS production, resulting in a delay in mPTP opening and an increase in cell survival. Such decrease in ⌬⌿m primarily attenuates mitochondrial ROS production, with consequential decrease in mitochondrial Ca 2ϩ uptake.cardioprotection; oxidative stress; mitochondria; reactive oxygen species DAMAGE DURING ISCHEMIA and reperfusion (I/R) of the heart involves complex processes where the cellular machinery itself becomes a source of deleterious mediators of injury. Such processes include excessive production of mitochondrial reactive oxygen species (ROS) and cellular Ca 2ϩ overload (6, 37), which trigger opening of the mitochondrial permeability transition pore (mPTP) (16, 19), a critical event in the transition towards cell death (18). The mPTP opening instantly dissipates mitochondrial membrane potential (⌬⌿ m ), ceases mitochondrial ATP production, and initiates cell death pathways (6).Studies suggest that most of the cell death occurs during reperfusion (51, 53), which can be attenuated with antioxidants (52), indicating an important role of ROS. In cardiomyocytes, ROS are primarily generated at complexes I and III of the mitochondrial electron transport chain (50). During I/R, accumulation of cytosolic Ca 2ϩ , which drives accumulation of mitochondrial Ca 2ϩ (45), is primarily attributed to insufficient ATP production and derangement of intracellular ion homeostasis (37). It is suggested that excess ROS production and mitochondrial Ca 2ϩ overload are mutually de...

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“…ATP synthesis rates by isolated mitochondria was assessed using a chemiluminescence-based method utilizing firefly luciferase and luciferin (ATP Determination Kit; Invitrogen), as described previously (Ljubkovic et al, 2007). The reaction solution contained respiration buffer, 0.2 M diadenosine pentaphosphate, 5 mM pyruvate, 5 mM malate, 2 mg/l mitochondria, 200 M luciferin, and 1.25 mg/l luciferase.…”

Section: Mitochondrial Isolation and Functional Assaysmentioning

confidence: 99%

The A₃ Adenosine Receptor Agonist CP-532,903 [N⁶-(2,5-Dichlorobenzyl)-3′-aminoadenosine-5′-N-methylcarboxamide] Protects against Myocardial Ischemia/Reperfusion Injury via the Sarcolemmal ATP-Sensitive Potassium Channel

Wan¹,

Ge²,

Tampo³

et al. 2007

J Pharmacol Exp Ther

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We examined the cardioprotective profile of the new A 3 adenosine receptor (AR) agonist 903 [N 6 -(2,5-dichlorobenzyl)-3Ј-aminoadenosine-5Ј-N-methylcarboxamide] in an in vivo mouse model of infarction and an isolated heart model of global ischemia/reperfusion injury. In radioligand binding and cAMP accumulation assays using human embryonic kidney 293 cells expressing recombinant mouse ARs, CP-532,903 was found to bind with high affinity to mouse A 3 ARs (K i ϭ 9.0 Ϯ 2.5 nM) and with high selectivity versus mouse A 1 AR (100-fold) and A 2A ARs (1000-fold). In in vivo ischemia/reperfusion experiments, pretreating mice with 30 or 100 g/kg CP-532,903 reduced infarct size from 59.2 Ϯ 2.1% of the risk region in vehicle-treated mice to 42.5 Ϯ 2.3 and 39.0 Ϯ 2.9%, respectively. Likewise, treating isolated mouse hearts with CP-532,903 (10, 30, or 100 nM) concentration dependently improved recovery of contractile function after 20 min of global ischemia and 45 min of reperfusion, including developed pressure and maximal rate of contraction/relaxation. In both models of ischemia/reperfusion injury, CP-532,903 provided no benefit in studies using mice with genetic disruption of the A 3 AR gene, A 3 knockout (KO) mice. In isolated heart studies, protection provided by CP-532,903 and ischemic preconditioning induced by three brief ischemia/ reperfusion cycles were lost in Kir6.2 KO mice lacking expression of the pore-forming subunit of the sarcolemmal ATPsensitive potassium (K ATP ) channel. Whole-cell patch-clamp recordings provided evidence that the A 3 AR is functionally coupled to the sarcolemmal K ATP channel in murine cardiomyocytes. We conclude that CP-532,903 is a highly selective agonist of the mouse A 3 AR that protects against ischemia/reperfusion injury by activating sarcolemmal K ATP channels.A 3 adenosine receptor (AR) agonists have been shown to effectively limit infarct size and reduce contractile dysfunction in several different animal models of ischemia/reperfusion injury (Auchampach et al., 1997b(Auchampach et al., , 2003Tracey et al., 1997Tracey et al., , 1998Tracey et al., , 2003Jordan et al., 1999;Thourani et al., 1999;Ge et al., 2004Ge et al., , 2006. A 3 AR agonists are attractive as cardioprotective agents because they do not alter systemic hemodynamic parameters in nonrodent species and are effective if administered before the ischemic event or only during reperfusion (Auchampach et al

show abstract

Isoflurane preconditioning uncouples mitochondria and protects against hypoxia-reoxygenation

Cited by 74 publications

References 57 publications

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Mitochondrial depolarization underlies delay in permeability transition by preconditioning with isoflurane: roles of ROS and Ca²⁺

The A₃ Adenosine Receptor Agonist CP-532,903 [N⁶-(2,5-Dichlorobenzyl)-3′-aminoadenosine-5′-N-methylcarboxamide] Protects against Myocardial Ischemia/Reperfusion Injury via the Sarcolemmal ATP-Sensitive Potassium Channel

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Isoflurane preconditioning uncouples mitochondria and protects against hypoxia-reoxygenation

Cited by 74 publications

References 57 publications

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Mitochondrial depolarization underlies delay in permeability transition by preconditioning with isoflurane: roles of ROS and Ca2+

The A3 Adenosine Receptor Agonist CP-532,903 [N6-(2,5-Dichlorobenzyl)-3′-aminoadenosine-5′-N-methylcarboxamide] Protects against Myocardial Ischemia/Reperfusion Injury via the Sarcolemmal ATP-Sensitive Potassium Channel

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Mitochondrial depolarization underlies delay in permeability transition by preconditioning with isoflurane: roles of ROS and Ca²⁺

The A₃ Adenosine Receptor Agonist CP-532,903 [N⁶-(2,5-Dichlorobenzyl)-3′-aminoadenosine-5′-N-methylcarboxamide] Protects against Myocardial Ischemia/Reperfusion Injury via the Sarcolemmal ATP-Sensitive Potassium Channel