Myocardial ischemia decreases oxidative phosphorylation through cytochrome oxidase in subsarcolemmal mitochondria

Lesnefsky, Edward J.; Tandler, B.; Ye, Jian; Slabe, Thomas J.; Turkaly, Julia S.; Hoppel, Charles L.

doi:10.1152/ajpheart.1997.273.3.h1544

Cited by 159 publications

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“…Results showing ubiquinone-cytochrome c oxidoreductase (complex III) activity unchanged by ischemia in both WT and MLS-STAT3E mitochondria (Table 3) indicated that the ischemia-induced blockade of ETC was localized to cytochrome c oxidase (complex IV). It has been shown that ischemic damage to TMPD/ ascorbate respiration was related to cytochrome c release from mitochondria (23). Western blot analysis revealed over 30% reduced amounts of cytochrome c in WT mitochondria after ischemia (Fig.…”

Section: Mls-stat3e Expression Prevents Ischemia-induced Decrease In mentioning

confidence: 87%

“…Mitochondrial Oxidative Phosphorylation-Oxygen consumption by intact mitochondria was measured using a Clarktype oxygen electrode (Strathkelvin Instruments, North Lanarkshire, UK) at 30°C in respiration buffer at pH 7.4 (80 mM KCl, 50 mM MOPS, 1 mM EGTA, 5 mM KH 2 PO 4 , 1 mg/ml of defatted BSA) as previously described (22,23). Substrates for complex I (20 mM glutamate ϩ 5 mM malate), complex II (20 mM succinate with 7.5 M rotenone), and complex IV (1 mM TMPD, 20 mM L-ascorbate with 7.5 M rotenone) were used and state 3 (0.2 mM ADP-stimulated), state 4 (ADP-limited) respiration, respiratory control ratio (RCR), maximal rate of state 3 respiration (2 mM ADP), and rate of uncoupled respiration (0.04 mM dinitrophenol, DNP) were determined.…”

Section: Sds-page Andmentioning

confidence: 99%

“…ETC and Citrate Synthase Enzyme Activities-The following enzyme activities were measured spectrophotometrically in detergent-solubilized mitochondria using previously described methods (22)(23)(24): NADH-ubiquinone oxidoreductase, rotenone-sensitive (complex I), NADH-ferricyanide reductase (NFR); succinate-ubiquinone oxidoreductase, theonyltrifluoroacetone sensitive (complex II); ubiquinol-cytochrome c oxidoreductase, antimycin A sensitive (complex III); cytochrome c oxidase (complex IV) and citrate synthase. Frozen-thawed mitochondria were solubilized at a final protein concentration of 1 g/l in 0.5% cholate in MSM/EDTA buffer, pH 7.4 (220 mM mannitol, 70 mM sucrose, 5 mM MOPS, 2 mM EDTA).…”

Section: Sds-page Andmentioning

confidence: 99%

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Mitochondrial-targeted Signal Transducer and Activator of Transcription 3 (STAT3) Protects against Ischemia-induced Changes in the Electron Transport Chain and the Generation of Reactive Oxygen Species

Szczepanek

Chen

Derecka

et al. 2011

Journal of Biological Chemistry

199

229

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Expression of the STAT3 transcription factor in the heart is cardioprotective and decreases the levels of reactive oxygen species. Recent studies indicate that a pool of STAT3 resides in the mitochondria where it is necessary for the maximal activity of complexes I and II of the electron transport chain. However, it has not been explored whether mitochondrial STAT3 modulates cardiac function under conditions of stress. Transgenic mice with cardiomyocyte-specific overexpression of mitochondria-targeted STAT3 with a mutation in the DNA-binding domain (MLS-STAT3E) were generated. We evaluated the role of mitochondrial STAT3 in the preservation of mitochondrial function during ischemia. Under conditions of ischemia heart mitochondria expressing MLS-STAT3E exhibited modest decreases in basal activities of complexes I and II of the electron transport chain. In contrast to WT hearts, complex I-dependent respiratory rates were protected against ischemic damage in MLS-STAT3E hearts. MLS-STAT3E prevented the release of cytochrome c into the cytosol during ischemia. In contrast to WT mitochondria, ischemia did not augment reactive oxygen species production in MLS-STAT3E mitochondria likely due to an MLS-STAT3E-mediated partial blockade of electron transport through complex I. Given the caveat of STAT3 overexpression, these results suggest a novel protective mechanism mediated by mitochondrial STAT3 that is independent of its canonical activity as a nuclear transcription factor. STAT3 was originally identified as an IL-6-induced transcriptional activator of acute phase genes (1). However, other members of the IL-6 family, which utilize gp-130 receptor, as well as leptin, IL-12, IFN␣/␤, IL-10, GM-CSF, several growth factors, oncogenes, and stress such as hypoxia, also activate STAT3 (1). STAT3 is vital to embryonic development and STAT3-null mice are embryonic lethal (2). Analysis of tissuespecific conditional STAT3 knock-out mice has provided strong evidence that transcriptional activity of STAT3 plays a central role in the control of cell growth and host responses to inflammation and cellular stress (1). STAT3 positively regulates expression of anti-apoptotic (Bcl-2 and Bcl-xL) (1) and antioxidative proteins (MnSOD and metallothionein-1 and -2) (3, 4).Expression of STAT3 in the heart is associated with cardiac survival (5). When STAT3 is selectively deleted in cardiomyocytes, mice develop enhanced cardiac inflammation with fibrosis, dilated cardiomyopathy, and die prematurely due to congestive heart failure (5). Female mice, where STAT3 is not expressed in cardiomyocytes, develop post-partum cardiomyopathy, which is also seen in humans with reduced STAT3 expression in the myocardium (6). Ventricles from STAT3-null hearts show elevated levels of reactive oxygen species (ROS) 2 (6). Ischemic and pharmacologic preconditioning protected the viability of wild type but not STAT3 Ϫ/Ϫ cardiomyocytes (5). When STAT3 is overexpressed in cardiomyocytes, mice are less sensitive to the cardiotoxic effects of doxorubicin, which exerts i...

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Section: Mls-stat3e Expression Prevents Ischemia-induced Decrease In mentioning

confidence: 87%

Section: Sds-page Andmentioning

confidence: 99%

Section: Sds-page Andmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial-targeted Signal Transducer and Activator of Transcription 3 (STAT3) Protects against Ischemia-induced Changes in the Electron Transport Chain and the Generation of Reactive Oxygen Species

Szczepanek

Chen

Derecka

et al. 2011

Journal of Biological Chemistry

199

229

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“…Static morphological distinctions include mitochondria in intermyofibrillar locations, subsarcolemmal mito- chondria, and perinuclear mitochondria (16,17). It has also been suggested that these differentially localized mitochondria may have different functional properties (18,19).…”

Section: Discussionmentioning

confidence: 99%

Spatio-temporal oscillations of individual mitochondria in cardiac myocytes reveal modulation of synchronized mitochondrial clusters

Kurz

Aon

O’Rourke

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

123

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Mitochondrial networks in cardiac myocytes under oxidative stress show collective (cluster) behavior through synchronization of their inner membrane potentials (ΔΨ m ). However, it is unclear whether the oscillation frequency and coupling strength between individual mitochondria affect the size of the cluster and vice versa. We used the wavelet transform and developed advanced signal processing tools that allowed us to capture individual mitochondrial ΔΨ m oscillations in cardiac myocytes and examine their dynamic spatio-temporal properties. Heterogeneous frequency behavior prompted us to sort mitochondria according to their frequencies. Signal analysis of the mitochondrial network showed an inverse relationship between cluster size and cluster frequency as well as between cluster amplitude and cluster size. High cross-correlation coefficients between neighboring mitochondria clustered longitudinally along the myocyte striations, indicated anisotropic communication between mitochondria. Isochronal mapping of the onset of myocyte-wide ΔΨ m depolarization further exemplified heterogeneous ΔΨ m among mitochondria. Taken together, the results suggest that frequency and amplitude modulation of clusters of synchronized mitochondria arises by means of strong changes in local coupling between neighboring mitochondria.wavelets | frequency | amplitude | mitochondrial oscillator | mitochondrial coupling M itochondria in cardiac myocytes under the influence of substrate deprivation or oxidative stress have a fundamental role as determinants of cell life or death, with implications that scale to affect the function of the whole heart (1, 2). Cardiac mitochondria are organized in a highly ordered network consisting of intermyofibrillar, subcarcolemmal, and perinuclear (3) mitochondria whose coordinated function controls the energy metabolism of the myocyte (4).In cardiac myocytes, the localized perturbation of a few mitochondria within the overall mitochondrial network can trigger the transition from the physiological to the pathophysiological state by producing synchronized whole-myocyte oscillations of ΔΨ m that can be monitored with the fluorescent dye tetramethylrhodamine ethyl ester (TMRE) (5). The imbalance between reactive oxygen species (ROS) generation and ROS scavenging capacity in a significant proportion of the network (∼60%) (5) is thought to destabilize ΔΨ m beyond a critical point into a state of ROS-induced ROS release. Increased ROS overflow exceeding a threshold level results in the appearance of a spanning cluster of mitochondria oscillating in apparent synchrony throughout the cell as the mitochondrial network locks into a low-frequency, high-amplitude oscillatory mode (6, 7).In many disparate examples of physically and chemically coupled oscillators, synchronization of the system generally arises from an initial nucleus of (spontaneously) synchronized oscillators that integrate neighboring oscillators, thereby increasing the size and signal amplitude of the initial oscillatory nucleus (8-11).When the clus...

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“…I/R injury has been shown to result in increased mitochondrial heterogeneity across numerous functional parameters, including Ca 21 content, redox status and membrane potential, as measured by fluorescent confocal microscopy [207,213]. The rate of OxPhos was shown to decrease only in subsarcolemmal mitochondria, following 45 minutes global ischemia [214], while the loss of Dc M with I/R was shown to propagate [215] longitudinally from point of initiation, with overall heterogeneity in the spatial distribution of mitochondria affected [206]. The loss of Dc M within individual mitochondria, suggested to occur as early as I/R injury, led to the development of the concept of 'mitochondrial criticality', used to describe the propagation of Dc M loss in response to small alterations in ROS levels [216] that leads to functional alterations to the cardiomyocyte and eventually the myocardium.…”

Section: Mitochondrial Morphology and Structurementioning

confidence: 99%

Mitochondria: A mirror into cellular dysfunction in heart disease

White

Edwards

Cordwell

et al. 2008

Proteomics Clinical Apps

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Cardiovascular (CV) disease is the single most significant cause of morbidity and mortality worldwide. The emerging global impact of CV disease means that the goals of early diagnosis and a wider range of treatment options are now increasingly pertinent. As such, there is a greater need to understand the molecular mechanisms involved and potential targets for intervention. Mitochondrial function is important for physiological maintenance of the cell, and when this function is altered, the cell can begin to suffer. Given the broad range and significant impacts of the cellular processes regulated by the mitochondria, it becomes important to understand the roles of the proteins associated with this organelle. Proteomic investigations of the mitochondria are hampered by the intrinsic properties of the organelle, including hydrophobic mitochondrial membranes; high proportion of basic proteins (pI greater than 8.0); and the relative dynamic range issues of the mitochondria. For these reasons, many proteomic studies investigate the mitochondria as a discrete subproteome. Once this has been achieved, the alterations that result in functional changes with CV disease can be observed. Those alterations that lead to changes in mitochondrial function, signaling and morphology, which have significant implications for the cardiomyocyte in the development of CV disease, are discussed.

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Myocardial ischemia decreases oxidative phosphorylation through cytochrome oxidase in subsarcolemmal mitochondria

Cited by 159 publications

References 0 publications

Mitochondrial-targeted Signal Transducer and Activator of Transcription 3 (STAT3) Protects against Ischemia-induced Changes in the Electron Transport Chain and the Generation of Reactive Oxygen Species

Mitochondrial-targeted Signal Transducer and Activator of Transcription 3 (STAT3) Protects against Ischemia-induced Changes in the Electron Transport Chain and the Generation of Reactive Oxygen Species

Spatio-temporal oscillations of individual mitochondria in cardiac myocytes reveal modulation of synchronized mitochondrial clusters

Mitochondria: A mirror into cellular dysfunction in heart disease

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