Mitochondrial calcium handling and oxidative stress

Halestrap, Andrew P.; Griffiths, Elinor J.; Connern, Cathal P.

doi:10.1042/bst0210353

Cited by 73 publications

(47 citation statements)

References 10 publications

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“…Regulation of [ATP] (72), a phenomenon possibly involved in the creation of nonspecific pores in the mitochondrial membrane during hypoxia and other cellular stresses (the "mitochondrial permeability transition") (73). The current data suggest that changes in intramitochondrial or cytosolic [Ca 2ϩ ] might also have a role in the regulation of ATP/ADP translocase activity under nonpathological conditions.…”

Section: Response Of Primary Islet ␤-Cells To Increases In Extracellumentioning

confidence: 73%

Glucose Generates Sub-plasma Membrane ATP Microdomains in Single Islet β-Cells

Kennedy

Pouli

Ainscow

et al. 1999

Journal of Biological Chemistry

304

295

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Increases in the concentration of free ATP within the islet ␤-cell may couple elevations in blood glucose to insulin release by closing ATP-sensitive K ؉ (K ATP ) channels and activating Ca 2؉ influx. Here, we use recombinant targeted luciferases and photon counting imaging to monitor changes in free [ATP] Increases in extracellular glucose concentration stimulate the exocytosis of insulin from islet ␤-cells. This is probably achieved by an increase in glycolysis and flux through the citrate cycle (1), leading to elevated intracellular levels of likely coupling factors (2), including ATP. Closure of ATP-sensitive K ϩ channels (3-5) then leads to plasma membrane depolarization and the influx of Ca 2ϩ through voltage gated Ca 2ϩ channels. Increases in the total intracellular concentration of ATP have been measured in isolated islets (6) and cell lines (7) exposed to increases in extracellular glucose concentration. However, the measured changes are generally small and difficult to interpret because of the large depot of intragranular ATP, and the presence of non-␤-cells (8). Furthermore, such measurements give no indication of the concentration of unbound ATP. Unfortunately, measurements of free [ATP] in living cells, for example by 31 P NMR (9), cannot easily be extended to the islet micro-organ and do not provide sufficient sensitivity to detect changes at the cellular or subcellular level. This is an important question because differences in [ATP] at different intracellular sites have been predicted. In particular, locally high ATP consumption by the plasma membrane Na ϩ -K ϩ and Ca 2ϩ -ATPase, may mean that [ATP] is lower in this domain than in the bulk of the cell cytosol (1). Similarly, the electrogenic nature of the mitochondrial ATP/ADP translocase (10) is predicted to create differences in ATP/ADP ratio across the inner mitochondrial membrane (cytosolic high).The role of changes in free Ca 2ϩ ion concentration ([Ca 2ϩ ]) in regulating ␤-cell metabolism and ATP concentration is controversial. Increases in [Ca 2ϩ ] following plasma membrane depolarization act both to stimulate ATP requiring processes (i.e. secretory granule movement and exocytosis) (11) and possibly to enhance mitochondrial oxidative metabolism (12, 13). Recent measurements of total ATP content of whole islets have suggested that the former may dominate and that Ca 2ϩ influx may diminish glucose-induced increases in ATP/ADP ratio (14).The use of firefly luciferase, targeted to discrete intracellular domains, should provide an extremely sensitive method of monitoring free [ATP] dynamically and at the subcellular level. In previous studies, we have shown that photon counting imaging of total luciferase activity in single cells provides a convenient means to measure changes in gene expression in single cells (15,16). Luciferase has previously been employed to measure intracellular ATP concentration in single cardiac myocytes (17) and hepatocytes (18), but only after microinjection of the purified protein. In recent reports, Maechler...

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Section: Response Of Primary Islet ␤-Cells To Increases In Extracellumentioning

confidence: 73%

Glucose Generates Sub-plasma Membrane ATP Microdomains in Single Islet β-Cells

Kennedy

Pouli

Ainscow

et al. 1999

Journal of Biological Chemistry

304

295

View full text Add to dashboard Cite

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“…mtPTP opening was measured by monitoring the decrease in light scattering associated with mitochondrial swelling at 540 nm, as described previously (2). Briefly, mtPTP opening is facilitated under conditions of elevated Ca 2ϩ concentration and oxidative stress, causing massive mitochondrial swelling, outer membrane rupture, and proapoptotic release (19,21,22,47). Briefly, isolated IMF mitochondria were resuspended (to obtain a final con- Fig.…”

Section: Methodsmentioning

confidence: 99%

Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle

Adhihetty¹,

O'Leary²,

Chabi³

et al. 2007

Journal of Applied Physiology

211

240

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November 22, 2006; doi:10.1152/japplphysiol.00768.2006.-Chronic muscle disuse induced by denervation reduces mitochondrial content and produces muscle atrophy. To investigate the molecular mechanisms responsible for these adaptations, we assessed 1) mitochondrial biogenesis-and apoptosis-related proteins and 2) apoptotic susceptibility and cell death following denervation. Rats were subjected to 5, 7, 14, 21, or 42 days of unilateral denervation of the sciatic or peroneal nerve. Muscle mass and mitochondrial content were reduced by 40 -65% after 21 and 42 days of denervation. Denervation-induced decrements in mitochondrial content occurred along with 60% and 70% reductions in transcription factor A (Tfam) and peroxisome proliferator-activated receptor-␥ coactivator (PGC)-1␣, respectively. After 42 days of denervation, Bax was elevated by 115% and Bcl-2 was decreased by 89%, producing a 16-fold increase in the Bax-toBcl-2 ratio. Mitochondrial reactive oxygen species production was markedly elevated by 5-to 7.5-fold in subsarcolemmal mitochondria after 7, 14, and 21 days of denervation, whereas reactive oxygen species production in intermyofibrillar (IMF) mitochondria was reduced by 40 -50%. Subsarcolemmal and IMF mitochondrial levels of MnSOD were also reduced by 40 -50% after 14 -21 days of denervation. The maximal rate of IMF mitochondrial pore opening (Vmax) was elevated by 25-35%, and time to V max was reduced by 20 -25% after 14 and 21 days, indicating increased apoptotic susceptibility. Myonuclear decay, assessed by DNA fragmentation, was elevated at 7-21 days of denervation. Our data indicate that PGC-1␣ and Tfam are important factors that likely contribute to the reduced mitochondrial content after chronic disuse. In addition, our results illustrate that, despite the reduced mitochondrial content, denervated muscle has greater mitochondrial apoptotic susceptibility, which coincided with elevated apoptosis, and these processes may contribute to denervation-induced muscle atrophy. mitochondrial biogenesis; muscle disuse; reactive oxygen species; mitochondrial respiration; peroxisome proliferator-activated receptor-␥ coactivator-1␣

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“…In most organs, the lack of oxygen means a lack of electron acceptors, ending oxidative phosphorylation and the production of ATP (10). The rapid depletion of ATP causes a decrease in the membrane potential of the mitochondria (79) and allows calcium to escape the mitochondria, triggering apoptotic processes. ROS are generated as a result of the changes in membrane potential (32).…”

Section: Mechanisms Of Lung Injury During Irmentioning

confidence: 99%

Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process

Hengst

Gielis

Lin

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

324

280

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Lung ischemia-reperfusion injury remains one of the major complications after cardiac bypass surgery and lung transplantation. Due to its dual blood supply system and the availability of oxygen from alveolar ventilation, the pathogenetic mechanisms of ischemia-reperfusion injury in the lungs are more complicated than in other organs, where loss of blood flow automatically leads to hypoxia. In this review, an extensive overview is given of the molecular and cellular mechanisms that are involved in the pathogenesis of lung ischemia-reperfusion injury and the possible therapeutic strategies to reduce or prevent it. In addition, the roles of neutrophils, alveolar macrophages, cytokines, and chemokines, as well as the alterations in the cell-death related pathways, are described in detail. pulmonary; lung transplantation; ventilated ischemia IN THE PAST, THE LUNG WAS thought to be relatively resistant to ischemia because of its dual circulation and the availability of oxygen from alveolar ventilation. However, the depletion of lung oxygenation by stopping the ventilation leads to the same degree of lung impairment as a decrease in mechanotransduction by loss of blood flow, as determined by increases in vascular pressure and permeability (11), indicating that any deficiency from oxygenation or mechanotransduction can have significant repercussions (149).Reperfusion of the ischemic lung is a double-edged sword. Reestablishing the perfusion of the ischemic lung is absolutely required to maintain the viability of the lung, but reperfusion itself can trigger a complex cascade of events, the so-called pulmonary ischemia-reperfusion injury (LIRI) (48), characterized by increased microvascular permeability (Pvasc), increased pulmonary vascular resistance (PVR), pulmonary edema, impaired oxygenation, and pulmonary hypertension. Ischemia of the lung, without loss of ventilation, results in a complex pathophysiological situation and, therefore, is not comparable with ischemia in other organs. During ventilated ischemia, for example, the adenosine triphosphate (ATP) levels remain normal while reactive oxygen species (ROS) are formed (70), illustrating aspects of complexity of the pathophysiology of ventilated and anoxic lung ischemia. Therefore, a distinction should be made between ventilated ischemia, meaning a loss of blood flow, and anoxia/reoxygenation, indicating the loss of oxygenation and/or perfusion. In this review, the terms anoxia/reoxygenation and ventilated ischemia will be used, if the specific model is known and/or the mechanism is suggested to be model specific. Ischemia alone will be used, if it applies for both mechanisms, if the specific model is not known, or the research involves other organs.Complete and prolonged lung anoxia for up to several hours is unavoidable during lung transplantation, with dire consequences. Reperfusion of the transplanted lung can lead to nonspecific alveolar damage, pulmonary edema, and hypoxemia within 72 h after lung transplantation. Even with the advancements in lung preservati...

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Mitochondrial calcium handling and oxidative stress

Cited by 73 publications

References 10 publications

Glucose Generates Sub-plasma Membrane ATP Microdomains in Single Islet β-Cells

Glucose Generates Sub-plasma Membrane ATP Microdomains in Single Islet β-Cells

Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle

Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process

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