Mitochondrial functions in ischemic myocardium I. Proton electrochemical gradient, inner membrane permeability, calcium transport and oxidative phosphorylation in isolated mitochondria

Toleikis, Algirdas; Dzeja, Petras P.; Praškevičius, Antanas; Jasaitis, Audrius

doi:10.1016/0022-2828(79)90452-8

Cited by 30 publications

(5 citation statements)

References 26 publications

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“…During ischemia, reactive oxygen species are generated by mitochondria, despite the low oxygen tension (5,34). In the intact heart, oxidation of cardiolipin can lead to the direct destruction of cardiolipin (24,44) or to covalent cardiolipin-protein complexes that render cardiolipin undetectable as a phospholipid (60). Thus oxidative processes remain a potential mechanism of the ischemia-induced decrease in cardiolipin content in SSM.…”

Section: Discussionmentioning

confidence: 99%

Ischemia, rather than reperfusion, inhibits respiration through cytochrome oxidase in the isolated, perfused rabbit heart: role of cardiolipin

Lesnefsky¹,

Chen²,

Slabe³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

115

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Ischemia and reperfusion result in mitochondrial dysfunction, with decreases in oxidative capacity, loss of cytochrome c, and generation of reactive oxygen species. During ischemia of the isolated perfused rabbit heart, subsarcolemmal mitochondria, located beneath the plasma membrane, sustain a loss of the phospholipid cardiolipin, with decreases in oxidative metabolism through cytochrome oxidase and the loss of cytochrome c. We asked whether additional injury to the distal electron chain involving cardiolipin with loss of cytochrome c and cytochrome oxidase occurs during reperfusion. Reperfusion did not lead to additional damage in the distal electron transport chain. Oxidation through cytochrome oxidase and the content of cytochrome c did not further decrease during reperfusion. Thus injury to cardiolipin, cytochrome c, and cytochrome oxidase occurs during ischemia rather than during reperfusion. The ischemic injury leads to persistent defects in oxidative function during the early reperfusion period. The decrease in cardiolipin content accompanied by persistent decrements in the content of cytochrome c and oxidation through cytochrome oxidase is a potential mechanism of additional myocyte injury during reperfusion.

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Section: Discussionmentioning

confidence: 99%

Ischemia, rather than reperfusion, inhibits respiration through cytochrome oxidase in the isolated, perfused rabbit heart: role of cardiolipin

Lesnefsky¹,

Chen²,

Slabe³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

115

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“…Succinate dehydrogenase is a four-subunit membrane molecular complex integrated with the mitochondrial respiratory chain that links the tricarbocylic acid and coenzyme Q cycles promoting electron flow and energy-dependent mitochondrial functions, such as ATP production and Ca 2ϩ transport (21,33). Vigorous succinate oxidation, associated with high activity of succinate dehydrogenase, hyperpolarizes mitochondrial inner membrane to sustain higher rates of ATP production compared with oxidation of NAD-dependent substrates (12,21,64). However, excessive succinate oxidation, which occurs on reoxygenation after ischemia as succinate accumulates (70), could be a major source of ROS and tissue damage (7,30,67).…”

Section: Discussionmentioning

confidence: 99%

Targeting nucleotide-requiring enzymes: implications for diazoxide-induced cardioprotection

Dzeja

Bast

Özcan

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

101

106

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Modulation of mitochondrial respiratory chain, dehydrogenase, and nucleotide-metabolizing enzyme activities is fundamental to cellular protection. Here, we demonstrate that the potassium channel opener diazoxide, within its cardioprotective concentration range, modulated the activity of flavin adenine dinucleotide-dependent succinate dehydrogenase with an IC50 of 32 microM and reduced the rate of succinate-supported generation of reactive oxygen species (ROS) in heart mitochondria. 5-Hydroxydecanoic fatty acid circumvented diazoxide-inhibited succinate dehydrogenase-driven electron flow, indicating a metabolism-dependent supply of redox equivalents to the respiratory chain. In perfused rat hearts, diazoxide diminished the generation of malondialdehyde, a marker of oxidative stress, which, however, increased on diazoxide washout. This effect of diazoxide mimicked ischemic preconditioning and was associated with reduced oxidative damage on ischemia-reperfusion. Diazoxide reduced cellular and mitochondrial ATPase activities, along with nucleotide degradation, contributing to preservation of myocardial ATP levels during ischemia. Thus, by targeting nucleotide-requiring enzymes, particularly mitochondrial succinate dehydrogenase and cellular ATPases, diazoxide reduces ROS generation and nucleotide degradation, resulting in preservation of myocardial energetics under stress.

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“…These findings have been confirmed by many other researchers (for a review, see Piper et al [8]). In accordance with the decreased respiratory capacity, oxidative phosphorylation was also found to be depressed in experimental models of ischaemia and reperfusion [52][53][54].…”

Section: General Observationsmentioning

confidence: 94%

Biochemical dysfunction in heart mitochondria exposed to ischaemia and reperfusion

Solaini

Harris

2005

Biochemical Journal

210

160

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Heart tissue is remarkably sensitive to oxygen deprivation. Although heart cells, like those of most tissues, rapidly adapt to anoxic conditions, relatively short periods of ischaemia and subsequent reperfusion lead to extensive tissue death during cardiac infarction. Heart tissue is not readily regenerated, and permanent heart damage is the result. Although mitochondria maintain normal heart function by providing virtually all of the heart's ATP, they are also implicated in the development of ischaemic damage. While mitochondria do provide some mechanisms that protect against ischaemic damage (such as an endogenous inhibitor of the F1Fo-ATPase and antioxidant enzymes), they also possess a range of elements that exacerbate it, including ROS (reactive oxygen species) generators, the mitochondrial permeability transition pore, and their ability to release apoptotic factors. This review considers the process of ischaemic damage from a mitochondrial viewpoint. It considers ischaemic changes in the inner membrane complexes I-V, and how this might affect formation of ROS and high-energy phosphate production/degradation. We discuss the contribution of various mitochondrial cation channels to ionic imbalances which seem to be a major cause of reperfusion injury. The different roles of the H+, Ca2+ and the various K+ channel transporters are considered, particularly the K+(ATP) (ATP-dependent K+) channels. A possible role for the mitochondrial permeability transition pore in ischaemic damage is assessed. Finally, we summarize the metabolic and pharmacological interventions that have been used to alleviate the effects of ischaemic injury, highlighting the value of these or related interventions in possible therapeutics.

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Mitochondrial functions in ischemic myocardium I. Proton electrochemical gradient, inner membrane permeability, calcium transport and oxidative phosphorylation in isolated mitochondria

Cited by 30 publications

References 26 publications

Ischemia, rather than reperfusion, inhibits respiration through cytochrome oxidase in the isolated, perfused rabbit heart: role of cardiolipin

Ischemia, rather than reperfusion, inhibits respiration through cytochrome oxidase in the isolated, perfused rabbit heart: role of cardiolipin

Targeting nucleotide-requiring enzymes: implications for diazoxide-induced cardioprotection

Biochemical dysfunction in heart mitochondria exposed to ischaemia and reperfusion

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