The Interaction of Q Analogs, Particularly Hydroxydecyl Benzoquinone (Idebenone), with the Respiratory Complexes of Heart Mitochondria

Esposti, Mauro Degli; Ngo, Anna; Ghelli, Anna; Benelli, Bruna; Carelli, Valerio; McLennan, Holly; Linnane, Anthony W.

doi:10.1006/abbi.1996.0267

Cited by 98 publications

(88 citation statements)

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“…Enzyme and Other Assays-The activities of mitochondrial redox enzymes were determined as described in previous studies (19,28). Mitochondrial membrane potential (⌬ m ) was monitored in living cells with 100 nM tetramethylrhodamine ethyl ester (29) under the same conditions as those used for NAD(P)H autofluorescence.…”

Section: Methodsmentioning

confidence: 99%

Bcl-2 and Mitochondrial Oxygen Radicals

Esposti

Hatzinisiriou

McLennan

et al. 1999

Journal of Biological Chemistry

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162

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Investigations into the capacity of the Bcl-2 protein to prevent apoptosis have targeted mitochondria as key sites of the preventative action accorded by Bcl-2 to cells. Using novel approaches with fluorescence probes and autofluorescence detection of endogenous NAD(P)H, we have examined the effects of expressing Bcl-2 in the Bcl-2 negative Burkitt's lymphoma cell line Daudi. We evaluated for the first time the effect of Bcl-2 expression on the intracellular distribution and production of hydrogen peroxide, under basal conditions and after treatment with apoptosis inducing agents, ceramide analogs and tumor necrosis factor (TNF)-␣. Increased availability of mitochondrial NAD(P)H was detected in Bcl-2-expressing cells and was correlated with an increased constitutive mitochondrial production of hydrogen peroxide. Although production of hydrogen peroxide was increased by either C 6 -ceramide or TNF-␣ in Bcl-2 negative Daudi cells commensurate with the early phases of apoptosis, this increase did not occur in Bcl-2-expressing cells. Thus, Bcl-2 appears to allow cells to adapt to an increased state of oxidative stress, fortifying the cellular anti-oxidant defenses and counteracting the radical overproduction imposed by different cell death stimuli. Furthermore, we report altered cytological features of mitochondria during the early phases of apoptosis induced by C 6 -ceramide and TNF-␣. In particular, mitochondria changed in appearance, clustering in the perinuclear region and Bcl-2 expression prevented these changes from occurring.

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Section: Methodsmentioning

confidence: 99%

Bcl-2 and Mitochondrial Oxygen Radicals

Esposti

Hatzinisiriou

McLennan

et al. 1999

Journal of Biological Chemistry

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162

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“…The one-electron donor to oxygen in Complex I is a nonphysiological hydrophilic site (11) that reduces several quinones to the corresponding semiquinone forms, which are unstable and reduce oxygen to superoxide. This mechanism is shared by several quinones, including anthracyclines (18) and the CoQ analog, idebenone (19). The hydrophilic, rotenone-insensitive, site can apparently reduce oxygen to superoxide in absence of intermediate acceptors (16).…”

Section: Complex Imentioning

confidence: 99%

“…Among the quinones tested, idebenone was particularly effective in inducing a dramatic increase of superoxide production. Because idebenone is clinically used in mitochondrial cytopathies and neurodegenerative diseases (19), its strong pro-oxidant effect raises doubts on its safety as a drug. On the other hand, p-hydroxy-mercuribenzoate, which inhibits Complex I at the level of iron-sulfur clusters, inhibited superoxide production.…”

Section: Complex Imentioning

confidence: 99%

The Mitochondrial Production of Reactive Oxygen Species: Mechanisms and Implications in Human Pathology

2001

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SummaryMitochondria are major sources of reactive oxygen species (ROS); the main sites of superoxide radical production in the respiratory chain are Complexes III and I; however, other mitochondrial enzymes, such as Complex II, glycerol-1-phosphate dehydrogenase, and dihydroorotate dehydrogenase, are also involved in production of ROS. ROS appear to be released both in the matrix and in the intermembrane space; however, their appearance outside the mitochondria may not be physiologically relevant. ROS production is increased in State 4 and in all conditions when the respiratory components are substantially in the reduced form. Accordingly, defects inducing decrease of electron transfer in the respiratory chain, as in many pathological conditions, are bound to enhance ROS production.

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“…The first pathway goes from NADH to the physiological hydrophobic ubiquinone-binding site, and couples electron flux to proton extrusion in a rotenone-sensitive manner. The second pathway goes from NADH to a hydrophilic binding site (28), is rotenone-insensitive, and is not coupled to proton translocation (26 -28). Thus, Ub 0 may be able to oxidize NADH through the rotenone-insensitive site without increasing electron flux through the rotenone-sensitive pathway, consistent with the results of Fig.…”

Section: Mechanism Of Ptp Modulation By Electron Flux At Complex I-mentioning

confidence: 99%

Regulation of the Permeability Transition Pore in Skeletal Muscle Mitochondria

Fontaine¹,

Eriksson²,

Ichas

et al. 1998

Journal of Biological Chemistry

291

104

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We have investigated the regulation of the permeability transition pore (PTP), a cyclosporin A-sensitive channel, in rat skeletal muscle mitochondria. As is the case with mitochondria isolated from a variety of sources, skeletal muscle mitochondria can undergo a permeability transition following Ca 2؉ uptake in the presence of P i . We find that the PTP opening is dramatically affected by the substrates used for energization, in that much lower Ca 2؉ loads are required when electrons are provided to complex I rather than to complex II or IV. This increased sensitivity of PTP opening does not depend on differences in membrane potential, matrix pH, Ca 2؉ uptake, oxidation-reduction status of pyridine nucleotides, or production of H 2 O 2 , but is directly related to the rate of electron flow through complex I. Indeed, and with complex I substrates only, pore opening can be observed when depolarization is induced with uncoupler (increased electron flow) but not with cyanide (decreased electron flow). Consistent with pore regulation by electron flow, we find that PTP opening is inhibited by ubiquinone 0 at concentrations that partially inhibit respiration and do not depolarize the inner membrane. These data allow identification of a novel site of regulation of the PTP, suggest that complex I may be part of the pore complex, and open new perspectives for its pharmacological modulation in living cells.The permeability transition is an in vitro increase of the inner mitochondrial membrane permeability to solutes, which is favored by Ca 2ϩ uptake. This phenomenon is now interpreted as due to the opening of a proteinaceous but yet unidentified large conductance channel, the PTP.1 The PTP openclosed transitions are modulated by the transmembrane electrical potential, by matrix pH, by redox potential, by adenine nucleotides, and by Me 2ϩ . Finally, the permeability transition can be induced or inhibited by a variety of drugs (1-4). It has been proposed that the PTP may provide mitochondria with a fast Ca 2ϩ release channel (4), and recent evidence indeed indicates that transient PTP opening in a low conductance mode (i.e. a state permeable to ions but not to larger molecules such as sucrose) may contribute to physiological Ca 2ϩ signaling through amplification of inositol 1,4,5-trisphosphate-dependent Ca 2ϩ release (5). PTP opening in vitro leads to collapse of the proton-motive force, disruption of ionic homeostasis, mitochondrial swelling, and massive ATP hydrolysis by the F 0 F 1 ATPase. This sequence of events has drawn considerable attention to the permeability transition as a potential player in the cellular pathways to cell death through at least four mechanisms, i.e. decreased levels of cellular ATP (6, 7), increase of cytosolic Ca 2ϩ (6,8,9), release of apoptosis-inducing factor, a mitochondrial caspase (10), and release of cytochrome c (11,12).With the long term goal of defining the role of mitochondria in the pathways to muscle cell death, we carried out a characterization of PTP regulation in isolated skeletal ...

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The Interaction of Q Analogs, Particularly Hydroxydecyl Benzoquinone (Idebenone), with the Respiratory Complexes of Heart Mitochondria

Cited by 98 publications

References 0 publications

Bcl-2 and Mitochondrial Oxygen Radicals

Bcl-2 and Mitochondrial Oxygen Radicals

The Mitochondrial Production of Reactive Oxygen Species: Mechanisms and Implications in Human Pathology

Regulation of the Permeability Transition Pore in Skeletal Muscle Mitochondria

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