The significance and mechanism of mitochondrial proton conductance

Brindle, KM; Buckingham, JA; Harper, James M.; Rolfe, David F. S.; Stuart, JA

doi:10.1038/sj.ijo.0800936

Cited by 139 publications

(134 citation statements)

References 29 publications

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“…UCP3 is a UCP1 homologue that is highly skeletal-muscle-specific [29,30]. Its uncoupling activity is a matter of debate [4][5][6]10,12]. We first postulated that the increase in respiration rate was due to an activation of a UCP3 uncoupling activity.…”

Section: Effects Of Nucleotides On the Proton Conductance Of Mitochonmentioning

confidence: 99%

“…The resulting electrochemical proton gradient performs useful work when protons re-enter the matrix through the F o F " -ATPase (causing synthesis of ATP from ADP and P i [1]) or through other proteins to drive ion and substrate transport. However, the electrochemical proton gradient can also be dissipated by leak reactions catalysed by endogenous mitochondrial proton-conductance pathways [2][3][4][5]. In the absence of oxidative phosphorylation, all the protons pumped by the respiratory chain out of the mitochondria return by this proton leak, and there is oxygen consumption without coupled ATP synthesis.…”

Section: Introductionmentioning

confidence: 99%

“…There are two types of proton conductance : basal and inducible [4,5]. Both can be assayed reliably by measuring their kinetics [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…Basal proton conductance is found in all mitochondria. Its mechanism and regulation are unclear, but the evidence that it is catalysed by specific uncoupling proteins is weak [4][5][6]. It is responsible for 50 % of the respiration of resting perfused rat skeletal muscle [7], and for 35 % of the respiration of a maximally stimulated hindlimb muscle model [8].…”

Section: Introductionmentioning

confidence: 99%

“…The existence and mechanisms of inducible proton leak in other tissues are not yet established, but it is widely hypothesized that UCP3 in skeletal muscle, and UCP2 in a range of tissues, may catalyse proton leak and may be regulated by fatty acids and nucleotides (see [4,5,[10][11][12]). …”

Section: Introductionmentioning

confidence: 99%

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Effects of magnesium and nucleotides on the proton conductance of rat skeletal-muscle mitochondria

Cadenas

Brand

2000

Biochemical Journal

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During oxidative phosphorylation most of the protons pumped out to the cytosol across the mitochondrial inner membrane return to the matrix through the ATP synthase, driving ATP synthesis. However, some of them leak back to the matrix through a proton-conductance pathway in the membrane. When the ATP synthase is inhibited with oligomycin and ATP is not being synthesized, all of the respiration is used to drive the proton leak. We report here that Mg# + inhibits the proton conductance in rat skeletal-muscle mitochondria. Addition of Mg# + inhibited both oligomycin-inhibited respiration and the proton conductance, while removal of Mg# + using EDTA activated these processes. The proton conductance was inhibited by more than 80 % as free Mg# + was raised from 25 nM to 220 µM. Half-maximal inhibition occurred at about 1 µM free Mg# + ,

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Section: Effects Of Nucleotides On the Proton Conductance Of Mitochonmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…There are two types of proton conductance : basal and inducible [4,5]. Both can be assayed reliably by measuring their kinetics [2,3].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Effects of magnesium and nucleotides on the proton conductance of rat skeletal-muscle mitochondria

Cadenas

Brand

2000

Biochemical Journal

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Uncoupling protein‐2 induction in rat hepatocytes after acute carbon tetrachloride liver injury

Demori

Burlando

Gerdoni

et al. 2008

Journal Cellular Physiology

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This study is focused on the role of UCP-2 in hepatic oxidative metabolism following acute CCl(4) administration to rats. UCP-2 mRNA, almost undetectable in the liver of controls, was significantly increased 24 h after CCl(4) administration, peaked at 72 h and then tended to disappear. UCP-2 protein, undetectable in controls, increased 48-72 h after CCl(4) treatment. Experiments with isolated liver cells indicated that in control rats UCP-2 was expressed in non-parenchymal cells and not in hepatocytes, whereas in CCl(4)-treated rats UCP-2 expression was induced in hepatocytes and was not affected in non-parenchymal cells. Addition of CCl(4) to the culture medium of hepatocytes from control rats failed to induce UCP-2 expression. Liver mitochondria from CCl(4)-treated rats showed an increase of H(2)O(2) release at 12-24 h, followed by a rise of TBARS. Vitamin E protected liver from CCl(4) injury and reduced the expression of UCP-2. Treatment with GdCl(3) prior to CCl(4), in order to inhibit Kupffer cells, reduced TBARS and UCP-2 mRNA increase in hepatic mitochondria. Our data indicate that CCl(4) induces the expression of UCP-2 in hepatocytes with a redox-dependent mechanism involving Kupffer cells. A role of UCP-2 in moderating CCl(4)-induced oxidative stress during tissue regeneration after injury is suggested.

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Mitochondrial dysfunction in a neural cell model of spinal muscular atrophy

Acsádi

Lee

et al. 2009

J of Neuroscience Research

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Mutations of the survival motor neuron (SMN) gene in spinal muscular atrophy (SMA) lead to anterior horn cell death. The cause is unknown, but motor neurons depend substantially on mitochondrial oxidative phosphorylation (OxPhos) for normal function. Therefore, mitochondrial parameters were analyzed in an SMA cell culture model using small interfering RNA (siRNA) transfection that decreased Smn expression in NSC-34 cells to disease levels. Smn siRNA knock-down resulted in 35% and 66% reduced Smn protein levels 48 and 72 hr posttransfection, respectively. ATP levels were reduced by 14% and 26% at 48 and 72 hr posttransfection, respectively, suggesting decreased ATP production or increased energy demand in neural cells. Smn knock-down resulted in increased mitochondrial membrane potential and increased free radical production. Changes in activity of cytochrome c oxidase (CcO), a key OxPhos component, were observed at 72 hr with a 26% increase in oxygen consumption. This suggests a compensatory activation of the aerobic pathway, resulting in increased mitochondrial membrane potentials, a condition known to lead to the observed increase in free radical production. Further testing suggested that changes in ATP at 24 hr precede observable indices of cell injury at 48 hr. We propose that energy paucity and increased mitochondrial free radical production lead to accumulated cell damage and eventual cell death in Smn-depleted neural cells. Mitochondrial dysfunction may therefore be important in SMA pathology and may represent a new therapeutic target.

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The significance and mechanism of mitochondrial proton conductance

Cited by 139 publications

References 29 publications

Effects of magnesium and nucleotides on the proton conductance of rat skeletal-muscle mitochondria

Effects of magnesium and nucleotides on the proton conductance of rat skeletal-muscle mitochondria

Uncoupling protein‐2 induction in rat hepatocytes after acute carbon tetrachloride liver injury

Mitochondrial dysfunction in a neural cell model of spinal muscular atrophy

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