Adenine nucleotide transport during cardiac ischemia

LaNoue, K. F.; Watts, John A.; Koch, Cornelia

doi:10.1152/ajpheart.1981.241.5.h663

Cited by 27 publications

(11 citation statements)

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“…Accordingly, PC-induced ROS production has been ascribed to an incomplete blockade of the respiratory chain [38]. In the present study the decrease in ANT activity induced by PC is presumably due to its conversion into palmitoyl-CoA rather than a direct effect, as LCAC does not inhibit ANT on submitochondrial particles [5,39,40]. In addition, free fatty acids have been proposed to uncouple mitochondria via the ANT either through an allosterical stimulation of H + transfer or through the translocation of fatty acid under their anionic form.…”

Section: Discussionmentioning

confidence: 44%

Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase

Roussel

Thireau

Brenner

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Long chain fatty acids bind to carnitine and form long chain acyl carnitine (LCAC), to enter into the mitochondria. They are oxidized in the mitochondrial matrix. LCAC accumulates rapidly under metabolic disorders, such as acute cardiac ischemia, chronic heart failure or diabetic cardiomyopathy. LCAC accumulation is associated with severe cardiac arrhythmia including ventricular tachycardia or fibrillation. We thus hypothesized that palmitoyl-carnitine (PC), alters mitochondrial function leading to Ca(2+) dependent-arrhythmia. In isolated cardiac mitochondria from C57Bl/6 mice, application of 10μM PC decreased adenine nucleotide translocase (ANT) activity without affecting mitochondrial permeability transition pore (mPTP) opening. Mitochondrial reactive oxygen species (ROS) production, measured with MitoSOX Red dye in isolated ventricular cardiomyocytes, increased significantly under PC application. Inhibition of ANT by bongkrekic acid (20 μM) prevented PC-induced mitochondrial ROS production. In addition, PC increased type 2 ryanodine receptor (RyR2) oxidation, S-nitrosylation and dissociation of FKBP12.6 from RyR2, and therefore increased sarcoplasmic reticulum (SR) Ca(2+) leak. ANT inhibition or anti-oxidant strategy (N-acetylcysteine) prevented SR Ca(2+) leak, FKBP12.6 depletion and RyR2 oxidation/S-nitrosylation induced by PC. Finally, both bongkrekic acid and NAC significantly reduced spontaneous Ca(2+) wave occurrences under PC. Altogether, these results suggest that an elevation of PC disturbs ANT activity and alters Ca(2+) handling in a ROS-dependent pathway, demonstrating a new pathway whereby altered FA metabolism may contribute to the development of ventricular arrhythmia in pathophysiological conditions.

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Section: Discussionmentioning

confidence: 44%

Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase

Roussel

Thireau

Brenner

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Interestingly, it has been suggested that mitochondrial ATP/ ADP transport is inhibited during ischemia. 20,33 Our data indicate that overexpression of Bcl-2 does not block adenine nucleotide transport into mitochondria under normal aerobic conditions; however, on addition of an uncoupler, mitochondria from Bcl-2 hearts exhibit a reduced rate of ATP hydrolysis, consistent with reduced entry of ATP into the mitochondria. Bcl-2 insertion into the mitochondrial membrane is enhanced by decreased pH, 5 which occurs during ischemia.…”

Section: Imahashi Et Almentioning

confidence: 68%

Transgenic Expression of Bcl-2 Modulates Energy Metabolism, Prevents Cytosolic Acidification During Ischemia, and Reduces Ischemia/Reperfusion Injury

Imahashi

Schneider

Steenbergen

et al. 2004

Circulation Research

179

147

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Abstract-The antiapoptotic protein Bcl-2 is targeted to the mitochondria, but it is uncertain whether Bcl-2 affects only myocyte survival after ischemia, or whether it also affects metabolic functions of mitochondria during ischemia. Hearts from mice overexpressing human Bcl-2 and from their wild-type littermates (WT) were subjected to 24 minutes of global ischemia followed by reperfusion. During ischemia, the decrease in pH i and the initial rate of decline in ATP were significantly reduced in Bcl-2 hearts compared with WT hearts (PϽ0.05). The reduced acidification during ischemia was dependent on the activity of mitochondrial F 1 F 0 -ATPase. In the presence of oligomycin (Oligo), an F 1 F 0 -ATPase inhibitor, the decrease in pH i was attenuated in WT hearts, but in Bcl-2 hearts, Oligo had no additional effect on pH i during ischemia. Likewise, addition of Oligo to WT hearts slowed the rate of decline in ATP during ischemia to a level similar to that observed in Bcl-2 hearts, but addition of Oligo had no significant effect on the rate of decline in ATP in Bcl-2 hearts during ischemia. These data are consistent with Bcl-2-mediated inhibition of consumption of glycolytic ATP. Furthermore, mitochondria from Bcl-2 hearts have a reduced rate of consumption of ATP on uncoupler addition. This could be accomplished by limiting ATP entry into the mitochondria through the voltage-dependent anion channel, and/or the adenine nucleotide transporter, or by direct inhibition of the F 1 F 0 -ATPase. Immunoprecipitation showed greater interaction between Bcl-2 and voltage-dependent anion channel during ischemia. These data indicate that Bcl-2 modulation of metabolism contributes to cardioprotection.

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“…For it has been shown that ACoA may rise without influence on ANT activity in living cells, probably due to adsorption to cytosolic binding proteins (2,3). Another argument has been recently proposed by La Noue et al (21). They tried to show that the loss of ANT activity, observed in mitochondria from ischemic tissue, is more likely caused by changes of adenine nueleotide distribution than by accumulated ACoA.…”

Section: General Aspectsmentioning

confidence: 98%

Acyl-carnitine effects on isolated cardiac mitochondria and erythrocytes

et al. 1984

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The effects of various long-chain acyl-carnitines (AC) on mitochondrial functions and red cell membrane stability were studied. Lower concentrations slightly stimulate respiration-dependent functions such as phosphorylation rate and Ca++ uptake velocity, whereas higher concentrations inhibit these functions with concomitant depression of the ATP/O ratio. The order of effectiveness among the AC is very similar for different mitochondrial functions. The differences among AC in their actions on red cell stability in hypotonic media and their differences in influence on mitochondrial functions exhibit less resemblance. The relative order of erythrolytic concentrations of AC follows the order of their critical micellar concentrations. Model calculations indicate that the concentrations of AC found in ischemic hearts are below those which exhibit inhibitory effects in vitro. Ultrastructural changes in mitochondria incubated with AC are different from those found in ischemic tissue. From this, it seems questionable whether the elevated AC levels in ischemic hearts are indeed as important for the development of membrane damage as is often supposed.

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Adenine nucleotide transport during cardiac ischemia

Cited by 27 publications

References 0 publications

Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase

Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase

Transgenic Expression of Bcl-2 Modulates Energy Metabolism, Prevents Cytosolic Acidification During Ischemia, and Reduces Ischemia/Reperfusion Injury

Acyl-carnitine effects on isolated cardiac mitochondria and erythrocytes

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