scholarly journals Doxorubicin-induced cardiac dysfunction is attenuated by ciclosporin treatment in mice through improvements in mitochondrial bioenergetics

2011 ◽  
Vol 121 (9) ◽  
pp. 405-413 ◽  
Author(s):  
Xavier Marechal ◽  
David Montaigne ◽  
Camille Marciniak ◽  
Philippe Marchetti ◽  
Sidi Mohamed Hassoun ◽  
...  
Keyword(s):  
Body Weight ◽  
Membrane Potential ◽  
Mitochondrial Permeability Transition ◽  
Heart Function ◽  
Permeability Transition ◽  
Mitochondrial Fusion ◽  
Mitochondrial Fragmentation ◽  
Mitochondrial Permeability ◽  
Chronic Models

We tested whether inhibition of mitochondrial membrane potential dissipation by CsA (ciclosporin A) would prevent doxorubicin-induced myocardial and mitochondrial dysfunction. Acute and subchronic models of doxorubicin exposition were performed in mice with either a single intraperitoneal bolus (10 mg/kg of body weight, intraperitoneal) or one injection of 4 mg·kg−1 of body weight·week−1 during 5 weeks. Follow-up was at 1.5 weeks and 16 weeks in acute and subchronic models respectively. Mice received either CsA (1 mg/kg of body weight, intraperitoneal on alternate days) or saline until follow-up. Heart function was evaluated by echocardiography. Mitochondrial measurements included oxygen consumption, membrane potential and externally added calcium-induced mitochondrial permeability transition. Mitochondrial mass was evaluated by transmission electronic microscopy and mtDNA (mitochondrial DNA) content. Mitochondrial dynamics were detected as the expression of GTPases involved in mitochondrial fusion and fission. In both the acute and chronic models, doxorubicin decreased left ventricular fractional shortening and survival. Heart function and survival were improved by CsA, but not by tacrolimus (FK506), a ciclosporin derivative with no inhibitory effect on the mitochondrial transition pore. In the acute model, doxorubicin exposure was associated with increased mtDNA content, mitochondrial fragmentation and changes in mitochondrial fusion- and fission-related transcripts [increases in Mfn2 (mitofusin 2), Opa1 (optic atrophy 1 homologue) and Fis1 (fission 1 homologue), and no changes in Drp1 (dynamin 1-like)]. CsA did not alter mitochondrial biogenesis, but prevented mitochondrial fragmentation and partially restored the mitochondrial energy-producing capacity. These findings suggest that in vivo CsA treatment may limit MPTP (mitochondrial permeability transition pore) opening, mitochondrial potential loss and contractile depression in acute and chronic models of cardiac toxicity induced by doxorubicin.

The mitochondrial permeability transition: its molecular mechanism and role in reperfusion injury

1999 ◽  
Vol 66 ◽  
pp. 181-203 ◽  
Author(s):  
Andrew P. Halestrap
Keyword(s):  
Oxidative Stress ◽  
Cyclosporin A ◽  
Reperfusion Injury ◽  
Molecular Mechanism ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Apoptotic Cell ◽  
Heart Function ◽  
Permeability Transition ◽  
Mitochondrial Permeability

The mitochondrial permeability transition (mPT) involves the opening of a non-specific pore in the inner membrane of mitochondria, converting them from organelles whose production of ATP sustains the cell, to instruments of death. Here, I first summarize the evidence in favour of our model for the molecular mechanism of the mPT. It is proposed that the adenine nucleotide translocase (ANT) is converted into a non-specific pore through a calcium-mediated conformational change. This requires the binding of a unique cyclophilin (cyclophilin-D, CyP-D) to the ANT, except when matrix [Ca2+] is very high. Binding of CyP-D is increased in response to oxidative stress and some thiol reagents which sensitize the mPT to [Ca2+]. Matrix adenine nucleotides decrease the sensitivity of the mPT to [Ca2+] by binding to the ANT. This is antagonized by carboxyatractyloside (an inhibitor of the ANT) and by modification of specific thiol groups on the ANT by oxidative stress or thiol reagents; such treatments thus enhance the mPT. In contrast, decreasing intracellular pH below 7.0 greatly desensitizes the mPT to [Ca2+]. Conditions which sensitize the mPT towards [Ca2+] are found in hearts reperfused after a period of ischaemia, a process that may irreversibly damage the heart (reperfusion injury). We have demonstrated directly that mPT pores open during reperfusion (but not ischaemia) using a technique that involves entrapment of [3H]deoxyglucose in mitochondria that have undergone the mPT. The mPT may subsequently reverse in hearts that recover from ischaemia/reperfusion, the extent of resealing correlating with recovery of heart function. A variety of agents that antagonize the mPT protect the heart from reperfusion injury, including cyclosporin A, pyruvate and propofol. Mitochondria that undergo the mPT and then reseal may cause cytochrome c release and thus initiate apoptosis in cells subjected to stresses less severe than those causing necrosis. An example is the apoptotic cell death in the hippocampus that occurs several days after insulin-induced hypoglycaemia, and can be prevented by prior treatment with cyclosporin A.

Two mechanisms by which ATP depletion potentiates induction of the mitochondrial permeability transition

1997 ◽  
Vol 273 (2) ◽  
pp. C479-C488 ◽  
Author(s):  
G. Simbula ◽  
P. A. Glascott ◽  
S. Akita ◽  
J. B. Hoek ◽  
J. L. Farber
Keyword(s):  
Cell Death ◽  
Membrane Potential ◽  
Liver Cell ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Atp Depletion ◽  
Mitochondrial Permeability ◽  
A 23187 ◽  
Liver Cell Death

The present and a previous study [J. W. Snyder, J. G. Pastorino, A. M. Attie, and J. L. Farber, Am. J. Physiol. 264 (Cell Physiol. 33): C709-C714, 1993] define two mechanisms whereby ATP depletion promotes liver cell death. ATP depletion and cell death are linked by the mitochondrial permeability transition (MPT). Mitochondrial deenergization promotes the MPT, and ATP maintains a membrane potential by reversal of ATP synthase. With an increased influx of Ca2+ induced by the ionophore A-23187, oligomycin depleted the cells of ATP without loss of the mitochondrial membrane potential and further elevated the intracellular Ca2+ concentration. Cyclosporin A (CyA) prevented the accompanying cell killing. Fructose also preserved the viability of the cells. With the increased cytosolic Ca2+ imposed by A-23187, viability is maintained by ATP-dependent processes. Upon depletion of ATP, Ca2+ homeostasis cannot be maintained, and the MPT is induced. Rotenone also depleted the cells of ATP, and A-23187 accelerated the loss of the mitochondrial membrane potential occurring with rotenone alone. CyA and fructose prevented the cell killing with rotenone and A-23187. Oligomycin did not prevent this action of fructose. We conclude that ATP is needed to maintain Ca2+ homeostasis to prevent the MPT and the resultant liver cell death. ATP is also needed to maintain mitochondrial energization when electron transport is inhibited.

scholarly journals Antimicrobial peptide CGA-N12 decreases the Candida tropicalis mitochondrial membrane potential via mitochondrial permeability transition pore

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Ruifang Li ◽  
Jiarui Zhao ◽  
Liang Huang ◽  
Yanjie Yi ◽  
Aihua Li ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Candida Tropicalis ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Mptp Opening

Abstract Amino acid sequence from 65th to 76th residue of the N-terminus of Chromogranin A (CGA-N12) is an antimicrobial peptide (AMP). Our previous studies showed that CGA-N12 reduces Candida tropicalis mitochondrial membrane potential. Here, we explored the mechanism that CGA-N12 collapsed the mitochondrial membrane potential by investigations of its action on the mitochondrial permeability transition pore (mPTP) complex of C. tropicalis. The results showed that CGA-N12 induced cytochrome c (Cyt c) leakage, mitochondria swelling and led to polyethylene glycol (PEG) of molecular weight 1000 Da penetrate mitochondria. mPTP opening inhibitors bongkrekic acid (BA) could contract the mitochondrial swelling induced by CGA-N12, but cyclosporin A (CsA) could not. Therefore, we speculated that CGA-N12 could induce C. tropicolis mPTP opening by preventing the matrix-facing (m) conformation of adenine nucleotide transporter (ANT), thereby increasing the permeability of the mitochondrial membrane and resulted in the mitochondrial potential dissipation.

Abstract 3563: Postconditioning Inhibits Mitochondrial Permeability Transition Pore Opening Independently of any Modification of the Oxidative Phosphorylation and of the Inner Membrane Potential at Reperfusion

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Mélanie Paillard ◽  
Ludovic Gomez ◽  
Lionel Augeul ◽  
Joseph Loufouat ◽  
Michel Ovize
Keyword(s):  
Membrane Potential ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Area At Risk ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Myocardial Area

Mitochondrial permeability transition pore (mPTP) inhibition plays a crucial role in postconditioning (PostC). We sought to determine whether oxidative phosphorylation and mitochondrial membrane potential (ΔΨ m ), which both modulate mPTP opening, are involved in the inhibition of mPTP opening in the postconditioned heart. Anesthetized rabbits underwent 30 minutes of ischemia followed by 10 minutes of reperfusion. At the onset of reperfusion, they received either no intervention (Control, C), 4 cycles of 1 min ischemia followed by 1 min reperfusion (PostC), or an IV injection of 5mg/kg of the powerful inhibitor of mPTP opening, i.e. cyclosporine A (CsA). Sham rabbits underwent no ischemic insult throughout the 40 minute experiment. At the end of the 10 minute reperfusion period, the myocardial area at risk was excised, and mitochondria were isolated by differential centrifugations. Calcium retention capacity, an index of mPTP inhibition (CRC: nmol Ca 2+ /mg prot) and ΔΨ m (at state 4: % of FCCP-evoked maximum) were assessed by spectrofluorimetry in isolated subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria. Oxidative phosphorylation (at states 3 and 4: nmol O 2 /min/mg) was assessed using a Clark-type electrode (RCR: state 3 / state 4). As expected, PostC and CsA treatments improved CRC when compared to the C group. Control, PostC and CsA mitochondria exhibited a comparable significant dissipation of ΔΨ m , together with a comparable significant decrease of RCR in both SSM and IFM. In all three groups, this latter effect was related to a concomitant significant decrease in state 3 and to an increase in state 4 respiration. These data suggest that during the early minutes of reperfusion, postconditioning inhibits mPTP opening, independent of any specific modification of the oxidative phosphorylation or of ΔΨ m . Summarized data:

Regulation of the mitochondrial permeability transition by matrix Ca2+ and voltage during anoxia/reoxygenation

2001 ◽  
Vol 280 (3) ◽  
pp. C517-C526 ◽  
Author(s):  
Paavo Korge ◽  
Henry M. Honda ◽  
James N. Weiss
Keyword(s):  
Membrane Potential ◽  
Electron Transport ◽  
Cyclosporin A ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Matrix Volume ◽  
Reoxygenation Injury ◽  
Load Size

We studied the interplay between matrix Ca2+ concentration ([Ca2+]) and mitochondrial membrane potential (Δψ) in regulation of the mitochondrial permeability transition (MPT) during anoxia and reoxygenation. Without Ca2+loading, anoxia caused near-synchronous Δψ dissipation, mitochondrial Ca2+ efflux, and matrix volume shrinkage when a critically low Po 2 was reached, which was rapidly reversible upon reoxygenation. These changes were related to electron transport inhibition, not MPT. Cyclosporin A-sensitive MPT did occur when extramitochondrial [Ca2+] was increased to promote significant Ca2+ uptake during anoxia, depending on the Ca2+ load size and ability to maintain Δψ. However, when [Ca2+] was increased after complete Δψ dissipation, MPT did not occur until reoxygenation, at which time reactivation of electron transport led to partial Δψ regeneration. In the setting of elevated extramitochondrial Ca2+, this enhanced matrix Ca2+ uptake while promoting MPT because of less than full recovery of Δψ. The interplay between Δψ and matrix [Ca2+] in accelerating or inhibiting MPT during anoxia/reoxygenation has implications for preventing reoxygenation injury associated with MPT.

scholarly journals The Myxoma Poxvirus Protein, M11L, Prevents Apoptosis by Direct Interaction with the Mitochondrial Permeability Transition Pore

2002 ◽  
Vol 196 (9) ◽  
pp. 1127-1140 ◽  
Author(s):  
Helen Everett ◽  
Michele Barry ◽  
Xuejun Sun ◽  
Siow Fong Lee ◽  
Christine Frantz ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Potential Loss ◽  
Mitochondrial Membrane Potential Loss

M11L, an antiapoptotic protein essential for the virulence of the myxoma poxvirus, is targeted to mitochondria and prevents the loss of mitochondrial membrane potential that accompanies cell death. In this study we show, using a cross-linking approach, that M11L physically associates with the mitochondrial peripheral benzodiazepine receptor (PBR) component of the permeability transition (PT) pore. Close association of M11L and the PBR is also indicated by fluorescence resonance energy transfer (FRET) analysis. Stable expression of M11L prevents the release of mitochondrial cytochrome c induced by staurosporine or protoporphyrin IX (PPIX), a ligand of the PBR. Transiently expressed M11L also prevents mitochondrial membrane potential loss induced by PPIX, or induced by staurosporine in combination with PK11195, another ligand of the PBR. Myxoma virus infection and the associated expression of early proteins, including M11L, protects cells from staurosporine- and Fas-mediated mitochondrial membrane potential loss and this effect is augmented by the presence of PBR. We conclude that M11L regulates the mitochondrial permeability transition pore complex, most likely by direct modulation of the PBR.

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