Chaotropic Agents and Increased Matrix Volume Enhance Binding of Mitochondrial Cyclophilin to the Inner Mitochondrial Membrane and Sensitize the Mitochondrial Permeability Transition to [Ca2+] †

Biochemistry ◽  
1996 ◽  
Vol 35 (25) ◽  
pp. 8172-8180 ◽  
Author(s):  
Cathal P. Connern ◽  
Andrew P. Halestrap
Keyword(s):  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Permeability ◽  
Matrix Volume ◽  
Chaotropic Agents

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 Role of Adenine Nucleotide Translocase in the Mitochondrial Permeability Transition

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2686
Author(s):  
Nickolay Brustovetsky
Keyword(s):  
Atp Synthase ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition ◽  
Adenine Nucleotide Translocase ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Permeability ◽  
F0f1 Atp Synthase

The mitochondrial permeability transition, a Ca2+-induced significant increase in permeability of the inner mitochondrial membrane, plays an important role in various pathologies. The mitochondrial permeability transition is caused by induction of the permeability transition pore (PTP). Despite significant effort, the molecular composition of the PTP is not completely clear and remains an area of hot debate. The Ca2+-modified adenine nucleotide translocase (ANT) and F0F1 ATP synthase are the major contenders for the role of pore in the PTP. This paper briefly overviews experimental results focusing on the role of ANT in the mitochondrial permeability transition and proposes that multiple molecular entities might be responsible for the conductance pathway of the PTP. Consequently, the term PTP cannot be applied to a single specific protein such as ANT or a protein complex such as F0F1 ATP synthase, but rather should comprise a variety of potential contributors to increased permeability of the inner mitochondrial membrane.

scholarly journals The Mitochondrial Permeability Transition in Mitochondrial Disorders

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Justina Šileikytė ◽  
Michael Forte
Keyword(s):  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Physiological Role ◽  
Mitochondrial Diseases ◽  
Atp Synthesis ◽  
Permeability Transition ◽  
Mitochondrial Disorders ◽  
Molecular Entity ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Permeability

Mitochondrial permeability transition pore (PTP), a (patho)physiological phenomenon discovered over 40 years ago, is still not completely understood. PTP activation results in a formation of a nonspecific channel within the inner mitochondrial membrane with an exclusion size of 1.5 kDa. PTP openings can be transient and are thought to serve a physiological role to allow quick Ca2+ release and/or metabolite exchange between mitochondrial matrix and cytosol or long-lasting openings that are associated with pathological conditions. While matrix Ca2+ and oxidative stress are crucial in its activation, the consequence of prolonged PTP opening is dissipation of the inner mitochondrial membrane potential, cessation of ATP synthesis, bioenergetic crisis, and cell death—a primary characteristic of mitochondrial disorders. PTP involvement in mitochondrial and cellular demise in a variety of disease paradigms has been long appreciated, yet the exact molecular entity of the PTP and the development of potent and specific PTP inhibitors remain areas of active investigation. In this review, we will (i) summarize recent advances made in elucidating the molecular nature of the PTP focusing on evidence pointing to mitochondrial FoF1-ATP synthase, (ii) summarize studies aimed at discovering novel PTP inhibitors, and (iii) review data supporting compromised PTP activity in specific mitochondrial diseases.

scholarly journals Inorganic polyphosphate is a potent activator of the mitochondrial permeability transition pore in cardiac myocytes

2012 ◽  
Vol 139 (5) ◽  
pp. 321-331 ◽  
Author(s):  
Lea K. Seidlmayer ◽  
Maria R. Gomez-Garcia ◽  
Lothar A. Blatter ◽  
Evgeny Pavlov ◽  
Elena N. Dedkova
Keyword(s):  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Inner Mitochondrial Membrane ◽  
Inorganic Polyphosphate ◽  
Mitochondrial Permeability ◽  
Mptp Opening

Mitochondrial dysfunction caused by excessive Ca2+ accumulation is a major contributor to cardiac cell and tissue damage during myocardial infarction and ischemia–reperfusion injury (IRI). At the molecular level, mitochondrial dysfunction is induced by Ca2+-dependent opening of the mitochondrial permeability transition pore (mPTP) in the inner mitochondrial membrane, which leads to the dissipation of mitochondrial membrane potential (ΔΨm), disruption of adenosine triphosphate production, and ultimately cell death. Although the role of Ca2+ for induction of mPTP opening is established, the exact molecular mechanism of this process is not understood. The aim of the present study was to test the hypothesis that the adverse effect of mitochondrial Ca2+ accumulation is mediated by its interaction with inorganic polyphosphate (polyP), a polymer of orthophosphates linked by phosphoanhydride bonds. We found that cardiac mitochondria contained significant amounts (280 ± 60 pmol/mg of protein) of short-chain polyP with an average length of 25 orthophosphates. To test the role of polyP for mPTP activity, we investigated kinetics of Ca2+ uptake and release, ΔΨm and Ca2+-induced mPTP opening in polyP-depleted mitochondria. polyP depletion was achieved by mitochondria-targeted expression of a polyP-hydrolyzing enzyme. Depletion of polyP in mitochondria of rabbit ventricular myocytes led to significant inhibition of mPTP opening without affecting mitochondrial Ca2+ concentration by itself. This effect was observed when mitochondrial Ca2+ uptake was stimulated by increasing cytosolic [Ca2+] in permeabilized myocytes mimicking mitochondrial Ca2+ overload observed during IRI. Our findings suggest that inorganic polyP is a previously unrecognized major activator of mPTP. We propose that the adverse effect of polyphosphate might be caused by its ability to form stable complexes with Ca2+ and directly contribute to inner mitochondrial membrane permeabilization.

scholarly journals Quantification of active mitochondrial permeability transition pores using GNX-4975 inhibitor titrations provides insights into molecular identity

2016 ◽  
Vol 473 (9) ◽  
pp. 1129-1140 ◽  
Author(s):  
Andrew P. Richardson ◽  
Andrew P. Halestrap
Keyword(s):  
Cell Death ◽  
Membrane Proteins ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Molecular Identity ◽  
Permeability Transition Pores

The molecular identity of the mitochondrial permeability transition pore (MPTP), a key player in cell death, remains controversial. Here we use a novel MPTP inhibitor to demonstrate that formation of the pore involves native mitochondrial membrane proteins adopting novel conformations.

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