scholarly journals Hypoxia Increases Activity of the BK-Channel in the Inner Mitochondrial Membrane and Reduces Activity of the Permeability Transition Pore

2008 ◽  
Vol 22 (1-4) ◽  
pp. 127-136 ◽  
Author(s):  
Yu Cheng ◽  
Xiang Gu ◽  
Piotr Bednarczyk ◽  
Falk Wiedemann ◽  
Gabriel Haddad ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Bk Channel ◽  
Inner Mitochondrial Membrane

A role for mitochondrial aquaporins in cellular life-and-death decisions?

2006 ◽  
Vol 291 (2) ◽  
pp. C195-C202 ◽  
Author(s):  
Wing-Kee Lee ◽  
Frank Thévenod
Keyword(s):  
Cell Death ◽  
Mitochondrial Membrane ◽  
Water Movement ◽  
Apoptotic Cell ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Swelling ◽  
Inner Mitochondrial Membrane ◽  
Osmotic Swelling ◽  
Life And Death

Mitochondria dominate the process of life-and-death decisions of the cell. Continuous generation of ATP is essential for cell sustenance, but, on the other hand, mitochondria play a central role in the orchestra of events that lead to apoptotic cell death. Changes of mitochondrial volume contribute to the modulation of physiological mitochondrial function, and several ion permeability pathways located in the inner mitochondrial membrane have been implicated in the mediation of physiological swelling-contraction reactions, such as the K+ cycle. However, the channels and transporters involved in these processes have not yet been identified. Osmotic swelling is also one of the fundamental characteristics exhibited by mitochondria in pathological situations, which activates downstream cascades, culminating in apoptosis. The permeability transition pore has long been postulated to be the primary mediator for water movement in mitochondrial swelling during cell death, but its molecular identity remains obscure. Inevitably, accumulating evidence shows that mitochondrial swelling induced by apoptotic stimuli can also occur independently of permeability transition pore activation. Recently, a novel mechanism for osmotic swelling of mitochondria has been described. Aquaporin-8 and -9 channels have been identified in the inner mitochondrial membrane of various tissues, including the kidney, liver, and brain, where they may mediate water transport associated with physiological volume changes, contribute to the transport of metabolic substrates, and/or participate in osmotic swelling induced by apoptotic stimuli. Hence, the recent discovery that aquaporins are expressed in mitochondria opens up new areas of investigation in health and disease.

Cd2+-induced swelling-contraction dynamics in isolated kidney cortex mitochondria: role of Ca2+ uniporter, K+ cycling, and protonmotive force

2005 ◽  
Vol 289 (3) ◽  
pp. C656-C664 ◽  
Author(s):  
Wing-Kee Lee ◽  
Malte Spielmann ◽  
Ulrich Bork ◽  
Frank Thévenod
Keyword(s):  
Mitochondrial Membrane ◽  
Rat Kidney ◽  
Choline Chloride ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Kidney Cortex ◽  
Protonmotive Force ◽  
Inner Mitochondrial Membrane ◽  
Rat Kidney Cortex ◽  
The Matrix

The nephrotoxic metal Cd2+ causes mitochondrial damage and apoptosis of kidney proximal tubule cells. A K+ cycle involving a K+ uniporter and a K+/H+ exchanger in the inner mitochondrial membrane (IMM) is thought to contribute to the maintenance of the structural and functional integrity of mitochondria. In the present study, we have investigated the effect of Cd2+ on K+ cycling in rat kidney cortex mitochondria. Cd2+ (EC50 ∼19 μM) induced swelling of nonenergized mitochondria suspended in isotonic salt solutions according to the sequence KCl = NaCl > LiCl ≫ choline chloride. Cd2+-induced swelling of energized mitochondria had a similar EC50 value and showed the same cation dependence but was followed by a spontaneous contraction. Mitochondrial Ca2+ uniporter (MCU) blockers, but not permeability transition pore inhibitors, abolished swelling, suggesting the need for Cd2+ influx through the MCU for swelling to occur. Complete loss of mitochondrial membrane potential (ΔΨm) induced by K+ influx did not prevent contraction, but addition of the K+/H+ exchanger blocker, quinine (1 mM), or the electroneutral protonophore nigericin (0.4 μM), abolished contraction, suggesting the mitochondrial pH gradient (ΔpHm) driving contraction. Accordingly, a quinine-sensitive partial dissipation of ΔpHm was coincident with the swelling-contraction phase. The data indicate that Cd2+ enters the matrix through the MCU to activate a K+ cycle. Initial K+ load via a Cd2+-activated K+ uniporter in the IMM causes osmotic swelling and breakdown of ΔΨm and triggers quinine-sensitive K+/H+ exchange and contraction. Thus Cd2+-induced activation of a K+ cycle contributes to the dissipation of the mitochondrial protonmotive force.

scholarly journals Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 998 ◽  
Author(s):  
Massimo Bonora ◽  
Simone Patergnani ◽  
Daniela Ramaccini ◽  
Giampaolo Morciano ◽  
Gaia Pedriali ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Inner Mitochondrial Membrane ◽  
Human Pathology ◽  
Cell Death Mechanisms ◽  
Mitochondrial Membrane Permeabilization

Mitochondrial permeability transition (MPT) is the sudden loss in the permeability of the inner mitochondrial membrane (IMM) to low-molecular-weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate outer-mitochondrial-membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade and caspase-independent cell-death mechanisms. The induction of MPT is mostly dependent on mitochondrial reactive oxygen species (ROS) and Ca2+, but is also dependent on the metabolic stage of the affected cell and signaling events. Therefore, since its discovery in the late 1970s, the role of MPT in human pathology has been heavily investigated. Here, we summarize the most significant findings corroborating a role for MPT in the etiology of a spectrum of human diseases, including diseases characterized by acute or chronic loss of adult cells and those characterized by neoplastic initiation.

scholarly journals Coupled transmembrane mechanisms control MCU-mediated mitochondrial Ca2+uptake

2020 ◽  
Vol 117 (35) ◽  
pp. 21731-21739 ◽  
Author(s):  
Horia Vais ◽  
Riley Payne ◽  
Usha Paudel ◽  
Carmen Li ◽  
J. Kevin Foskett
Keyword(s):  
Mitochondrial Membrane ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Regulatory Mechanisms ◽  
Intermembrane Space ◽  
Channel Activity ◽  
Inner Mitochondrial Membrane ◽  
Energy Demands ◽  
Transport Chain ◽  
The Matrix

Ca2+uptake by mitochondria regulates bioenergetics, apoptosis, and Ca2+signaling. The primary pathway for mitochondrial Ca2+uptake is the mitochondrial calcium uniporter (MCU), a Ca2+-selective ion channel in the inner mitochondrial membrane. MCU-mediated Ca2+uptake is driven by the sizable inner-membrane potential generated by the electron-transport chain. Despite the large thermodynamic driving force, mitochondrial Ca2+uptake is tightly regulated to maintain low matrix [Ca2+] and prevent opening of the permeability transition pore and cell death, while meeting dynamic cellular energy demands. How this is accomplished is controversial. Here we define a regulatory mechanism of MCU-channel activity in which cytoplasmic Ca2+regulation of intermembrane space-localized MICU1/2 is controlled by Ca2+-regulatory mechanisms localized across the membrane in the mitochondrial matrix. Ca2+that permeates through the channel pore regulates Ca2+affinities of coupled inhibitory and activating sensors in the matrix. Ca2+binding to the inhibitory sensor within the MCU amino terminus closes the channel despite Ca2+binding to MICU1/2. Conversely, disruption of the interaction of MICU1/2 with the MCU complex disables matrix Ca2+regulation of channel activity. Our results demonstrate how Ca2+influx into mitochondria is tuned by coupled Ca2+-regulatory mechanisms on both sides of the inner mitochondrial membrane.

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.

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