scholarly journals Cellular calcification induced by inorganic polyphosphate involves ATP depletion and opening of the mitochondrial permeability transition pore ( mPTP )

FEBS Open Bio ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 1617-1622 ◽  
Author(s):  
Kaori Tsutsumi ◽  
Tatsuya Sasase
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Atp Depletion ◽  
Inorganic Polyphosphate ◽  
Mitochondrial Permeability

scholarly journals Mechanisms Underlying Acute Protection From Cardiac Ischemia-Reperfusion Injury

2008 ◽  
Vol 88 (2) ◽  
pp. 581-609 ◽  
Author(s):  
Elizabeth Murphy ◽  
Charles Steenbergen
Keyword(s):  
Cell Death ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ion Homeostasis ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Atp Depletion ◽  
Mitochondrial Permeability

Mitochondria play an important role in cell death and cardioprotection. During ischemia, when ATP is progressively depleted, ion pumps cannot function resulting in a rise in calcium (Ca2+), which further accelerates ATP depletion. The rise in Ca2+during ischemia and reperfusion leads to mitochondrial Ca2+accumulation, particularly during reperfusion when oxygen is reintroduced. Reintroduction of oxygen allows generation of ATP; however, damage to the electron transport chain results in increased mitochondrial generation of reactive oxygen species (ROS). Mitochondrial Ca2+overload and increased ROS can result in opening of the mitochondrial permeability transition pore, which further compromises cellular energetics. The resultant low ATP and altered ion homeostasis result in rupture of the plasma membrane and cell death. Mitochondria have long been proposed as central players in cell death, since the mitochondria are central to synthesis of both ATP and ROS and since mitochondrial and cytosolic Ca2+overload are key components of cell death. Many cardioprotective mechanisms converge on the mitochondria to reduce cell death. Reducing Ca2+overload and reducing ROS have both been reported to reduce ischemic injury. Preconditioning activates a number of signaling pathways that reduce Ca2+overload and reduce activation of the mitochondrial permeability transition pore. The mitochondrial targets of cardioprotective signals are discussed in detail.

scholarly journals Inorganic polyphosphate (polyP) as an activator and structural component of the mitochondrial permeability transition pore

2016 ◽  
Vol 44 (1) ◽  
pp. 7-12 ◽  
Author(s):  
Maria E. Solesio ◽  
Pia A. Elustondo ◽  
Eleonora Zakharian ◽  
Evgeny V. Pavlov
Keyword(s):  
Structural Component ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Atpase ◽  
Inorganic Polyphosphate ◽  
Atp Production ◽  
Mitochondrial Permeability ◽  
Large Channel

Mitochondrial permeability transition pore (mPTP) is a large channel located in the mitochondrial inner membrane. The opening of mPTP during pathological calcium overload leads to the membrane depolarization and disruption of ATP production. mPTP activation has been implicated as a central event during the process of stress-induced cell death. mPTP is a supramolecular complex composed of many proteins. Recent studies suggest that mitochondrial ATPase plays the central role in the formation of mPTP. However, the structure of the central conducting pore part of mPTP (mPTPore) remains elusive. Here we review current models proposed for the mPTPore and involvement of polyP in its formation and regulation. We discuss the underestimated role of polyP as an effector and a putative structural component of the mPTPore. We propose the hypothesis that inclusion of polyP can explain such properties of mPTP activity as calcium activation, selectivity and voltage-dependence.

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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