Inorganic polyphosphate in cardiac myocytes: from bioenergetics to the permeability transition pore and cell survival

2016 ◽  
Vol 44 (1) ◽  
pp. 25-34 ◽  
Author(s):  
Elena N. Dedkova
Keyword(s):  
Cardiac Myocytes ◽  
Mitochondrial Permeability Transition ◽  
Average Length ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
High Energy ◽  
Ros Generation ◽  
Inorganic Polyphosphate ◽  
Heart Metabolism ◽  
Mptp Opening

Inorganic polyphosphate (polyP) is a linear polymer of Pi residues linked together by high-energy phosphoanhydride bonds as in ATP. PolyP is present in all living organisms ranging from bacteria to human and possibly even predating life of this planet. The length of polyP chain can vary from just a few phosphates to several thousand phosphate units long, depending on the organism and the tissue in which it is synthesized. PolyP was extensively studied in prokaryotes and unicellular eukaryotes by Kulaev's group in the Russian Academy of Sciences and by the Nobel Prize Laureate Arthur Kornberg at Stanford University. Recently, we reported that mitochondria of cardiac ventricular myocytes contain significant amounts (280±60 pmol/mg of protein) of polyP with an average length of 25 Pi and that polyP is involved in Ca2+-dependent activation of the mitochondrial permeability transition pore (mPTP). Enzymatic polyP depletion prevented Ca2+-induced mPTP opening during ischaemia; however, it did not affect reactive oxygen species (ROS)-mediated mPTP opening during reperfusion and even enhanced cell death in cardiac myocytes. We found that ROS generation was actually enhanced in polyP-depleted cells demonstrating that polyP protects cardiac myocytes against enhanced ROS formation. Furthermore, polyP concentration was dynamically changed during activation of the mitochondrial respiratory chain and stress conditions such as ischaemia/reperfusion (I/R) and heart failure (HF) indicating that polyP is required for the normal heart metabolism. This review discusses the current literature on the roles of polyP in cardiovascular health and disease.

Abstract 359: Higher ROS Generation and Lower Threshold of mPTP Opening May Underlie Increased Vulnerability of Late Pregnant Heart to Ischemia-Reperfusion Injury

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Jingyuan Li ◽  
Andrea Iorga ◽  
Ji-Youn Youn ◽  
Hua Cai ◽  
Vera Regitz-Zagrosek ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ros Generation ◽  
Hemodynamic Parameters ◽  
Mptp Opening

Although the murine late pregnant (LP) heart is speculated to be a better functioning heart during physiological conditions, the susceptibility of LP hearts to I/R injury is still unknown. The aims of this study were to investigate the cardiac vulnerability of LP rodents to ischemia/reperfusion (I/R) injury and to explore its underlying mechanisms. In-vivo female rat hearts (non-pregnant (NP) or LP) or Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion. The infarct size was ∼4 fold larger in LP compared to NP both in the in-vivo rat model and ex-vivo mouse model. The hemodynamic parameters were similar between NP and LP before ischemia. However, the postischemic functional recovery was extremely poor in LP mice comparing to NP mice. RPP was reduced from 12818±1213mmHg*beats/min in NP to 1617± 287mmHg*beats/min in LP mice at the end of reperfusion. Interestingly, all of the hemodynamic parameters almost fully recovered in hearts seven days post-partum (PP7)( RPP= 9604±1215 mmHg*beats/min). To explore the mitochondrial function involvement in the higher vulnerability of LP hearts to I/R injury, mitochondrial respiration and ROS production were measured. Respiratory control index(RCI) were significantly decreased in LP subjected to I/R compared to NP and PP7 (RCI=1.9±0.1 in LP, 4.0±0.5 in NP and 3.9±0.5 in PP7, P<0.05 LP vs. NP and PP7). The superoxide production was also significantly higher in isolated cardiac mitochondria from LP hearts subjected to I/R injury (10.7±1.7mM/min/mg protein in NP; 21.3±3.1mM/min/mg protein in LP and 9.3±3.3mM/min/mg protein in PP7; p<0.05 LP vs. NP and PP7). The threshold for opening of mitochondrial permeability transition pore (mPTP) in response to Ca2+ overload was much lower in LP hearts (calcium retention capacity(CRC)=167±10 nmol/mg-mitochondrial protein) compared with NP (233±18 nmol/mg-mitochondrial protein) and PP7 (260±12 nmol/mg-mitochondrial protein, P<0.01). In conclusion, the higher susceptibility of LP hearts to I/R injury is associated with a lower threshold for triggering the mitochondrial permeability transition pore (mPTP) opening in response to Ca2+ overload which may at least be in part due to higher ROS generation and lower mitochondrial respiration.

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 The Multifaceted Roles of Zinc in Neuronal Mitochondrial Dysfunction

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 489
Author(s):  
Hilary Y. Liu ◽  
Jenna R. Gale ◽  
Ian J. Reynolds ◽  
John H. Weiss ◽  
Elias Aizenman
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Neuronal Damage ◽  
Mitochondrial Fission ◽  
Permeability Transition ◽  
High Energy ◽  
Atp Depletion ◽  
Ros Generation ◽  
Cellular Functions ◽  
Calcium Deregulation ◽  
Energy Demands

Zinc is a highly abundant cation in the brain, essential for cellular functions, including transcription, enzymatic activity, and cell signaling. However, zinc can also trigger injurious cascades in neurons, contributing to the pathology of neurodegenerative diseases. Mitochondria, critical for meeting the high energy demands of the central nervous system (CNS), are a principal target of the deleterious actions of zinc. An increasing body of work suggests that intracellular zinc can, under certain circumstances, contribute to neuronal damage by inhibiting mitochondrial energy processes, including dissipation of the mitochondrial membrane potential (MMP), leading to ATP depletion. Additional consequences of zinc-mediated mitochondrial damage include reactive oxygen species (ROS) generation, mitochondrial permeability transition, and excitotoxic calcium deregulation. Zinc can also induce mitochondrial fission, resulting in mitochondrial fragmentation, as well as inhibition of mitochondrial motility. Here, we review the known mechanisms responsible for the deleterious actions of zinc on the organelle, within the context of neuronal injury associated with neurodegenerative processes. Elucidating the critical contributions of zinc-induced mitochondrial defects to neurotoxicity and neurodegeneration may provide insight into novel therapeutic targets in the clinical setting.

scholarly journals Mitochondrial depolarization underlies delay in permeability transition by preconditioning with isoflurane: roles of ROS and Ca2+

2010 ◽  
Vol 299 (2) ◽  
pp. C506-C515 ◽  
Author(s):  
Filip Sedlic ◽  
Ana Sepac ◽  
Danijel Pravdic ◽  
Amadou K. S. Camara ◽  
Martin Bienengraeber ◽  
...  
Keyword(s):  
Cell Survival ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Underlying Mechanism ◽  
Ros Production ◽  
Trypan Blue Exclusion ◽  
Mptp Opening ◽  
Mitochondrial Ros ◽  
Cardioprotective Effects

During reperfusion, the interplay between excess reactive oxygen species (ROS) production, mitochondrial Ca2+ overload, and mitochondrial permeability transition pore (mPTP) opening, as the crucial mechanism of cardiomyocyte injury, remains intriguing. Here, we investigated whether an induction of a partial decrease in mitochondrial membrane potential (ΔΨm) is an underlying mechanism of protection by anesthetic-induced preconditioning (APC) with isoflurane, specifically addressing the interplay between ROS, Ca2+, and mPTP opening. The magnitude of APC-induced decrease in ΔΨm was mimicked with the protonophore 2,4-dinitrophenol (DNP), and the addition of pyruvate was used to reverse APC- and DNP-induced decrease in ΔΨm. In cardiomyocytes, ΔΨm, ROS, mPTP opening, and cytosolic and mitochondrial Ca2+ were measured using confocal microscope, and cardiomyocyte survival was assessed by Trypan blue exclusion. In isolated cardiac mitochondria, antimycin A-induced ROS production and Ca2+ uptake were determined spectrofluorometrically. In cells exposed to oxidative stress, APC and DNP increased cell survival, delayed mPTP opening, and attenuated ROS production, which was reversed by mitochondrial repolarization with pyruvate. In isolated mitochondria, depolarization by APC and DNP attenuated ROS production, but not Ca2+ uptake. However, in stressed cardiomyocytes, a similar decrease in ΔΨm attenuated both cytosolic and mitochondrial Ca2+ accumulation. In conclusion, a partial decrease in ΔΨm underlies cardioprotective effects of APC by attenuating excess ROS production, resulting in a delay in mPTP opening and an increase in cell survival. Such decrease in ΔΨm primarily attenuates mitochondrial ROS production, with consequential decrease in mitochondrial Ca2+ uptake.

Abstract 168: Resveratrol Translocates Gsk-3β To Mitochondria And Protects The Heart At Reperfusion By Targeting The Mitochondrial Permeability Transition Pore

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jinkun Xi ◽  
Huihua Wang ◽  
Guillaume Chanoit ◽  
Guang Cheng ◽  
Robert A Mueller ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Risk Zone ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Gsk 3Β

Although resveratrol has been demonstrated to be cardioprotective, the detailed cellular and molecular mechanisms that mediate the protection remain elusive. We aimed to determine if resveratrol protects the heart at reperfusion by modulating the mitochondrial permeability transition pore (mPTP) opening through glycogen synthase kinase 3β (GSK-3β). Resveratrol (10μM) given at reperfusion reduced infarct size (12.2 ± 2.5 % of risk zone vs. 37.9 ± 3.1 % of risk zone in control, n = 6) in isolated rat hearts subjected to 30 min regional ischemia followed by 2 h of reperfusion, an effect that was abrogated by the mPTP opener atractyloside (30.9 ± 8.1 % of risk zone), implying that resveratrol may protect the heart at reperfusion by modulating the mPTP opening. To define the signaling mechanism underlying the action of resveratrol, we determined GSK-3β activity by measuring its phosphorylation at Ser 9 . Resveratrol significantly enhanced GSK-3β phosphorylation upon reperfusion (225.2 ± 30.0 % of control at 5 min of reperfusion). Further experiments showed that resveratrol induces translocation of GSK-3β to mitochondria and translocated GSK-3β interacts with the mPTP component cyclophilin D but not VDAC (the voltage-dependent anion channel) or ANT (the adenine nucleotide translocator) in cardiac mitochondria. Taken together, these data suggest that resveratrol prevents myocardial reperfusion injury by targeting the mPTP opening via GSK-3β. Translocation of GSK-3β to mitochondria and its interaction with the mPTP component cyclophilin D may serve as an essential mechanism that mediates the protective effect of resveratrol on reperfusion injury.

Protectors of the mitochondrial permeability transition pore activated by iron and doxorubicin

2021 ◽  
Vol 21 ◽  
Author(s):  
Tatiana A. Fedotcheva ◽  
Nadezhda I. Fedotcheva
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Membrane Damage ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Selective Electrode ◽  
Mitochondrial Permeability ◽  
Isolated Mitochondria ◽  
Mptp Opening ◽  
Dependent Cell

Aim: The study of action of iron, DOX, and their complex on the mitochondrial permeability transition pore (MPTP) opening and the detection of possible protectors of MPTP in the conditions close to mitochondria-dependent ferroptosis. Background: The toxicity of doxorubicin (DOX) is mainly associated with the free iron accumulation and mitochondrial dysfunction. DOX can provoke ferroptosis, iron-dependent cell death driven by the membrane damage. The mitochondrial permeability transition pore (MPTP) is considered as a common pathway leading to the development of apoptosis, necrosis, and, possibly, ferroptosis. The influence of DOX on the Ca2+ -induced opening of MPTP in the presence of iron has not yet been studied. Objective: The study was conducted on isolated liver and heart mitochondria. MPTP and succinate-ubiquinone oxidoreductase were studied as targets of DOX in mitochondria-dependent ferroptosis. Methods: The study was conducted on isolated mitochondria of the liver and heart. Changes of threshold calcium concentrations required for MPTP opening were measured by a Ca2+ selective electrode, mitochondrial membrane potential was registered by tetraphenylphosphonium (TPP+)-selective electrode, and mitochondrial swelling was recorded as a decrease in absorbance at 540 nm. The activity of succinate dehydrogenase (SDH) was determined by the reduction of the electron acceptor DCPIP. Conclusion: MPTP and the respiratory complex II are identified as the main targets of the iron-dependent action of DOX on the isolated mitochondria. All MPTP protectors tested abolished or weakened the effect of iron and a complex of iron with DOX on Ca2+ -induced MPTP opening, acting in different stages of MPTP activation. These data open new approaches to the modulation of the toxic influence of DOX on mitochondria with the aim to reduce their dysfunction

Abstract 17188: Cryoem Analysis in Cardiac Isolated Mitochondria Reveals New Insights for CsA and mPTP Activation

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Jasiel O Strubbe ◽  
Jason Schrad ◽  
James F Conway ◽  
Kristin N Parent ◽  
Jason N Bazil
Keyword(s):  
Time Course ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Myocardial Necrosis ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Granule Formation ◽  
Membrane Rupture ◽  
Mptp Opening

Excessive Ca 2+ accumulation is the main source of cardiac tissue and cell death during myocardial ischemia-reperfusion injury (IR injury) and myocardial infarction. Calcium dysregulation and overload leads to mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, catastrophic energy failure, and opening of the cyclosporine A-sensitive mitochondrial permeability transition pore (mPTP). Mitochondrial Ca 2+ accumulation also results in the formation of amorphous Ca 2+ -phosphate granules localized in the mitochondrial matrix. These amorphous electron-dense granules are main components of the mitochondrial Ca 2+ sequestration and buffering system by mechanisms not yet well understood. The two aims of the present study are to test the relationship of Ca 2+ -phosphate granule size and number in cardiac mitochondria 1) exposed to a bolus calcium sufficient to elicit permeabilization and 2) whether CsA-treated mitochondria alters granule formation and size. A time course series of CryoEM images was analyzed to follow the permeabilization process. CryoEM results showed that mitochondrial incubated for longer time-courses have increased number of small granules (40 - 110 nm), swelling, membrane rupture and induction of mPTP opening. Conversely, shorter incubation time resulted in less granules per mitochondrion yet of similar size (35 - 90 nm). CsA- treated mitochondria, on the other hand, showed bigger phosphate granules (120 - 160 nm), and both lower granules per mitochondria and mPTP opening susceptibility. These results suggest a novel mechanism for CsA in which Ca 2+ -phosphate granule sizes are enhanced while maintaining fewer per mitochondrion. This effect may explain why CsA-treated mitochondria have higher calcium tolerance, delayed Ca 2+ -dependent opening of the mPTP, and protects against reperfusion-induced myocardial necrosis.

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