Attenuation of liver normothermic ischemia-reperfusion injury by preservation of mitochondrial functions with S-15176, a potent trimetazidine derivative11Abbreviations: ASAT, aspartate aminotransferase; ALAT, alanine aminotransferase; PTP, permeability transition pore; RCR, respiratory control ratio; ROS, reactive oxygen species; and ΔΨ, mitochondrial membrane potential.

2001 ◽  
Vol 62 (4) ◽  
pp. 509-516 ◽  
Author(s):  
Aziz Elimadi ◽  
Rosa Sapena ◽  
Abdellatif Settaf ◽  
Herve Le Louet ◽  
Jean-Paul Tillement ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Respiratory Control ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Oxygen Species ◽  
Respiratory Control Ratio ◽  
Mitochondrial Functions ◽  
Ros Reactive Oxygen Species

Exercise training decreases rat heart mitochondria free radical generation but does not prevent Ca2+-induced dysfunction

2007 ◽  
Vol 102 (5) ◽  
pp. 1793-1798 ◽  
Author(s):  
Joseph W. Starnes ◽  
Brian D. Barnes ◽  
Marissa E. Olsen
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Electron Flow ◽  
Respiratory Control ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Calcium Overload ◽  
Ros Generation ◽  
Ros Production ◽  
Ptp Opening

Exercise provides cardioprotection against ischemia-reperfusion injury, a process involving mitochondrial reactive oxygen species (ROS) generation and calcium overload. This study tested the hypotheses that isolated mitochondria from hearts of endurance-trained rats have decreased ROS production and improved tolerance against Ca2+-induced dysfunction. Male Fischer 344 rats were either sedentary (Sed, n = 8) or endurance exercise trained (ET, n = 11) by running on a treadmill for 16 wk (5 days/wk, 60 min/day, 25 m/min, 6° grade). Mitochondrial oxidative phosphorylation measures were determined with glutamate-malate or succinate as substrates, and H2O2 production and permeability transition pore (PTP) opening were determined with succinate. All assays were carried out in the absence and presence of calcium. In response to 25 and 50 μM CaCl2, Sed and ET displayed similar decreases in state 3 respiration, respiratory control ratio, and ADP:O ratio. Ca2+-induced PTP opening was also similar. However, H2O2 production by ET was lower than Sed ( P < 0.05) in the absence of calcium (323 ± 12 vs. 362 ± 11 pmol·min−1·mg protein−1) and the presence of 50 μM CaCl2 (154 ± 3 vs. 197 ± 7 pmol·min−1·mg protein−1). Rotenone, which blocks electron flow from succinate to complex 1, reduced H2O2 production and eliminated differences between ET and Sed. Mitochondrial superoxide dismutase and glutathione peroxidase were not affected by exercise. Catalase activity was extremely low but increased 49% in ET ( P < 0.05). In conclusion, exercise reduces ROS production in myocardial mitochondria through adaptations specific to complex 1 but does not improve mitochondrial tolerance to calcium overload.

scholarly journals Regulation of STAT3 and its role in cardioprotection by conditioning: focus on non-genomic roles targeting mitochondrial function

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Stefano Comità ◽  
Saveria Femmino ◽  
Cecilia Thairi ◽  
Giuseppe Alloatti ◽  
Kerstin Boengler ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ischemic Disease ◽  
Survival Pathways ◽  
Transport Chain ◽  
Mitochondrial Functions

AbstractIschemia–reperfusion injury (IRI) is one of the biggest challenges for cardiovascular researchers given the huge death toll caused by myocardial ischemic disease. Cardioprotective conditioning strategies, namely pre- and post-conditioning maneuvers, represent the most important strategies for stimulating pro-survival pathways essential to preserve cardiac health. Conditioning maneuvers have proved to be fundamental for the knowledge of the molecular basis of both IRI and cardioprotection. Among this evidence, the importance of signal transducer and activator of transcription 3 (STAT3) emerged. STAT3 is not only a transcription factor but also exhibits non-genomic pro-survival functions preserving mitochondrial function from IRI. Indeed, STAT3 is emerging as an influencer of mitochondrial function to explain the cardioprotection phenomena. Studying cardioprotection, STAT3 proved to be crucial as an element of the survivor activating factor enhancement (SAFE) pathway, which converges on mitochondria and influences their function by cross-talking with other cardioprotective pathways. Clearly there are still some functional properties of STAT3 to be discovered. Therefore, in this review, we highlight the evidence that places STAT3 as a promoter of the metabolic network. In particular, we focus on the possible interactions of STAT3 with processes aimed at maintaining mitochondrial functions, including the regulation of the electron transport chain, the production of reactive oxygen species, the homeostasis of Ca2+ and the inhibition of opening of mitochondrial permeability transition pore. Then we consider the role of STAT3 and the parallels between STA3/STAT5 in cardioprotection by conditioning, giving emphasis to the human heart and confounders.

scholarly journals Mitochondrial dysfunction in uremic cardiomyopathy

2015 ◽  
Vol 308 (6) ◽  
pp. F579-F587 ◽  
Author(s):  
David Taylor ◽  
Sunil Bhandari ◽  
Anne-Marie L. Seymour
Keyword(s):  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Respiratory Control ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Oxidative Capacity ◽  
Mitochondrial Redox State ◽  
Uremic Cardiomyopathy

Uremic cardiomyopathy (UCM) is characterized by metabolic remodelling, compromised energetics, and loss of insulin-mediated cardioprotection, which result in unsustainable adaptations and heart failure. However, the role of mitochondria and the susceptibility of mitochondrial permeability transition pore (mPTP) formation in ischemia-reperfusion injury (IRI) in UCM are unknown. Using a rat model of chronic uremia, we investigated the oxidative capacity of mitochondria in UCM and their sensitivity to ischemia-reperfusion mimetic oxidant and calcium stressors to assess the susceptibility to mPTP formation. Uremic animals exhibited a 45% reduction in creatinine clearance ( P < 0.01), and cardiac mitochondria demonstrated uncoupling with increased state 4 respiration. Following IRI, uremic mitochondria exhibited a 58% increase in state 4 respiration ( P < 0.05), with an overall reduction in respiratory control ratio ( P < 0.01). Cardiomyocytes from uremic animals displayed a 30% greater vulnerability to oxidant-induced cell death determined by FAD autofluorescence ( P < 0.05) and reduced mitochondrial redox state on exposure to 200 μM H2O2 ( P < 0.01). The susceptibility to calcium-induced permeability transition showed that maximum rates of depolarization were enhanced in uremia by 79%. These results demonstrate that mitochondrial respiration in the uremic heart is chronically uncoupled. Cardiomyocytes in UCM are characterized by a more oxidized mitochondrial network, with greater susceptibility to oxidant-induced cell death and enhanced vulnerability to calcium-induced mPTP formation. Collectively, these findings indicate that mitochondrial function is compromised in UCM with increased vulnerability to calcium and oxidant-induced stressors, which may underpin the enhanced predisposition to IRI in the uremic heart.

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.

scholarly journals Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

2015 ◽  
Vol 112 (17) ◽  
pp. E2253-E2262 ◽  
Author(s):  
Youn Wook Chung ◽  
Claudia Lagranha ◽  
Yong Chen ◽  
Junhui Sun ◽  
Guang Tong ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mouse Heart ◽  
Targeted Disruption

Although inhibition of cyclic nucleotide phosphodiesterase type 3 (PDE3) has been reported to protect rodent heart against ischemia/reperfusion (I/R) injury, neither the specific PDE3 isoform involved nor the underlying mechanisms have been identified. Targeted disruption of PDE3 subfamily B (PDE3B), but not of PDE3 subfamily A (PDE3A), protected mouse heart from I/R injury in vivo and in vitro, with reduced infarct size and improved cardiac function. The cardioprotective effect in PDE3B−/− heart was reversed by blocking cAMP-dependent PKA and by paxilline, an inhibitor of mitochondrial calcium-activated K channels, the opening of which is potentiated by cAMP/PKA signaling. Compared with WT mitochondria, PDE3B−/− mitochondria were enriched in antiapoptotic Bcl-2, produced less reactive oxygen species, and more frequently contacted transverse tubules where PDE3B was localized with caveolin-3. Moreover, a PDE3B−/− mitochondrial fraction containing connexin-43 and caveolin-3 was more resistant to Ca2+-induced opening of the mitochondrial permeability transition pore. Proteomics analyses indicated that PDE3B−/− heart mitochondria fractions were enriched in buoyant ischemia-induced caveolin-3–enriched fractions (ICEFs) containing cardioprotective proteins. Accumulation of proteins into ICEFs was PKA dependent and was achieved by ischemic preconditioning or treatment of WT heart with the PDE3 inhibitor cilostamide. Taken together, these findings indicate that PDE3B deletion confers cardioprotective effects because of cAMP/PKA-induced preconditioning, which is associated with the accumulation of proteins with cardioprotective function in ICEFs. To our knowledge, our study is the first to define a role for PDE3B in cardioprotection against I/R injury and suggests PDE3B as a target for cardiovascular therapies.

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