scholarly journals Bidirectional action of nitric oxide on mitochondrial respiration and permeability transition pore induced by calcium and palmitoylcarnitine

2018 ◽  
Author(s):  
Vladimir V. Dynnik ◽  
Elena V. Grishina ◽  
Nadezhda I Fedotcheva
Keyword(s):  
Guanylate Cyclase ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
No Synthase ◽  
Rat Liver Mitochondria ◽  
Control Of Respiration ◽  
Signaling System ◽  
No Donors ◽  
Mptp Opening ◽  
Pore Opening

AbstractThe role of mitochondrial calcium-dependent NO synthase in the control of respiration and mitochondrial permeability transition pore (MPTP) opening, as well as possible involvement of mitochondrial NO synthase/guanylate cyclase/kinase G-signaling system (mtNOS-SS) in the regulation of these processes are not sufficiently studied. In this work, using rat liver mitochondria, we applied specific inhibitors of the enzymes of this signaling system to evaluate its role in the control of respiration and MPTP. The respiration was supported by pyruvate and glutamate or succinate in the presence of hexokinase, glucose and ADP. The results indicate that L-arginine and NO donors SNP and SNAP produce bidirectional concentration-dependent effects on the respiration and MPTP opening evoked by calcium ions or D,L-palmitoylcarnitine. Maximal activation of respiration was observed at 20 µM of L-arginine or SNP. At low concentrations, L-arginine (to 500 µM) and NO donors (to 50 µM) increased the threshold concentrations of calcium and D,L-palmitoylcarnitine required for the dissipation of the mitochondrial membrane potential and pore opening. The application of the inhibitors of NO synthase, guanylate cyclase, and kinase G eliminated both effects. These data indicate the involvement of mtNOS-SS in the activation of respiration and deceleration of MPTP opening. At high concentrations, L-arginine and NO donors inhibited the respiration and promoted pore opening, indicating that the inhibition induced by NO excess dominates over the protection caused by mtNOS-SS. These results demonstrate that the functioning of mtNOS-SS might provide a feedforward activation of respiration and a lowering of MPTP sensitivity to calcium and palmitoylcarnitine overload.

scholarly journals SPG7 targets the m-AAA protease complex to process MCU for uniporter assembly, Ca2+ influx, and regulation of mitochondrial permeability transition pore opening

2019 ◽  
Vol 294 (28) ◽  
pp. 10807-10818 ◽  
Author(s):  
Stephen Hurst ◽  
Ariele Baggett ◽  
Gyorgy Csordas ◽  
Shey-Shing Sheu
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Spastic Paraplegia ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Permeability Transition Pore Opening ◽  
Pore Opening

The mitochondrial matrix ATPase associated with diverse cellular activities (m-AAA) protease spastic paraplegia 7 (SPG7) has been recently implicated as either a negative or positive regulatory component of the mitochondrial permeability transition pore (mPTP) by two research groups. To address this controversy, we investigated possible mechanisms that explain the discrepancies between these two studies. We found that loss of the SPG7 gene increased resistance to Ca2+-induced mPTP opening. However, this occurs independently of cyclophilin D (cyclosporine A insensitive) rather it is through decreased mitochondrial Ca2+ concentrations and subsequent adaptations mediated by impaired formation of functional mitochondrial Ca2+ uniporter complexes. We found that SPG7 directs the m-AAA complex to favor association with the mitochondrial Ca2+ uniporter (MCU) and MCU processing regulates higher order MCU-complex formation. The results suggest that SPG7 does not constitute a core component of the mPTP but can modulate mPTP through regulation of the basal mitochondrial Ca2+ concentration.

Morphine prevents the mitochondrial permeability transition pore opening through NO/cGMP/PKG/Zn2+/GSK-3β signal pathway in cardiomyocytes

2010 ◽  
Vol 298 (2) ◽  
pp. H601-H607 ◽  
Author(s):  
Jinkun Xi ◽  
Wei Tian ◽  
Lei Zhang ◽  
Yulan Jin ◽  
Zhelong Xu
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Glycogen Synthase ◽  
Specific Inhibitor ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Pore Opening ◽  
Gsk 3Β

The aim of this study was to test whether morphine prevents the mitochondrial permeability transition pore (mPTP) opening through Zn2+ and glycogen synthase kinase 3β (GSK-3β). Fluorescence dyes including Newport Green Dichlorofluorescein (DCF), 4-amino-5-methylamino-2′,7′-difluorofluorescein (DAF-FM), and tetramethylrhodamine ethyl ester (TMRE) were used to image free Zn2+, nitric oxide (NO), and mitochondrial membrane potential (ΔΨm), respectively. Fluorescence images were obtained with confocal microscopy. Cardiomyocytes treated with morphine for 10 min showed a significant increase in Newport Green DCF fluorescence intensity, an effect that was reversed by the NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME), indicating that morphine mobilizes Zn2+ via NO. Morphine rapidly produced NO. ODQ and NS2028, the inhibitors of guanylyl cyclase, prevented Zn2+ release by morphine, implying that cGMP is involved in the action of morphine. The effect of morphine on Zn2+ release was also abolished by KT5823, a specific inhibitor of protein kinase G (PKG). Morphine prevented oxidant-induced loss of ΔΨm, indicating that morphine can modulate the mPTP opening. The effect of morphine on the mPTP was reversed by KT5823 and the Zn2+ chelator N, N, N′, N′-tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN). The action of morphine on the mPTP was lost in cells transfected with the constitutively active GSK-3β mutant, suggesting that morphine may prevent the mPTP opening by inactivating GSK-3β. In support, morphine significantly enhanced phosphorylation of GSK-3β at Ser9, and this was blocked by TPEN. GSK-3β small interfering RNA prevented the pore opening in the control cardiomyocytes but failed to enhance the effect of morphine on the mPTP opening. In conclusion, morphine mobilizes intracellular Zn2+ through the NO/cGMP/PKG signaling pathway and prevents the mPTP opening by inactivating GSK-3β through Zn2+.

scholarly journals Cyclosporin A Increases Mitochondrial Buffering of Calcium: An Additional Mechanism in Delaying Mitochondrial Permeability Transition Pore Opening

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1052 ◽  
Author(s):  
Jyotsna Mishra ◽  
Ariea J. Davani ◽  
Gayathri K. Natarajan ◽  
Wai-Meng Kwok ◽  
David F. Stowe ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Extended Period ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Mptp Opening ◽  
Permeability Transition Pore Opening ◽  
Pore Opening ◽  
Matrix Free

Regulation of mitochondrial free Ca2+ is critically important for cellular homeostasis. An increase in mitochondrial matrix free Ca2+ concentration ([Ca2+]m) predisposes mitochondria to opening of the permeability transition pore (mPTP). Opening of the pore can be delayed by cyclosporin A (CsA), possibly by inhibiting cyclophilin D (Cyp D), a key regulator of mPTP. Here, we report on a novel mechanism by which CsA delays mPTP opening by enhanced sequestration of matrix free Ca2+. Cardiac-isolated mitochondria were challenged with repetitive CaCl2 boluses under Na+-free buffer conditions with and without CsA. CsA significantly delayed mPTP opening primarily by promoting matrix Ca2+ sequestration, leading to sustained basal [Ca2+]m levels for an extended period. The preservation of basal [Ca2+]m during the CaCl2 pulse challenge was associated with normalized NADH, matrix pH (pHm), and mitochondrial membrane potential (ΔΨm). Notably, we found that in PO43− (Pi)-free buffer condition, the CsA-mediated buffering of [Ca2+]m was abrogated, and mitochondrial bioenergetics variables were concurrently compromised. In the presence of CsA, addition of Pi just before pore opening in the Pi-depleted condition reinstated the Ca2+ buffering system and rescued mitochondria from mPTP opening. This study shows that CsA promotes Pi-dependent mitochondrial Ca2+ sequestration to delay mPTP opening and, concomitantly, maintains mitochondrial function.

scholarly journals Fractions of Adenopus breviflorus Extract Modulate Calcium-induced Mitochondrial Permeability Transition Pore Opening in Rat Liver

2018 ◽  
Vol 3 (1) ◽  
pp. 21-27
Author(s):  
Tolulope A. Oyedeji ◽  
Chibuzor I. Akobi ◽  
Daniel O. Onireti ◽  
Olufunso O. Olorunsogo
Keyword(s):  
Rat Liver ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Rat Liver Mitochondria ◽  
Mitochondrial Atpase ◽  
Dependent Manner ◽  
Mitochondrial Permeability ◽  
Pore Opening

AbstractMitochondrial dysfunction (MD) and impaired apoptotic pathways cause irreversible opening of the Mitochondrial Permeability Transition (MPT) pore, resulting in several pathological conditions e.g. cancer, ageing and neurodegenerative diseases. Many bioactive compounds from plants have been identified as modulators of the MPT pore which makes them possible drugs for the management of MD associated diseases. Adenopus breviflorus (A.breviflorus) is a tropical medicinal plant used in folkore medicine as an abortifacient and in treating gonorrhoea. In this study, the effects of ethylacetate and methanol fractions of A.breviflorus were assessed on rat liver MPT pore and Mitochondrial ATPase (mATPase). The fruit of A.breviflorus was extracted with water to obtain the aqueous Extract (AEAB), which was fractionated using vacuum liquid chromatography (VLC) to obtain ethylacetate and methanol fractions of A.breviflorus (EFAB, and MFAB). The extent of MPT pore opening and mATPase by EFAB and MFAB were assayed spectrophotometrically. The results obtained showed that EFAB and MFAB have no significant inductive effect on the MPT pore in the absence of Ca2+. However, in the presence of Ca2+, EFAB inhibited calcium-induced MPT pore opening in a non-concentration dependent manner. Maximum inhibition of MPT pore opening was 57.1% at 50 μg/ml. Interestingly, MFAB potentiated calcium ion effect by opening the pore further. Specifically, MFAB opened the MPT pore by 11, 10, 17 and 9% at 50, 150, 250 and 350 μg/ml, respectively. Furthermore, EFAB and MFAB inhibited mATPase activity in rat liver mitochondria at 62.5, 187.5, 312.5 and 437.5 μg/ml by 2.6, 18.8, 37.3, 52.6% and 41.8, 6.8, 24.3, 8.4%, respectively. The ethylacetate and methanol fractions of Adenopus breviflorus possess potential phytochemicals that can modulate opening of the mitochondrial permeability transition pore and inhibit mitochondrial ATPase activity in rat liver. These fractions may find use in drug development against diseases where excessive apoptosis takes place.

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