Induction of cyclosporine-sensitive mitochondrial permeability transition pore by substrates forming acetyl-CoA under normal conditions and in type 2 diabetes

Grishina, E. V.; Galimova, M. H.; Djafarov, R. H.; Сергеев, А. И.; Федотчева, Н. И.; Дынник, В. В.

doi:10.1134/s1990747815050049

Cited by 3 publications

(6 citation statements)

References 17 publications

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“…In this work, we used PC as the inductor of mPTP to examine the implication of mtNOS‐SS in the control of mPTP. Previously, we have shown that high concentrations of PC (above 50 µ m ) induced a steep dissipation of ΔΨm and loss of mitochondrial calcium, which may be prevented by SNAP . Results presented below further demonstrate that the induction of mPTP by PC excess is CsA‐dependent.…”

Section: Resultssupporting

confidence: 65%

“…To strengthen the dissipation of ΔΨm by PC, we included in the incubation medium the activator of mtNOS Ca 2+ . Calcium and PC act synergistically by reinforcing the effects of each other . In the absence of Ca 2+ in the medium, the PC* value was equal to 55.0 ± 5.0 µ m (black).…”

Section: Resultsmentioning

confidence: 99%

“…Long‐chain fatty acids and acylcarnitines are oxidized in mitochondria as long‐chain acyl‐CoAs, which inhibit various enzymes including NAD(P)H‐dependent dehydrogenases . Our preliminary results indicate that d , l ‐palmitoylcarnitine (PC) excess induces cyclosporin A (CsA)‐dependent dissipation of ΔΨm, which may be prevented by SNAP .…”

Section: Introductionmentioning

confidence: 88%

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The mitochondrial NO‐synthase/guanylate cyclase/protein kinase G signaling system underpins the dual effects of nitric oxide on mitochondrial respiration and opening of the permeability transition pore

2019

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Keywords mitochondrial nitric oxide synthase; mitochondrial respiration; nitric oxide; permeability transition pore; protein kinase G CorrespondenceThe available data on the involvement of nitric oxide (NO) and mitochondrial calcium-dependent NO synthase (mtNOS) in the control of mitochondrial respiration and the permeability transition pore (mPTP) are contradictory. We have proposed that the mitochondrial mtNOS/guanylate cyclase/protein kinase G signaling system (mtNOS-SS) is also implicated in the control of respiration and mPTP, providing the interplay between NO and mtNOS-SS, which, in turn, may result in inconsistent effects of NO. Therefore, 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 opening. Steady-state respiration was supported by pyruvate, glutamate, or succinate in the presence of hexokinase, glucose, and ADP. When applied at low concentrations, L-arginine (to 500 µM) and NO donors (to 50 µM) activated the respiration and increased the threshold concentrations of calcium and D,L-palmitoylcarnitine required for the dissipation of the mitochondrial membrane potential and pore opening. Both effects were eliminated by the inhibitors of NO synthase, guanylate cyclase, and kinase G, which denotes 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 adverse effects induced by an NO excess dominate over the protection provided by mtNOS-SS. Thus, these results demonstrate the opposite impact of NO and mtNOS-SS on the respiration and mPTP control, which can explain the dual effects of NO. 1526The FEBS Journal 287 (2020) 1525-1536 ª 2019 Federation of European Biochemical Societies Nitric oxide, respiration, and mPTP opening V. V. Dynnik et al.

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Section: Resultssupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

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The mitochondrial NO‐synthase/guanylate cyclase/protein kinase G signaling system underpins the dual effects of nitric oxide on mitochondrial respiration and opening of the permeability transition pore

2019

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“…Long-chain fatty acids and acylcarnitines are oxidized in mitochondria as long-chain acyl CoA's, which inhibit various enzymes including NAD(P)H-dependent dehydrogenases [42][43][44]. Our preliminary results indicate that D,L-palmitoylcarnitine (PC) excess induces CsA-dependent dissipation of Δ Ψ m, which may be prevented by SNAP [45].…”

Section: Introductionmentioning

confidence: 81%

“…Liver mitochondria were isolated using standard techniques of differential centrifugation in the medium containing 300 mM sucrose, 1 mM EGTA, and 10 mM Tris-HCl (pH 7.4). Mitochondrial preparations were washed twice with the release medium containing no EGTA, resuspended in the medium of the same composition, and stored on ice as described earlier [45]. Mitochondria incubation medium contained: 125 mM The opening of the MPTP was registered as a loss of calcium buffering capacity (a steep rise in calcium in the incubation medium) and/or dissipation of mitochondrial Δ Ψ m. MPTP 11 opening was induced by the sequential loading of the incubation medium with 20 µM Ca 2+ (CaCl 2 ) or D,L-palmitoylcarnitine (PC).…”

Section: Methodsmentioning

confidence: 99%

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

Дынник

2018

Preprint

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Abbreviations COX, cytochrome c oxidase; CRC, calcium retention capacity; CsA, cyclosporin A; Δ Ψ m, mitochondrial membrane potential; GC, nitric oxide-sensitive guanylyl cyclase; KT, KT5823; MPTP, mitochondrial permeability transition pore; mtNOS, mitochondrial NO synthase; mtNOS-SS , mtNOS/ GC/PKG-signaling system; 7-NI, 7-nitroindasole; NO, nitric oxide; ODQ, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; PKG, cGMP-dependent kinase G; PC, D,Lpalmitoylcarnitine; ROS, reactive oxygen species; SNAP, S-nitrosoacetylpenacillamine; SNP, sodium nitroprusside; VO 2 ss , steady state respiration rate. Keywords nitric oxide; mitochondrial respiration; permeability transition pore; mitochondrial nitric oxide synthase, guanylate cyclase and protein kinase G 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.

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The Effects of L-Arginine and Nitric Oxide Donors on the Induction of Mitochondrial Permeability Transition Pore by Calcium Ions and Palmitoylcarnitine. Possible Involvement of Mitochondrial NO/cGMP/PKG Signaling System

Дынник

Grishina

Федотчева

2021

Biochem. Moscow Suppl. Ser. A

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Induction of cyclosporine-sensitive mitochondrial permeability transition pore by substrates forming acetyl-CoA under normal conditions and in type 2 diabetes

Cited by 3 publications

References 17 publications

The mitochondrial NO‐synthase/guanylate cyclase/protein kinase G signaling system underpins the dual effects of nitric oxide on mitochondrial respiration and opening of the permeability transition pore

The mitochondrial NO‐synthase/guanylate cyclase/protein kinase G signaling system underpins the dual effects of nitric oxide on mitochondrial respiration and opening of the permeability transition pore

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

The Effects of L-Arginine and Nitric Oxide Donors on the Induction of Mitochondrial Permeability Transition Pore by Calcium Ions and Palmitoylcarnitine. Possible Involvement of Mitochondrial NO/cGMP/PKG Signaling System

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