The Effect Of NO Donor on Calcium Uptake and Reactive Nitrogen Species Production in Mitochondria

Abstract

Background/Aims: NO and reactive nitrogen species (RNS) are thought to be physiologically important effectors of mitochondrial calcium transport, but this issue was not studied in a living organism. According to literature, the modulation of Ca²⁺ uptake could influence RNS production via the action on mitochondrial NO synthase (mtNOS). The aim of this work was to study the effect of in vivo administration of NO donor nitroglycerine (NG) on matrix Ca²⁺ accumulation, RNS production and mtNOS activity. Methods: Ca²⁺ uptake was studied spectrophotometrically with arsenazo-III. The amounts of stable RNS (nitrite, nitrate and nitrosothiols) and L-citrulline, the product of enzymatic NOS activity, were determined analytically. Results: NG administration resulted in dose-dependent short-term increase in Ca²⁺-uptake accompanied by essential rise in L-citrulline and RNS content in mitochondria. In parallel, dose-dependent elevation of hydroperoxide production was detected. Ca²⁺-uniporter activity was not affected, but mitochondrial permeability transition pore (MPTP) was effectively blocked by NO. Conclusion: Our results indicate that MPTP blockage by NO was the primary cause for the increase in calcium uptake which eventually resulted in the activation of mtNOS and RNS production. Improved Ca²⁺ accumulation in mitochondria, together with MPTP blockage, may contribute to well-known cardioprotective effects of pharmacological donors of nitric oxide.

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

“…When analyzing the known contradictory effects of NO on the induction of mPTP by calcium , we assumed that calcium‐dependent mtNOS‐SS may represent a missing link involved in mitochondrial Ca 2+ and NO interplay and mPTP control.…”

“…Recent experiments also demonstrate that moderate doses of nitroglycerine increase CRC and prevent Ca 2+ ‐dependent mPTP opening. NO and reactive nitrogen species are considered as the mediators, which may improve mitochondrial calcium handling and suppress pore opening .…”

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

“…When analyzing the known contradictory effects of NO on the induction of MPTP by Ca 2+ [9][10][11][12][13][14][15], we assumed that calcium-dependent mtNOS-SS may represent a missing link involved in mitochondrial Ca 2+ and NO interplay and MPTP control. The application of the inhibitors of NOS, GC and PKG eliminated both effects, indicating the involvement of mtNOS-SS in the activation of respiration (Fig.…”

“…Modern experiments also demonstrate that moderate doses of nitroglycerine increase CRC and prevent Ca 2+ -dependent MPTP opening. NO and reactive nitrogen species are considered as the mediators, which may improve mitochondrial calcium handling and suppress pore opening [15].…”

Olesoxime Inhibits Cardioplegia-Induced Ischemia/Reperfusion Injury. A Study in Langendorff-Perfused Rabbit Hearts

“…Mitochondria play a key role in ischemia/reperfusion injury of the heart and are also one of the main producers of ROS and RNS during ischemia and reperfusion injury (Akopova et al, 2016; Madungwe et al, 2016). We could demonstrate that RNS production, which was measured indirectly by the formation of the more stable nitrotyrosine product (Wang et al, 2016) was significantly reduced in the olesoxime group.…”