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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
Author(s) -
Dynnik Vladimir V.,
Grishina Elena V.,
Fedotcheva Nadezhda I.
Publication year - 2020
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.15090
Subject(s) - respiration , mitochondrial permeability transition pore , mitochondrion , nitric oxide synthase , biology , biochemistry , nitric oxide , cgmp dependent protein kinase , microbiology and biotechnology , cellular respiration , mptp , chemistry , protein kinase a , biophysics , kinase , enzyme , endocrinology , apoptosis , anatomy , dopamine , dopaminergic , programmed cell death , cyclin dependent kinase 2
The 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 µ m ) and NO donors (to 50 µ m ) 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.