Kharechkina 2019 Biochim Biophys Acta Gen Subj
|Kharechkina ES, Nikiforova AB, Teplova VV, Odinokova IV, Krestinina OV, Baburina YL, Kruglova SA, Kruglov AG (2019) Regulation of permeability transition pore opening in mitochondria by external NAD(H). Biochim Biophys Acta Gen Subj [Epub ahead of print].|
Abstract: The opening of the permeability transition pore (PTP) in mitochondria plays a critical role in the pathogenesis of numerous diseases. Mitochondrial matrix pyridine nucleotides are potent regulators of the PTP, but the role of extramitochondrial nucleotides is unclear.
The PTP opening was explored in isolated mitochondria and mitochondria in permeabilized differentiated and undifferentiated cells in the presence of added NAD(P)(H) in combination with Mg2+, adenine nucleotides (AN), and the inhibitors of AN translocase (ANT), voltage-dependent anion channel (VDAC), and cyclophilin D.
Added NAD(H) and AN, but not NADP(H), inhibited the PTP opening with comparable potency. PTP suppression required neither NAD(H) oxidation nor reduction. The protective effects of NAD(H) and cyclosporin A were synergistic, and the effects of NAD(H) and millimolar AN were additive. The conformation-specific ANT inhibitors were unable to cancel the protective effect of NADH even under total ANT inhibition. Besides, NAD(H) activated the efflux of mitochondrial AN via ANT. VDAC ligand (Mg2+) and blockers (G3139 and 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid) potentiated and attenuated the protective effect of NAD(H), respectively. However, in embryonic and cancer (undifferentiated) cells, in contrast to isolated differentiated hepatocytes and cardiocytes, the suppression of PTP opening by NADH was negligible though all cells tested possessed a full set of VDAC isoforms.
The study revealed a novel mechanism of PTP regulation by external (cytosolic) NAD(H) through the allosteric site in the OM or the intermembrane space.
The mechanism might contribute to the resistance of differentiated cells under different pathological conditions including ischemia/reperfusion.
Copyright © 2019. Published by Elsevier B.V.
• Keywords: ATP, Differentiated cells, External site, NADH, Permeability transition pore, Poly(ADP-ribose) polymerase • Bioblast editor: Plangger M
Labels: MiParea: Respiration
Stress:Permeability transition Organism: Rat Tissue;cell: Liver Preparation: Isolated mitochondria
Regulation: Calcium, Redox state Coupling state: LEAK, OXPHOS, ET Pathway: S HRR: Oxygraph-2k