The effect of DS16570511, a new inhibitor of mitochondrial calcium uniporter, on calcium homeostasis, metabolism, and functional state of cultured cortical neurons and isolated brain mitochondria

Disorders of mitochondrial Ca2+ homeostasis play a key role in the glutamate excitotoxicity of brain neurons. DS16570511 (DS) is a new penetrating inhibitor of mitochondrial Ca2+ uniporter complex (MCUC). The paper examines the effects of DS on the cultivated cortical neurons and isolated mitochondr...

Full description

Saved in:

Bibliographic Details
Published in:	Biochimica et biophysica acta. General subjects Vol. 1865; no. 5; p. 129847
Main Authors:	Belosludtsev, Konstantin N., Sharipov, Rinat R., Boyarkin, Dmitry P., Belosludtseva, Natalia V., Dubinin, Mikhail V., Krasilnikova, Irina A., Bakaeva, Zanda V., Zgodova, Arina E., Pinelis, Vsevolod G., Surin, Alexander M.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-05-2021
Subjects:	Ca2+ uniporter Delayed calcium deregulation DS16570511 Glutamate excitotoxity Mitochondria Mitochondrial depolarization Glutamate excitotoxity DS16570511 Mitochondria Delayed calcium deregulation Mitochondrial depolarization Ca2+ uniporter Ca(2+) uniporter
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Disorders of mitochondrial Ca2+ homeostasis play a key role in the glutamate excitotoxicity of brain neurons. DS16570511 (DS) is a new penetrating inhibitor of mitochondrial Ca2+ uniporter complex (MCUC). The paper examines the effects of DS on the cultivated cortical neurons and isolated mitochondria of the rat brain. The functions of neurons and mitochondria were examined using fluorescence microscopy, XF24 microplate-based сell respirometry, ion-selective microelectrodes, spectrophotometry, and polarographic technique. At the doses of 30 and 45 μM, DS reliably slowed down the onset of glutamate-induced delayed calcium deregulation of neurons and suppressed their death. 30 μM DS caused hyperpolarization of mitochondria of resting neurons, and 45 μM DS temporarily depolarized neuronal mitochondria. It was also demonstrated that 30–60 μM DS stimulated cellular respiration. DS was shown to suppress Ca2+ uptake by isolated brain mitochondria. In addition, DS inhibited ADP-stimulated mitochondrial respiration and ADP-induced decrease in the mitochondrial membrane potential. It was found that DS inhibited the activity of complex II of the respiratory chain. In the presence of Ca2+, high DS concentrations caused a collapse of the mitochondrial membrane potential. The data obtained indicate that, in addition to the inhibition of MCUC, DS affects the main energy-transducing functions of mitochondria. The using DS as a tool for studying MCUC and its functional role in neuronal cells should be done with care, bearing in mind multiple effects of DS, a proper evaluation of which would require multivariate analysis. •DS16570511 causes hyperpolarization of mitochondria of resting cortical neurons•DS16570511 slows down the onset of glutamate-induced delayed calcium deregulation of neurons•DS16570511 inhibits Ca2+ uptake and ADP-stimulated respiration of isolated rat brain mitochondria•High DS16570511 concentrations causes a collapse of the mitochondrial membrane potential
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0304-4165 1872-8006
DOI:	10.1016/j.bbagen.2021.129847