Neuroprotective Effect of a Novel ATP-Synthase Inhibitor Bedaquiline in Cerebral Ischemia-Reperfusion Injury
Mitochondrial dysfunction during ischemic stroke ultimately manifests as ATP depletion. Mitochondrial ATP synthase upon loss of mitochondrial membrane potential during ischemia rapidly hydrolyses ATP and thus contributes to ATP depletion. Increasing evidence suggests that inhibition of ATP synthase...
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doaj-6b41dc6e2f3e4bd8b33706df6fc2d7332021-09-26T00:22:23ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-09-01229717971710.3390/ijms22189717Neuroprotective Effect of a Novel ATP-Synthase Inhibitor Bedaquiline in Cerebral Ischemia-Reperfusion InjuryDanielius Umbrasas0Odeta Arandarcikaite1Ramune Grigaleviciute2Rimantas Stakauskas3Vilmante Borutaite4Neuroscience Institute, Lithuanian University of Health Sciences, LT-47181 Kaunas, LithuaniaNeuroscience Institute, Lithuanian University of Health Sciences, LT-47181 Kaunas, LithuaniaBiological Research Center, Lithuanian University of Health Sciences, LT-47181 Kaunas, LithuaniaBiological Research Center, Lithuanian University of Health Sciences, LT-47181 Kaunas, LithuaniaNeuroscience Institute, Lithuanian University of Health Sciences, LT-47181 Kaunas, LithuaniaMitochondrial dysfunction during ischemic stroke ultimately manifests as ATP depletion. Mitochondrial ATP synthase upon loss of mitochondrial membrane potential during ischemia rapidly hydrolyses ATP and thus contributes to ATP depletion. Increasing evidence suggests that inhibition of ATP synthase limits ATP depletion and is protective against ischemic tissue damage. Bedaquiline (BDQ) is an anti-microbial agent, approved for clinical use, that inhibits ATP synthase of Mycobacteria; however recently it has been shown to act on mitochondrial ATP synthase, inhibiting both ATP synthesis and hydrolysis in low micromolar concentrations. In this study, we investigated whether preconditioning with BDQ can alleviate ischemia/reperfusion-induced brain injury in Wistar rats after middle cerebral artery occlusion-reperfusion and whether it affects mitochondrial functions. We found that BDQ was effective in limiting necrosis and neurological dysfunction during ischemia-reperfusion. BDQ also caused inhibition of ATPase activity, mild uncoupling of respiration, and stimulated mitochondrial respiration both in healthy and ischemic mitochondria. Mitochondrial calcium retention capacity was unaffected by BDQ preconditioning. We concluded that BDQ has neuroprotective properties associated with its action on mitochondrial respiration and ATPase activity.https://www.mdpi.com/1422-0067/22/18/9717mitochondrial respirationbedaquilinestrokeischemianeuroprotectionATP synthase |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Danielius Umbrasas Odeta Arandarcikaite Ramune Grigaleviciute Rimantas Stakauskas Vilmante Borutaite |
spellingShingle |
Danielius Umbrasas Odeta Arandarcikaite Ramune Grigaleviciute Rimantas Stakauskas Vilmante Borutaite Neuroprotective Effect of a Novel ATP-Synthase Inhibitor Bedaquiline in Cerebral Ischemia-Reperfusion Injury International Journal of Molecular Sciences mitochondrial respiration bedaquiline stroke ischemia neuroprotection ATP synthase |
author_facet |
Danielius Umbrasas Odeta Arandarcikaite Ramune Grigaleviciute Rimantas Stakauskas Vilmante Borutaite |
author_sort |
Danielius Umbrasas |
title |
Neuroprotective Effect of a Novel ATP-Synthase Inhibitor Bedaquiline in Cerebral Ischemia-Reperfusion Injury |
title_short |
Neuroprotective Effect of a Novel ATP-Synthase Inhibitor Bedaquiline in Cerebral Ischemia-Reperfusion Injury |
title_full |
Neuroprotective Effect of a Novel ATP-Synthase Inhibitor Bedaquiline in Cerebral Ischemia-Reperfusion Injury |
title_fullStr |
Neuroprotective Effect of a Novel ATP-Synthase Inhibitor Bedaquiline in Cerebral Ischemia-Reperfusion Injury |
title_full_unstemmed |
Neuroprotective Effect of a Novel ATP-Synthase Inhibitor Bedaquiline in Cerebral Ischemia-Reperfusion Injury |
title_sort |
neuroprotective effect of a novel atp-synthase inhibitor bedaquiline in cerebral ischemia-reperfusion injury |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-09-01 |
description |
Mitochondrial dysfunction during ischemic stroke ultimately manifests as ATP depletion. Mitochondrial ATP synthase upon loss of mitochondrial membrane potential during ischemia rapidly hydrolyses ATP and thus contributes to ATP depletion. Increasing evidence suggests that inhibition of ATP synthase limits ATP depletion and is protective against ischemic tissue damage. Bedaquiline (BDQ) is an anti-microbial agent, approved for clinical use, that inhibits ATP synthase of Mycobacteria; however recently it has been shown to act on mitochondrial ATP synthase, inhibiting both ATP synthesis and hydrolysis in low micromolar concentrations. In this study, we investigated whether preconditioning with BDQ can alleviate ischemia/reperfusion-induced brain injury in Wistar rats after middle cerebral artery occlusion-reperfusion and whether it affects mitochondrial functions. We found that BDQ was effective in limiting necrosis and neurological dysfunction during ischemia-reperfusion. BDQ also caused inhibition of ATPase activity, mild uncoupling of respiration, and stimulated mitochondrial respiration both in healthy and ischemic mitochondria. Mitochondrial calcium retention capacity was unaffected by BDQ preconditioning. We concluded that BDQ has neuroprotective properties associated with its action on mitochondrial respiration and ATPase activity. |
topic |
mitochondrial respiration bedaquiline stroke ischemia neuroprotection ATP synthase |
url |
https://www.mdpi.com/1422-0067/22/18/9717 |
work_keys_str_mv |
AT danieliusumbrasas neuroprotectiveeffectofanovelatpsynthaseinhibitorbedaquilineincerebralischemiareperfusioninjury AT odetaarandarcikaite neuroprotectiveeffectofanovelatpsynthaseinhibitorbedaquilineincerebralischemiareperfusioninjury AT ramunegrigaleviciute neuroprotectiveeffectofanovelatpsynthaseinhibitorbedaquilineincerebralischemiareperfusioninjury AT rimantasstakauskas neuroprotectiveeffectofanovelatpsynthaseinhibitorbedaquilineincerebralischemiareperfusioninjury AT vilmanteborutaite neuroprotectiveeffectofanovelatpsynthaseinhibitorbedaquilineincerebralischemiareperfusioninjury |
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1717366327922917376 |