A sphingosine kinase 2-mimicking TAT-peptide protects neurons against ischemia-reperfusion injury by activating BNIP3-mediated mitophagy

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dc.check.date2021-09-20
dc.check.infoAccess to this article is restricted until 12 months after publication by request of the publisher.en
dc.contributor.authorChen, Jia-Li
dc.contributor.authorWang, Xin-Xin
dc.contributor.authorChen, Lei
dc.contributor.authorTang, Jie
dc.contributor.authorXia, Yun-Fei
dc.contributor.authorQian, Ke
dc.contributor.authorQin, Zheng-Hong
dc.contributor.authorWaeber, Christian
dc.contributor.authorSheng, Rui
dc.contributor.funderNational Natural Science Foundation of Chinaen
dc.contributor.funderJiangsu Provincial Key Laboratory of Neuropsychiatric Diseases , Chinaen
dc.contributor.funderJiangsu Higher Education Institutes, Chinaen
dc.date.accessioned2020-10-16T07:35:41Z
dc.date.available2020-10-16T07:35:41Z
dc.date.issued2020-09-20
dc.date.updated2020-10-14T11:59:58Z
dc.description.abstractWe have previously shown that sphingosine kinase 2 (SPK2) interacts with Bcl-2 via its BH3 domain, activating autophagy by inducing the dissociation of Beclin-1/Bcl-2 complexes, and that a TAT-SPK2 peptide containing the BH3 domain of SPK2 protects neurons against ischemic injury. The goals of the present study were to establish the functional significance of these findings, by testing whether TAT-SPK2 was effective in a mouse model of ischemic stroke, and to explore potential underlying mechanisms. Mice were administered with TAT-SPK2 by intraperitoneal injection before or after transient middle cerebral artery occlusion (tMCAO). Infarct volume, neurological deficit and brain water content were assessed 24 h after reperfusion. Mitophagy inhibitor Mdivi-1 and BNIP3 siRNAs were used to examine the involvement of BNIP3-dependent mitophagy in the neuroprotection of TAT-SPK2. Mitophagy was quantified by immunoblotting, immunofluorescence and electron microscopy. The interaction between TAT-SPK2 and Bcl-2, Bcl-2 and BNIP3 was detected by co-immunoprecipitation. In the tMCAO model, pre-treatment with TAT-SPK2 significantly reduced infarct volume, improved neurological function and decreased brain edema. Neuroprotection by TAT-SPK2 was still seen when the peptide was administered 3 h after reperfusion. TAT-SPK2 also significantly improved functional recovery and reduced long-term brain atrophy of the ischemic hemisphere 30 days after administration. Our studies further showed that TAT-SPK2 directly binds to Bcl-2 and disrupts Bcl-2/Beclin-1 or Bcl-2/BNIP3 complexes to induce mitophagy. These results suggest that TAT-SPK2 protects neurons against ischemia reperfusion injury by activating BNIP3-mediated mitophagy. Agents exploiting this molecular mechanism are potential candidates for the treatment of ischemic stroke.en
dc.description.sponsorshipNational Natural Science Foundation of China (Nos. 81973315; 81673421; 81373402); Jiangsu Provincial Key Laboratory of Neuropsychiatric Diseases (BM2013003); Jiangsu Higher Education Institutes (Priority Academic Program Development (PAPD))en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationChen, J.-L., Wang, X.-X., Chen, L., Tang, J., Xia, Y.-F., Qian, K., Qin, Z.-H., Waeber, C. and Sheng, R. (2020) 'A sphingosine kinase 2-mimicking TAT-peptide protects neurons against ischemia-reperfusion injury by activating BNIP3-mediated mitophagy', Neuropharmacology, 181, 108326 (14pp). doi: 10.1016/j.neuropharm.2020.108326en
dc.identifier.doi10.1016/j.neuropharm.2020.108326en
dc.identifier.endpage14en
dc.identifier.issn1873-7064
dc.identifier.issn0028-3908
dc.identifier.journaltitleNeuropharmacologyen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/10657
dc.identifier.volume181en
dc.language.isoenen
dc.publisherElsevier B.V.en
dc.rights© 2020, Elsevier Ltd. All rights reserved. This manuscript version is made available under the CC BY-NC-ND 4.0 license.en
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectTAT-SPK2 peptideen
dc.subjectSphingosine kinase 2en
dc.subjectCerebral ischemiaen
dc.subjectMitophagyen
dc.subjectAutophagyen
dc.subjectBNIP3en
dc.titleA sphingosine kinase 2-mimicking TAT-peptide protects neurons against ischemia-reperfusion injury by activating BNIP3-mediated mitophagyen
dc.typeArticle (peer-reviewed)en
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