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ATF5-Mediated Mitochondrial Unfolded Protein Response (UPRmt) Protects Neurons Against Oxygen-Glucose Deprivation and Cerebral Ischemia.
An, Hong; Zhou, Bing; Hayakawa, Kazuhide; Durán Laforet, Violeta; Park, Ji-Hyun; Nakamura, Yoshihiko; Mandeville, Emiri T; Liu, Ning; Guo, Shuzhen; Yu, Zhanyang; Shi, Jingfei; Wu, Di; Li, Wenlu; Lo, Eng H; Ji, Xunming.
Affiliation
  • An H; Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University, China (H.A.).
  • Zhou B; Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (H.A., K.H., V.D.L., J.-H.P., Y.N., E.T.M., S.G., Z.Y., J.S., D.W., W.L., E.H.L.).
  • Hayakawa K; Cerebrovascular and Neuroscience Research Institute, Xuanwu Hospital, Capital Medical University, Beijing, China (H.A., J.S., D.W., X.J.).
  • Durán Laforet V; Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, China (B.Z.).
  • Park JH; Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (H.A., K.H., V.D.L., J.-H.P., Y.N., E.T.M., S.G., Z.Y., J.S., D.W., W.L., E.H.L.).
  • Nakamura Y; Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (H.A., K.H., V.D.L., J.-H.P., Y.N., E.T.M., S.G., Z.Y., J.S., D.W., W.L., E.H.L.).
  • Mandeville ET; Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Hospital 12 de Octubre, Spain (V.D.L.).
  • Liu N; Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (H.A., K.H., V.D.L., J.-H.P., Y.N., E.T.M., S.G., Z.Y., J.S., D.W., W.L., E.H.L.).
  • Guo S; Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (H.A., K.H., V.D.L., J.-H.P., Y.N., E.T.M., S.G., Z.Y., J.S., D.W., W.L., E.H.L.).
  • Yu Z; Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Japan (Y.N.).
  • Shi J; Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (H.A., K.H., V.D.L., J.-H.P., Y.N., E.T.M., S.G., Z.Y., J.S., D.W., W.L., E.H.L.).
  • Wu D; Clinical Neuroscience Research Center, Department of Neurosurgery and Neurology, Tulane University School of Medicine, New Orleans, LA (N.L.).
  • Li W; Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (H.A., K.H., V.D.L., J.-H.P., Y.N., E.T.M., S.G., Z.Y., J.S., D.W., W.L., E.H.L.).
  • Lo EH; Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (H.A., K.H., V.D.L., J.-H.P., Y.N., E.T.M., S.G., Z.Y., J.S., D.W., W.L., E.H.L.).
  • Ji X; Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (H.A., K.H., V.D.L., J.-H.P., Y.N., E.T.M., S.G., Z.Y., J.S., D.W., W.L., E.H.L.).
Stroke ; 55(7): 1904-1913, 2024 Jul.
Article in En | MEDLINE | ID: mdl-38913800
ABSTRACT

BACKGROUND:

The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPRmt may be a potential therapeutic target for ischemic stroke.

METHODS:

We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPRmt. We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro.

RESULTS:

Inducing UPRmt with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPRmt could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPRmt with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPRmt in vivo, which reduced infarction and improved neurological outcomes.

CONCLUSIONS:

These findings suggest that the UPRmt is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPRmt mechanism may provide a new therapeutic avenue for ischemic stroke.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Ischemia / Unfolded Protein Response / Glucose / Mitochondria / Neurons Limits: Animals Language: En Journal: Stroke Year: 2024 Type: Article
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Ischemia / Unfolded Protein Response / Glucose / Mitochondria / Neurons Limits: Animals Language: En Journal: Stroke Year: 2024 Type: Article