Cargando…
Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats
Mitophagy alleviates neuronal damage after cerebral ischemia by selectively removing dysfunctional mitochondria. Phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy is the most well-known type of mitophagy. However, little is known about the role of PINK...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213752/ https://www.ncbi.nlm.nih.gov/pubmed/34145219 http://dx.doi.org/10.1038/s41419-021-03900-8 |
_version_ | 1783709919417991168 |
---|---|
author | Wen, Haixia Li, Luxi Zhan, Lixuan Zuo, Yunyan Li, Kongping Qiu, Meiqian Li, Heying Sun, Weiwen Xu, En |
author_facet | Wen, Haixia Li, Luxi Zhan, Lixuan Zuo, Yunyan Li, Kongping Qiu, Meiqian Li, Heying Sun, Weiwen Xu, En |
author_sort | Wen, Haixia |
collection | PubMed |
description | Mitophagy alleviates neuronal damage after cerebral ischemia by selectively removing dysfunctional mitochondria. Phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy is the most well-known type of mitophagy. However, little is known about the role of PINK1/Parkin-mediated mitophagy in ischemic tolerance induced by hypoxic postconditioning (HPC) with 8% O(2) against transient global cerebral ischemia (tGCI). Hence, we aimed to test the hypothesis that HPC-mediated PINK1/Parkin-induced mitochondrial ubiquitination and promotes mitophagy, thus exerting neuroprotection in the hippocampal CA1 subregion against tGCI. We found that mitochondrial clearance was disturbed at the late phase of reperfusion after tGCI, which was reversed by HPC, as evidenced by the reduction of the translocase of outer mitochondrial membrane 20 homologs (TOMM20), translocase of inner mitochondrial membrane 23 (TIMM23) and heat shock protein 60 (HSP60) in CA1 after HPC. In addition, HPC further increased the ratio of LC3II/I in mitochondrial fraction and promoted the formation of mitophagosomes in CA1 neurons after tGCI. The administration of lysosome inhibitor chloroquine (CQ) intraperitoneally or mitophagy inhibitor (Mdivi-1) intracerebroventricularly abrogated HPC-induced mitochondrial turnover and neuroprotection in CA1 after tGCI. We also found that HPC activated PINK1/Parkin pathway after tGCI, as shown by the augment of mitochondrial PINK1 and Parkin and the promotion of mitochondrial ubiquitination in CA1. In addition, PINK1 or Parkin knockdown with small-interfering RNA (siRNA) suppressed the activation of PINK1/Parkin pathway and hampered mitochondrial clearance and attenuated neuroprotection induced by HPC, whereas PINK1 overexpression promoted PINK1/Parkin-mediated mitophagy and ameliorated neuronal damage in CA1 after tGCI. Taken together, the new finding in this study is that HPC-induced neuroprotection against tGCI through promoting mitophagy mediated by PINK1/Parkin-dependent pathway. |
format | Online Article Text |
id | pubmed-8213752 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82137522021-07-01 Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats Wen, Haixia Li, Luxi Zhan, Lixuan Zuo, Yunyan Li, Kongping Qiu, Meiqian Li, Heying Sun, Weiwen Xu, En Cell Death Dis Article Mitophagy alleviates neuronal damage after cerebral ischemia by selectively removing dysfunctional mitochondria. Phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy is the most well-known type of mitophagy. However, little is known about the role of PINK1/Parkin-mediated mitophagy in ischemic tolerance induced by hypoxic postconditioning (HPC) with 8% O(2) against transient global cerebral ischemia (tGCI). Hence, we aimed to test the hypothesis that HPC-mediated PINK1/Parkin-induced mitochondrial ubiquitination and promotes mitophagy, thus exerting neuroprotection in the hippocampal CA1 subregion against tGCI. We found that mitochondrial clearance was disturbed at the late phase of reperfusion after tGCI, which was reversed by HPC, as evidenced by the reduction of the translocase of outer mitochondrial membrane 20 homologs (TOMM20), translocase of inner mitochondrial membrane 23 (TIMM23) and heat shock protein 60 (HSP60) in CA1 after HPC. In addition, HPC further increased the ratio of LC3II/I in mitochondrial fraction and promoted the formation of mitophagosomes in CA1 neurons after tGCI. The administration of lysosome inhibitor chloroquine (CQ) intraperitoneally or mitophagy inhibitor (Mdivi-1) intracerebroventricularly abrogated HPC-induced mitochondrial turnover and neuroprotection in CA1 after tGCI. We also found that HPC activated PINK1/Parkin pathway after tGCI, as shown by the augment of mitochondrial PINK1 and Parkin and the promotion of mitochondrial ubiquitination in CA1. In addition, PINK1 or Parkin knockdown with small-interfering RNA (siRNA) suppressed the activation of PINK1/Parkin pathway and hampered mitochondrial clearance and attenuated neuroprotection induced by HPC, whereas PINK1 overexpression promoted PINK1/Parkin-mediated mitophagy and ameliorated neuronal damage in CA1 after tGCI. Taken together, the new finding in this study is that HPC-induced neuroprotection against tGCI through promoting mitophagy mediated by PINK1/Parkin-dependent pathway. Nature Publishing Group UK 2021-06-18 /pmc/articles/PMC8213752/ /pubmed/34145219 http://dx.doi.org/10.1038/s41419-021-03900-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Wen, Haixia Li, Luxi Zhan, Lixuan Zuo, Yunyan Li, Kongping Qiu, Meiqian Li, Heying Sun, Weiwen Xu, En Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats |
title | Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats |
title_full | Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats |
title_fullStr | Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats |
title_full_unstemmed | Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats |
title_short | Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats |
title_sort | hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via pink1/parkin-induced mitochondrial ubiquitination in adult rats |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213752/ https://www.ncbi.nlm.nih.gov/pubmed/34145219 http://dx.doi.org/10.1038/s41419-021-03900-8 |
work_keys_str_mv | AT wenhaixia hypoxicpostconditioningpromotesmitophagyagainsttransientglobalcerebralischemiaviapink1parkininducedmitochondrialubiquitinationinadultrats AT liluxi hypoxicpostconditioningpromotesmitophagyagainsttransientglobalcerebralischemiaviapink1parkininducedmitochondrialubiquitinationinadultrats AT zhanlixuan hypoxicpostconditioningpromotesmitophagyagainsttransientglobalcerebralischemiaviapink1parkininducedmitochondrialubiquitinationinadultrats AT zuoyunyan hypoxicpostconditioningpromotesmitophagyagainsttransientglobalcerebralischemiaviapink1parkininducedmitochondrialubiquitinationinadultrats AT likongping hypoxicpostconditioningpromotesmitophagyagainsttransientglobalcerebralischemiaviapink1parkininducedmitochondrialubiquitinationinadultrats AT qiumeiqian hypoxicpostconditioningpromotesmitophagyagainsttransientglobalcerebralischemiaviapink1parkininducedmitochondrialubiquitinationinadultrats AT liheying hypoxicpostconditioningpromotesmitophagyagainsttransientglobalcerebralischemiaviapink1parkininducedmitochondrialubiquitinationinadultrats AT sunweiwen hypoxicpostconditioningpromotesmitophagyagainsttransientglobalcerebralischemiaviapink1parkininducedmitochondrialubiquitinationinadultrats AT xuen hypoxicpostconditioningpromotesmitophagyagainsttransientglobalcerebralischemiaviapink1parkininducedmitochondrialubiquitinationinadultrats |