The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance
Abstract Mitochondrial quality control is crucial for the homeostasis of the mitochondrial network. The balance between mitophagy and biogenesis is needed to reduce cerebral ischemia-induced cell death. Ischemic preconditioning (IPC) represents an adaptation mechanism of CNS that increases tolerance...
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07339-z |
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| author | Maria Josè Sisalli Elena D’Apolito Ornella Cuomo Giovanna Lombardi Michele Tufano Lucio Annunziato Antonella Scorziello |
| author_facet | Maria Josè Sisalli Elena D’Apolito Ornella Cuomo Giovanna Lombardi Michele Tufano Lucio Annunziato Antonella Scorziello |
| author_sort | Maria Josè Sisalli |
| collection | DOAJ |
| description | Abstract Mitochondrial quality control is crucial for the homeostasis of the mitochondrial network. The balance between mitophagy and biogenesis is needed to reduce cerebral ischemia-induced cell death. Ischemic preconditioning (IPC) represents an adaptation mechanism of CNS that increases tolerance to lethal cerebral ischemia. It has been demonstrated that hypoxia-induced Seven in absentia Homolog 2 (Siah2) E3-ligase activation influences mitochondrial dynamics promoting the degradation of mitochondrial proteins. Therefore, in the present study, we investigated the role of Siah2 in the IPC-induced neuroprotection in in vitro and in vivo models of IPC. To this aim, cortical neurons were exposed to 30-min oxygen and glucose deprivation (OGD, sublethal insult) followed by 3 h OGD plus reoxygenation (lethal insult). Our results revealed that the mitochondrial depolarization induced by hypoxia activates Siah2 at the mitochondrial level and increases LC3-II protein expression, a marker of mitophagy, an effect counteracted by the reoxygenation phase. By contrast, hypoxia reduced the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a marker of mitochondrial biogenesis, whereas its expression was increased after reoxygenation thus improving mitochondrial membrane potential, mitochondrial calcium content, and mitochondrial morphology, hence leading to neuroprotection in IPC. Furthermore, Siah2 silencing confirmed these results. Collectively, these findings indicate that the balance between mitophagy and mitochondrial biogenesis, due to the activation of the Siah2-E3-ligase, might play a role in IPC-induced neuroprotection. |
| format | Article |
| id | doaj-art-143fa36453e04cf28eee74f32daa4c85 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-143fa36453e04cf28eee74f32daa4c852025-02-02T12:44:50ZengNature Publishing GroupCell Death and Disease2041-48892025-01-011611910.1038/s41419-025-07339-zThe E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain toleranceMaria Josè Sisalli0Elena D’Apolito1Ornella Cuomo2Giovanna Lombardi3Michele Tufano4Lucio Annunziato5Antonella Scorziello6Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples “Federico II”Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples “Federico II”Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples “Federico II”Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples “Federico II”Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples “Federico II”IRCCS Synlab SDN S.p.A, Via Gianturco 113Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples “Federico II”Abstract Mitochondrial quality control is crucial for the homeostasis of the mitochondrial network. The balance between mitophagy and biogenesis is needed to reduce cerebral ischemia-induced cell death. Ischemic preconditioning (IPC) represents an adaptation mechanism of CNS that increases tolerance to lethal cerebral ischemia. It has been demonstrated that hypoxia-induced Seven in absentia Homolog 2 (Siah2) E3-ligase activation influences mitochondrial dynamics promoting the degradation of mitochondrial proteins. Therefore, in the present study, we investigated the role of Siah2 in the IPC-induced neuroprotection in in vitro and in vivo models of IPC. To this aim, cortical neurons were exposed to 30-min oxygen and glucose deprivation (OGD, sublethal insult) followed by 3 h OGD plus reoxygenation (lethal insult). Our results revealed that the mitochondrial depolarization induced by hypoxia activates Siah2 at the mitochondrial level and increases LC3-II protein expression, a marker of mitophagy, an effect counteracted by the reoxygenation phase. By contrast, hypoxia reduced the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a marker of mitochondrial biogenesis, whereas its expression was increased after reoxygenation thus improving mitochondrial membrane potential, mitochondrial calcium content, and mitochondrial morphology, hence leading to neuroprotection in IPC. Furthermore, Siah2 silencing confirmed these results. Collectively, these findings indicate that the balance between mitophagy and mitochondrial biogenesis, due to the activation of the Siah2-E3-ligase, might play a role in IPC-induced neuroprotection.https://doi.org/10.1038/s41419-025-07339-z |
| spellingShingle | Maria Josè Sisalli Elena D’Apolito Ornella Cuomo Giovanna Lombardi Michele Tufano Lucio Annunziato Antonella Scorziello The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance Cell Death and Disease |
| title | The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance |
| title_full | The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance |
| title_fullStr | The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance |
| title_full_unstemmed | The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance |
| title_short | The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance |
| title_sort | e3 ligase siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance |
| url | https://doi.org/10.1038/s41419-025-07339-z |
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