Mitochondria dysfunction, a potential cytoprotection target against ischemia-reperfusion injury in a mouse stroke model
More than 50 % of patients undergoing mechanical thrombectomy (MT) for ischemic stroke have a poor functional outcome despite timely and successful angiographic reperfusion, highlighting the need for adjunctive treatments to reperfusion therapy. Mitochondria are key regulators of cell fate, by cont...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-03-01
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| Series: | Neurotherapeutics |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878747925000273 |
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| author | Elodie Ong Paul Clottes Christelle Leon Hala Guedouari Noelle Gallo-Bona Megane Lo Grasso Lucas Motter Radu Bolbos Michel Ovize Norbert Nighogossian Marlene Wiart Melanie Paillard |
| author_facet | Elodie Ong Paul Clottes Christelle Leon Hala Guedouari Noelle Gallo-Bona Megane Lo Grasso Lucas Motter Radu Bolbos Michel Ovize Norbert Nighogossian Marlene Wiart Melanie Paillard |
| author_sort | Elodie Ong |
| collection | DOAJ |
| description | More than 50 % of patients undergoing mechanical thrombectomy (MT) for ischemic stroke have a poor functional outcome despite timely and successful angiographic reperfusion, highlighting the need for adjunctive treatments to reperfusion therapy. Mitochondria are key regulators of cell fate, by controlling cell bioenergetics via oxidative phosphorylation (OXPHOS) and cell death through the mitochondrial permeability transition pore (mPTP). Whether these two main mitochondrial functions are altered by reperfusion and could represent a new cytoprotective approach remains to be elucidated in mice. Swiss male mice underwent either permanent or transient middle cerebral artery occlusion (pMCAO or tMCAO), with neuroscore evaluation and multimodal imaging. The area at risk of necrosis was evaluated by per-occlusion dynamic contrast-enhanced ultrasound. Final infarct size was assessed at day 1 by MRI. Cortical mitochondrial isolation was subsequently performed to assess mPTP sensitivity by calcium retention capacity (CRC) and OXPHOS. A cytoprotective treatment targeting mitochondria, ciclosporine A (CsA), was tested in tMCAO, to mimick the clinical situation of patients treated with MT. Reperfusion after 60 min of ischemia improves neuroscores but does not significantly reduce infarct size or mitochondrial dysfunction compared to permanent ischemia. CsA treatment at reperfusion mitigates stroke outcome, decreases final infarct size and improves mitochondrial CRC and OXPHOS. Mitochondrial dysfunctions, i.e. reduced mPTP sensitivity and decreased oxygen consumption rates, were observed in pMCAO and tMCAO regardless of the reperfusion status. CsA improved mitochondrial functions when injected at reperfusion. These suggest that both mPTP opening and OXPHOS alterations are thus early but reversible hallmarks of cerebral ischemia/reperfusion. |
| format | Article |
| id | doaj-art-37f6e14431864c079902f4d368784f0b |
| institution | OA Journals |
| issn | 1878-7479 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurotherapeutics |
| spelling | doaj-art-37f6e14431864c079902f4d368784f0b2025-08-20T02:00:59ZengElsevierNeurotherapeutics1878-74792025-03-01222e0054910.1016/j.neurot.2025.e00549Mitochondria dysfunction, a potential cytoprotection target against ischemia-reperfusion injury in a mouse stroke modelElodie Ong0Paul Clottes1Christelle Leon2Hala Guedouari3Noelle Gallo-Bona4Megane Lo Grasso5Lucas Motter6Radu Bolbos7Michel Ovize8Norbert Nighogossian9Marlene Wiart10Melanie Paillard11Stroke Department, Hospices Civils de Lyon, 69500 Bron, France; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500 Bron, FranceStroke Department, Hospices Civils de Lyon, 69500 Bron, France; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500 Bron, FranceLaboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500 Bron, FranceLaboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500 Bron, FranceLaboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500 Bron, FranceLaboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500 Bron, FranceLaboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500 Bron, FranceCERMEP-Imagerie du Vivant, 69500 Bron, FranceStroke Department, Hospices Civils de Lyon, 69500 Bron, France; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500 Bron, FranceStroke Department, Hospices Civils de Lyon, 69500 Bron, France; Laboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500 Bron, FranceLaboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500 Bron, France; CNRS, 69100 Villeurbanne, FranceLaboratoire CarMeN - IRIS Team, INSERM, INRA, Université Claude Bernard Lyon-1, Univ-Lyon, 69500 Bron, France; Corresponding author.More than 50 % of patients undergoing mechanical thrombectomy (MT) for ischemic stroke have a poor functional outcome despite timely and successful angiographic reperfusion, highlighting the need for adjunctive treatments to reperfusion therapy. Mitochondria are key regulators of cell fate, by controlling cell bioenergetics via oxidative phosphorylation (OXPHOS) and cell death through the mitochondrial permeability transition pore (mPTP). Whether these two main mitochondrial functions are altered by reperfusion and could represent a new cytoprotective approach remains to be elucidated in mice. Swiss male mice underwent either permanent or transient middle cerebral artery occlusion (pMCAO or tMCAO), with neuroscore evaluation and multimodal imaging. The area at risk of necrosis was evaluated by per-occlusion dynamic contrast-enhanced ultrasound. Final infarct size was assessed at day 1 by MRI. Cortical mitochondrial isolation was subsequently performed to assess mPTP sensitivity by calcium retention capacity (CRC) and OXPHOS. A cytoprotective treatment targeting mitochondria, ciclosporine A (CsA), was tested in tMCAO, to mimick the clinical situation of patients treated with MT. Reperfusion after 60 min of ischemia improves neuroscores but does not significantly reduce infarct size or mitochondrial dysfunction compared to permanent ischemia. CsA treatment at reperfusion mitigates stroke outcome, decreases final infarct size and improves mitochondrial CRC and OXPHOS. Mitochondrial dysfunctions, i.e. reduced mPTP sensitivity and decreased oxygen consumption rates, were observed in pMCAO and tMCAO regardless of the reperfusion status. CsA improved mitochondrial functions when injected at reperfusion. These suggest that both mPTP opening and OXPHOS alterations are thus early but reversible hallmarks of cerebral ischemia/reperfusion.http://www.sciencedirect.com/science/article/pii/S1878747925000273Cerebral ischemia-reperfusionPTPMitochondrial respirationTherapeutic |
| spellingShingle | Elodie Ong Paul Clottes Christelle Leon Hala Guedouari Noelle Gallo-Bona Megane Lo Grasso Lucas Motter Radu Bolbos Michel Ovize Norbert Nighogossian Marlene Wiart Melanie Paillard Mitochondria dysfunction, a potential cytoprotection target against ischemia-reperfusion injury in a mouse stroke model Neurotherapeutics Cerebral ischemia-reperfusion PTP Mitochondrial respiration Therapeutic |
| title | Mitochondria dysfunction, a potential cytoprotection target against ischemia-reperfusion injury in a mouse stroke model |
| title_full | Mitochondria dysfunction, a potential cytoprotection target against ischemia-reperfusion injury in a mouse stroke model |
| title_fullStr | Mitochondria dysfunction, a potential cytoprotection target against ischemia-reperfusion injury in a mouse stroke model |
| title_full_unstemmed | Mitochondria dysfunction, a potential cytoprotection target against ischemia-reperfusion injury in a mouse stroke model |
| title_short | Mitochondria dysfunction, a potential cytoprotection target against ischemia-reperfusion injury in a mouse stroke model |
| title_sort | mitochondria dysfunction a potential cytoprotection target against ischemia reperfusion injury in a mouse stroke model |
| topic | Cerebral ischemia-reperfusion PTP Mitochondrial respiration Therapeutic |
| url | http://www.sciencedirect.com/science/article/pii/S1878747925000273 |
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