Mitochondria dysfunction, a potential cytoprotection target against ischemia-reperfusion injury in a mouse stroke model

被引:2
作者
Ong, Elodie [1 ,2 ]
Clottes, Paul [1 ,2 ]
Leon, Christelle [2 ]
Guedouari, Hala [2 ]
Gallo-Bona, Noelle [2 ]
Lo Grasso, Megane [2 ]
Motter, Lucas [2 ]
Bolbos, Radu [3 ]
Ovize, Michel [1 ,2 ]
Nighogossian, Norbert [1 ,2 ]
Wiart, Marlene [2 ,4 ]
Paillard, Melanie [2 ]
机构
[1] Hosp Civils Lyon, Stroke Dept, F-69500 Bron, France
[2] Univ Lyon, Univ Claude Bernard Lyon 1, Lab CarMeN IRIS Team, INSERM,INRA, F-69500 Bron, France
[3] CERMEP Imagerie Vivant, F-69500 Bron, France
[4] CNRS, F-69100 Villeurbanne, France
关键词
Cerebral ischemia-reperfusion; PTP; Mitochondrial respiration; Therapeutic; FOCAL CEREBRAL-ISCHEMIA; PERMEABILITY TRANSITION; CYCLOSPORINE-A; CELL-DEATH; MRI; THERAPY; DAMAGE; EDEMA; HEART;
D O I
10.1016/j.neurot.2025.e00549
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
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页数:9
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