Journal of Investigative Medicine最新文献

{"title":"Exosomes-mediated delivery of miR-486-3p alleviates neuroinflammation via SIRT2-mediated inhibition of mitophagy after subarachnoid hemorrhage.","authors":"Bin Sheng, Sen Gao, XiangXin Chen, Yang Liu, Niansheng Lai, Jin Dong, Jiaqing Sun, Yan Zhou, Lingyun Wu, Chun-Hua Hang, Wei Li","doi":"10.1136/svn-2024-003509","DOIUrl":"https://doi.org/10.1136/svn-2024-003509","url":null,"abstract":"<p><strong>Background: </strong>Neuroinflammation participates in the pathogenesis of subarachnoid haemorrhage (SAH); however, no effective treatments exist. MicroRNAs regulate several aspects of neuronal dysfunction. In a previous study, we found that exosomal miR-486-3p is involved in the pathophysiology of SAH. Targeted delivery of miR-486-3p without blood-brain barrier (BBB) restriction to alleviate SAH is a promising neuroinflammation approach.</p><p><strong>Methods: </strong>In this study, we modified exosomes (Exo) to form an RVG-miR-486-3p-Exo (Exo/miR) to achieve targeted delivery of miR-486-3p to the brain. Neurological scores, brain water content, BBB damage, flow cytometry and FJC staining were used to determine the effect of miR-486-3p on SAH. Western blot analysis, ELISA and RT-qPCR were used to measure relevant protein and mRNA levels. Immunofluorescence staining and laser confocal detection were used to measure the expression of mitochondria, lysosomes and autophagosomes, and transmission electron microscopy was used to observe the level of mitophagy in the brain tissue of mice after SAH.</p><p><strong>Results: </strong>Tail vein injection of Exo/miR improved targeting of miR-486-3p to the brains of SAH mice. The injection reduced levels of neuroinflammation-related factors by changing the phenotype switching of microglia, inhibiting the expression of sirtuin 2 (SIRT2) and enhancing mitophagy. miR-486-3p treatment alleviated neurobehavioral disorders, brain oedema, BBB damage and neurodegeneration. Further research found that the mechanism was achieved by regulating the acetylation level of peroxisome proliferator-activated receptor γ coactivator l alpha (PGC-1α) after SIRT2 enters the nucleus.</p><p><strong>Conclusion: </strong>Exo/miR treatment attenuates neuroinflammation after SAH by inhibiting SIRT2 expression and stimulating mitophagy, suggesting potential clinical applications.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles bearing serum amyloid A1 exacerbate neuroinflammation after intracerebral haemorrhage.","authors":"Huimin Zhu, Ningning Wang, Yingying Chang, Ying Zhang, Shihe Jiang, Xiaoping Ren, Meng Yuan, Haoxiao Chang, Wei-Na Jin","doi":"10.1136/svn-2024-003525","DOIUrl":"https://doi.org/10.1136/svn-2024-003525","url":null,"abstract":"<p><strong>Introduction: </strong>Intracerebral haemorrhage (ICH) elicits a robust inflammatory response, which significantly contributes to secondary brain damage. Extracellular vesicles (EVs) play a pivotal role in intercellular communication by transporting immune-regulatory proteins. However, the precise contribution of these EV-carried proteins to neuroinflammation following ICH remains elusive. Here, we identified proteins dysregulated in EVs and further studied the EVs-enriched Serum amyloid A 1 (SAA1) to understand its role in neuroinflammation and ICH injury.</p><p><strong>Methods: </strong>We used mass spectrometry to analyse the EV protein cargo isolated from plasma samples of 30 ICH patients and 30 healthy controls. To validate the function of the dysregulated protein SAA1, an ICH mouse model was conducted to assess the effects of SAA1 neutralisation on brain oedema, neurological function and infiltration of peripheral leucocytes.</p><p><strong>Results: </strong>49 upregulated proteins and 12 downregulated proteins were observed in EVs from ICH patients compared with controls. Notably, SAA1 demonstrated a significant increase in EVs associated with ICH. We observed that exogenous SAA1 stimulation led to an augmentation in the population of microglia and astrocytes, exacerbating neuroinflammation. Neutralising SAA1 with an anti-SAA1 monoclonal antibody (mAb) diminished the prevalence of proinflammatory microglia and the infiltration of peripheral leucocytes, which ameliorates brain oedema and neurological function in ICH mice.</p><p><strong>Conclusion: </strong>Our findings provide compelling evidence implicating EVs and their cargo proteins in ICH pathogenesis. SAA1 emerges as a potential therapeutic target for mitigating neuroinjury and neuroinflammation following ICH.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angioplasty and/or stenting following successful mechanical thrombectomy for intracranial atherosclerosis-related emergent large vessel occlusive stroke (ASSET): protocol of a multicentre randomised trial.","authors":"Geng Liao, Hongyu Qiao, Chengbo Dai, Weiwen Yi, Liang Zhang, Zai Liang, Li Li, Yuemei He, Zhenyu Zhang, Zhong Ji, Li'an Huang","doi":"10.1136/svn-2024-003435","DOIUrl":"https://doi.org/10.1136/svn-2024-003435","url":null,"abstract":"<p><strong>Rationale: </strong>The management of residual stenosis after mechanical thrombectomy in patients with intracranial atherosclerotic stenosis-related emerge large vessel occlusive (ICAS-LVO) stroke is still unclear question in clinical practice.</p><p><strong>Aim: </strong>To demonstrate the design of a clinical trial on emergency balloon angioplasty and/or stenting (BAS) combined with standard medical treatment (SMT) for residual stenosis of ICAS-LVO stroke patients with successful recanalisation.</p><p><strong>Design: </strong>ASSET is a multicentre, prospective, randomised, open-label, blinded end-point, controlled clinical trial designed (PROBE) by investigators. This trial evaluates the effectiveness and the safety of emergency BAS in combination with SMT compared with SMT alone in ICAS-LVO stroke patients with successful recanalisation (defined as expanded treatment in cerebral ischaemia grade of 2b50-3 and maintained for more than 20 min) and residual stenosis (defined as ≥50%) up to 24 hours after the onset of symptoms or the last known well.</p><p><strong>Outcome: </strong>The primary outcome assessed at 90 (±7) days after randomisation is the incidence of ischaemic stroke in the responsible vessel. Symptomatic intracranial haemorrhage within 24 (±3) hours is the primary safety outcome.</p><p><strong>Discussion: </strong>The ASSET trial is designed to provide strong evidence on the effectiveness and safety of emergency BAS to treat residual stenosis after successful recanalisation in patients with ICAS-LVO stroke.</p><p><strong>Trial registration number: </strong>ChiCTR2300079069.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142356519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central post-stroke pain: advances in clinical and preclinical research.","authors":"Xiqian Yuan, Siyuan Hu, Xiaochong Fan, Chao Jiang, Yan Xu, Ruochen Hao, Zili Xu, Yiyang Yu, Yousef Rastegar-Kashkooli, Leo Huang, Tom J Wang, Qiao Wang, Songxue Su, Limin Wang, Junyang Wang, Menglu Wang, Yun Tai Kim, Ujjal K Bhawal, Fushun Wang, Ting Zhao, Junmin Wang, Xuemei Chen, Jian Wang","doi":"10.1136/svn-2024-003418","DOIUrl":"https://doi.org/10.1136/svn-2024-003418","url":null,"abstract":"<p><p>Central poststroke pain (CPSP) is a medical complication that arises poststroke and significantly impacts the quality of life and social functioning of affected individuals. Despite ongoing research, the exact pathomechanisms of CPSP remain unclear, and practical treatments are still unavailable. Our review aims to systematically analyse current clinical and preclinical studies on CPSP, which is critical for identifying gaps in knowledge and guiding the development of effective therapies. The review will clarify the clinical characteristics, evaluation scales and contemporary therapeutic approaches for CPSP based on clinical investigations. It will particularly emphasise the CPSP model initiated by stroke, shedding light on its underlying mechanisms and evaluating treatments validated in preclinical studies. Furthermore, the review will not only highlight methodological limitations in animal trials but also offer specific recommendations to researchers to improve the quality of future investigations and guide the development of effective therapies. This review is expected to provide valuable insights into the current knowledge regarding CPSP and can serve as a guide for future research and clinical practice. The review will contribute to the scientific understanding of CPSP and help develop effective clinical interventions.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142356520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictors of malignant swelling in space-occupying cerebellar infarction.","authors":"Enayatullah Baki, Lea Baumgart, Victoria Kehl, Felix Hess, Andreas Wolfgang Wolff, Arthur Wagner, Moritz Roman Hernandez Petzsche, Tobias Boeckh-Behrens, Bernhard Hemmer, Bernhard Meyer, Jens Gempt, Silke Wunderlich","doi":"10.1136/svn-2024-003360","DOIUrl":"10.1136/svn-2024-003360","url":null,"abstract":"<p><strong>Background: </strong>Malignant swelling is a fatal complication that can occur abruptly in space-occupying cerebellar infarction. We aimed to establish markers that predict malignant swelling in cerebellar infarction.</p><p><strong>Methods: </strong>We retrospectively analysed data of stroke patients who were treated in our hospital between 2014 and 2020. Malignant swelling was defined as a mass effect in the posterior cranial fossa, accompanied by a decrease in consciousness due to compression of the brainstem and/or the development of obstructive hydrocephalus. Statistical analyses were performed on multiple variables to identify predictors of malignant swelling.</p><p><strong>Results: </strong>Among 7284 stroke patients, we identified 487 patients with an infarct in the cerebellum. 93 patients were suitable for analysis having space-occupying cerebellar infarction. 33 of 93 (35.5%) patients developed malignant swelling. Multivariable analysis revealed infarct volume as the main predictor being independently associated with the development of malignant swelling with a cut-off infarct volume of 38 cm³ being associated with a swelling rate of >50% (OR 32.0, p<0.001). Higher NIHSS (National Institutes of Health Stroke Scale) score on admission (median NIHSS 12 vs 4, OR 1.078; p=0.008) and the presence of additional brainstem infarction (51.5% vs 16.7%, OR 5.312; p=0.013) were associated with the development of malignant swelling in univariate analyses. 13 of 33 (39.4%) cases of malignant swellings occurred after more than 3 days.</p><p><strong>Conclusions: </strong>Infarct volume was the key significant predictor of malignant swelling in space-occupying cerebellar infarction. With many cases of malignant swelling occurring after more than 72 hours, we advocate prolonged neurological monitoring.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Why non-human primates are needed in stroke preclinical research.","authors":"Xiya Long, Jinsheng Zeng","doi":"10.1136/svn-2024-003504","DOIUrl":"https://doi.org/10.1136/svn-2024-003504","url":null,"abstract":"<p><p>Numerous seemingly promising cerebroprotectants previously validated in rodents almost all have failed in stroke clinical trials. The failure of clinical translation strikes an essential need to employ more ideal animal models in stroke research. Compared with the most commonly used rodent models of stroke, non-human primates (NHPs) are far more comparable to humans regarding brain anatomy, functionality and pathological features. The aim of this perspective was to summarise the advantages of NHPs stroke models over rodents, discuss the current limitations of NHPs models, and cast an outlook on the future development of NHPs in stroke preclinical research.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surgical timing and long-term outcomes in patients with severe haemorrhagic spinal cord cavernous malformations.","authors":"An Tian, Ziwei Cui, Jian Ren, Yeqing Ren, Ming Ye, Guilin Li, Chuan He, Xiaoyu Li, Gao Zeng, Peng Hu, Yongjie Ma, Jiaxing Yu, Jingwei Li, Lisong Bian, Fan Yang, Qianwen Li, Feng Ling, Tao Hong, Liyong Sun, Hongqi Zhang","doi":"10.1136/svn-2023-002745","DOIUrl":"10.1136/svn-2023-002745","url":null,"abstract":"<p><strong>Background: </strong>Surgical resection of the lesions remains the main treatment method for most symptomatic spinal cord cavernous malformations (SCCMs) to eliminate the occupation and associated subsequent lifelong haemorrhagic risk. However, the timing of surgical intervention remains controversial, especially for patients in the acute stage after severe haemorrhage.</p><p><strong>Methods: </strong>Patients diagnosed with SCCMs who were surgically treated between January 2002 and December 2021 were selected and retrospectively reviewed. The Modified McCormick Scale (MMS) was used to evaluate neurological and disability status. All medical information was reviewed, and all patients were followed up for at least 6 months.</p><p><strong>Results: </strong>A total of 279 patients were ultimately included. With regard to long-term outcomes, 110 (39.4%) patients improved, 159 (57.0%) remained unchanged and 10 (3.6%) worsened. For patients with an MMS score of 2-5 on admission, in univariate and multivariate analyses, a ≤6 weeks period between onset and surgery (adjusted OR 3.211, 95% CI 1.504 to 6.856, p=0.003) was a significant predictor of improved MMS. Among 69 patients who first presented with severe haemorrhage, undergoing surgery within 6 weeks of the onset of severe haemorrhage (adjusted OR 4.901, 95% CI 1.126 to 21.325, p=0.034) was significantly associated with improvement of MMS score.</p><p><strong>Conclusion: </strong>Surgical timing can influence the long-term outcome of SCCMs. For patients with symptomatic SCCMs, especially those with severe haemorrhage, early surgical intervention within 6 weeks can provide more benefit.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72211460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reperfusion and cytoprotective agents are a mutually beneficial pair in ischaemic stroke therapy: an overview of pathophysiology, pharmacological targets and candidate drugs focusing on excitotoxicity and free radical.","authors":"Xiumei Xu, Mingyu Chen, Dongya Zhu","doi":"10.1136/svn-2023-002671","DOIUrl":"10.1136/svn-2023-002671","url":null,"abstract":"<p><p>Stroke is the second-leading cause of death and the leading cause of disability in much of the world. In particular, China faces the greatest challenge from stroke, since the population is aged quickly. In decades of clinical trials, no neuroprotectant has had reproducible efficacy on primary clinical end points, because reperfusion is probably a necessity for neuroprotection to be clinically beneficial. Fortunately, the success of thrombolysis and endovascular thrombectomy has taken us into a reperfusion era of acute ischaemic stroke (AIS) therapy. Brain cytoprotective agents can prevent detrimental effects of ischaemia, and therefore 'freeze' ischaemic penumbra before reperfusion, extend the time window for reperfusion therapy. Because reperfusion often leads to reperfusion injury, including haemorrhagic transformation, brain oedema, infarct progression and neurological worsening, cytoprotective agents will enhance the efficacy and safety of reperfusion therapy by preventing or reducing reperfusion injuries. Therefore, reperfusion and cytoprotective agents are a mutually beneficial pair in AIS therapy. In this review, we outline critical pathophysiological events causing cell death within the penumbra after ischaemia or ischaemia/reperfusion in the acute phase of AIS, focusing on excitotoxicity and free radicals. We discuss key pharmacological targets for cytoprotective therapy and evaluate the recent advances of cytoprotective agents going through clinical trials, highlighting multitarget cytoprotective agents that intervene at multiple levels of the ischaemic and reperfusion cascade.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41216801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebral small vessel disease modifies outcomes after minimally invasive surgery for intracerebral haemorrhage.","authors":"Yunke Li, Sung-Min Cho, Radhika Avadhani, Hassan Ali, Yi Hao, Santosh B Murthy, Joshua N Goldstein, Fan Xia, Xin Hu, Natalie L Ullman, Issam Awad, Daniel Hanley, Wendy C Ziai","doi":"10.1136/svn-2023-002463","DOIUrl":"10.1136/svn-2023-002463","url":null,"abstract":"<p><strong>Background: </strong>Minimally invasive surgery (MIS) for spontaneous supratentorial intracerebral haemorrhage (ICH) is controversial but may be beneficial if end-of-treatment (EOT) haematoma volume is reduced to ≤15 mL. We explored whether MRI findings of cerebral small vessel disease (CSVD) modify the effect of MIS on long-term outcomes.</p><p><strong>Methods: </strong>Prespecified blinded subgroup analysis of 288 subjects with qualified imaging sequences from the phase 3 Minimally Invasive Surgery Plus Alteplase for Intracerebral Haemorrhage Evacuation (MISTIE) trial. We tested for heterogeneity in the effects of MIS and MIS+EOT volume ≤15 mL on the trial's primary outcome of good versus poor function at 1 year by the presence of single CSVD features and CSVD scores using multivariable models.</p><p><strong>Results: </strong>Of 499 patients enrolled in MISTIE III, 288 patients had MRI, 149 (51.7%) randomised to MIS and 139 (48.3%) to standard medical care (SMC). Median (IQR) ICH volume was 42 (30-53) mL. In the full MRI cohort, there was no statistically significant heterogeneity in the effects of MIS versus SMC on 1-year outcomes by any specific CSVD feature or by CSVD scores (all P_interaction >0.05). In 94 MIS patients with EOT ICH volume ≤15 mL, significant reduction in odds of poor outcome was found with cerebral amyloid angiopathy score <2 (OR, 0.14 (0.05-0.42); P_interaction=0.006), absence of lacunes (OR, 0.37 (0.18-0.80); P_interaction=0.02) and absence of severe white matter hyperintensities (WMHs) (OR, 0.22 (0.08-0.58); P_interaction=0.03).</p><p><strong>Conclusions: </strong>Following successful haematoma reduction by MIS, we found significantly lower odds of poor functional outcome with lower total burden of CSVD in addition to absence of lacunes and severe WMHs. CSVD features may have utility for prognostication and patient selection in clinical trials of MIS.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72211457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Src inhibition rescues FUNDC1-mediated neuronal mitophagy in ischaemic stroke.","authors":"Tianchi Tang, Li-Bin Hu, Chao Ding, Zhihua Zhang, Ning Wang, Tingting Wang, Hang Zhou, Siqi Xia, Linfeng Fan, Xiong-Jie Fu, Feng Yan, Xiangnan Zhang, Gao Chen, Jianru Li","doi":"10.1136/svn-2023-002606","DOIUrl":"10.1136/svn-2023-002606","url":null,"abstract":"<p><strong>Background: </strong>Ischaemic stroke triggers neuronal mitophagy, while the involvement of mitophagy receptors in ischaemia/reperfusion (I/R) injury-induced neuronal mitophagy remain not fully elucidated. Here, we aimed to investigate the involvement of mitophagy receptor FUN14 domain-containing 1 (FUNDC1) and its modulation in neuronal mitophagy induced by I/R injury.</p><p><strong>Methods: </strong>Wild-type and FUNDC1 knockout mice were generated to establish models of neuronal I/R injury, including transient middle cerebral artery occlusion (tMCAO) in vivo and oxygen glucose deprivation/reperfusion in vitro. Stroke outcomes of mice with two genotypes were assessed. Neuronal mitophagy was analysed both in vivo and in vitro. Activities of FUNDC1 and its regulator Src were evaluated. The impact of Src on FUNDC1-mediated mitophagy was assessed through administration of Src antagonist PP1.</p><p><strong>Results: </strong>To our surprise, FUNDC1 knockout mice subjected to tMCAO showed stroke outcomes comparable to those of their wild-type littermates. Although neuronal mitophagy could be activated by I/R injury, FUNDC1 deletion did not disrupt neuronal mitophagy. Transient activation of FUNDC1, represented by dephosphorylation of Tyr18, was detected in the early stages (within 3 hours) of neuronal I/R injury; however, phosphorylated Tyr18 reappeared and even surpassed baseline levels in later stages (after 6 hours), accompanied by a decrease in FUNDC1-light chain 3 interactions. Spontaneous inactivation of FUNDC1 was associated with Src activation, represented by phosphorylation of Tyr416, which changed in parallel with the level of phosphorylated FUNDC1 (Tyr18) during neuronal I/R injury. Finally, FUNDC1-mediated mitophagy in neurons under I/R conditions can be rescued by pharmacological inhibition of Src.</p><p><strong>Conclusions: </strong>FUNDC1 is inactivated by Src during the later stage (after 6 hours) of neuronal I/R injury, and rescue of FUNDC1-mediated mitophagy may serve as a potential therapeutic strategy for treating ischaemic stroke.</p>","PeriodicalId":48733,"journal":{"name":"Journal of Investigative Medicine","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41152568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}