{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:06:55Z","timestamp":1790770015491,"version":"4.1.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T00:00:00Z","timestamp":1628812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T00:00:00Z","timestamp":1628812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002632","name":"Hallym University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002632","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Education","award":["2020R1l1A3070726"],"award-info":[{"award-number":["2020R1l1A3070726"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Decreased mitochondrial membrane potential in cerebrospinal fluid (CSF) was observed in patients with subarachnoid hemorrhage (SAH) accompanied by delayed cerebral ischemia (DCI). However, whether abnormal mechanisms of mitochondria are associated with the development of DCI has not been reported yet. Under cerebral ischemia, mitochondria can transfer into the extracellular space. Mitochondrial dysfunction can aggravate neurologic complications. The objective of this study was to evaluate whether mitochondrial dysfunction might be associated with autophagy and mitophagy in CSF cells to provide possible insight into DCI pathogenesis. CSF samples were collected from 56 SAH patients (DCI, n\u2009=\u200921; and non-DCI, n\u2009=\u200935). We analyzed CSF cells using autophagy and mitophagy markers (DAPK1, BNIP3L, BAX, PINK1, ULK1, and NDP52) via qRT-PCR and western blotting of proteins (BECN1, LC3, and p62). Confocal microscopy and immunogold staining were performed to demonstrate the differentially expression of markers within dysfunctional mitochondria. Significant induction of autophagic flux with accumulation of autophagic vacuoles, increased expression of BECN1, LC3-II, and p62 degradation were observed during DCI. Compared to non-DCI patients, DCI patients showed significantly increased mRNA expression levels (2\n                    <jats:sup>\u2212\u0394Ct<\/jats:sup>\n                    ) of DAPK1, BNIP3L, and PINK1, but not BAX, ULK1, or NDP52. Multivariable logistic regression analysis revealed that Hunt and Hess grade\u2009\u2265\u2009IV (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.023), DAPK1 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.003), and BNIP3L (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.039) were related to DCI. Increased mitochondrial dysfunction associated with autophagy and mitophagy could play an important role in DCI pathogenesis.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-96092-2","type":"journal-article","created":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T06:03:06Z","timestamp":1628834586000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Mitochondrial dysfunction associated with autophagy and mitophagy in cerebrospinal fluid cells of patients with delayed cerebral ischemia following subarachnoid hemorrhage"],"prefix":"10.1038","volume":"11","author":[{"given":"Dong Hyuk","family":"Youn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngmi","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bong Jun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myeong Seon","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jooeun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Kook","family":"Rhim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heung Cheol","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Pyeong","family":"Jeon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,13]]},"reference":[{"key":"96092_CR1","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1186\/s13054-015-1036-0","volume":"19","author":"H Lantigua","year":"2015","unstructured":"Lantigua, H. et al. Subarachnoid hemorrhage: Who dies, and why?. Crit. Care 19, 309 (2015).","journal-title":"Crit. Care"},{"key":"96092_CR2","doi-asserted-by":"publisher","first-page":"2391","DOI":"10.1161\/STROKEAHA.110.589275","volume":"41","author":"MD Vergouwen","year":"2010","unstructured":"Vergouwen, M. D. et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: Proposal of a multidisciplinary research group. Stroke 41, 2391\u20132395 (2010).","journal-title":"Stroke"},{"key":"96092_CR3","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1093\/bja\/aes264","volume":"109","author":"MJ Rowland","year":"2012","unstructured":"Rowland, M. J. et al. Delayed cerebral ischaemia after subarachnoid haemorrhage: Looking beyond vasospasm. Br. J. Anaesth. 109, 315\u2013329 (2012).","journal-title":"Br. J. Anaesth."},{"key":"96092_CR4","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.2174\/1570159X15666171123200646","volume":"16","author":"WM Ho","year":"2018","unstructured":"Ho, W. M. et al. Autophagy after subarachnoid hemorrhage: Can cell death be good?. Curr. Neuropharmacol. 16, 1314\u20131319 (2018).","journal-title":"Curr. Neuropharmacol."},{"key":"96092_CR5","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.brainres.2009.06.028","volume":"1287","author":"JY Lee","year":"2009","unstructured":"Lee, J. Y. et al. Activated autophagy pathway in experimental subarachnoid hemorrhage. Brain Res. 1287, 126\u2013135 (2009).","journal-title":"Brain Res."},{"key":"96092_CR6","doi-asserted-by":"publisher","first-page":"e0132499","DOI":"10.1371\/journal.pone.0132499","volume":"10","author":"W Wu","year":"2015","unstructured":"Wu, W. et al. Pink1-parkin-mediated mitophagy protects mitochondrial integrity and prevents metabolic stress-induced endothelial injury. PLoS ONE 10, e0132499 (2015).","journal-title":"PLoS ONE"},{"key":"96092_CR7","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/nature18928","volume":"535","author":"K Hayakawa","year":"2016","unstructured":"Hayakawa, K. et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature 535, 551\u2013555 (2016).","journal-title":"Nature"},{"key":"96092_CR8","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1186\/s12929-018-0487-4","volume":"25","author":"R Guan","year":"2018","unstructured":"Guan, R. et al. Mitophagy, a potential therapeutic target for stroke. J. Biomed. Sci. 25, 87 (2018).","journal-title":"J. Biomed. Sci."},{"key":"96092_CR9","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1161\/STROKEAHA.118.021590","volume":"50","author":"T Zhang","year":"2019","unstructured":"Zhang, T. et al. Mitophagy reduces oxidative stress via keap1 (kelch-like epichlorohydrin-associated protein 1)\/nrf2 (nuclear factor-e2-related factor 2)\/phb2 (prohibitin 2) pathway after subarachnoid hemorrhage in rats. Stroke 50, 978\u2013988 (2019).","journal-title":"Stroke"},{"key":"96092_CR10","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.pneurobio.2012.02.003","volume":"97","author":"FA Sehba","year":"2012","unstructured":"Sehba, F. A. et al. The importance of early brain injury after subarachnoid hemorrhage. Prog. Neurobiol. 97, 14\u201337 (2012).","journal-title":"Prog. Neurobiol."},{"key":"96092_CR11","doi-asserted-by":"crossref","unstructured":"Lin, C.L. et al. Cerebral vasospasm after aneurysmal subarachnoid hemorrhage: Mechanism and therapies. Biomed Res Int. 679014 (2014).","DOI":"10.1155\/2014\/679014"},{"key":"96092_CR12","doi-asserted-by":"publisher","first-page":"924","DOI":"10.14336\/AD.2017.1126","volume":"9","author":"F Liu","year":"2018","unstructured":"Liu, F. et al. Mitochondria in ischemic stroke: New insight and implications. Aging Dis. 9, 924\u2013937 (2018).","journal-title":"Aging Dis."},{"key":"96092_CR13","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1038\/nrm3479","volume":"13","author":"L Galluzzi","year":"2012","unstructured":"Galluzzi, L. et al. Mitochondria: Master regulators of danger signalling. Nat. Rev. Mol. Cell Biol. 13, 780\u2013788 (2012).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"96092_CR14","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1161\/STROKEAHA.117.017758","volume":"48","author":"SH Chou","year":"2017","unstructured":"Chou, S. H. et al. Extracellular mitochondria in cerebrospinal fluid and neurological recovery after subarachnoid hemorrhage. Stroke 48, 2231\u20132237 (2017).","journal-title":"Stroke"},{"key":"96092_CR15","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1007\/s12028-019-00895-1","volume":"33","author":"DH Youn","year":"2020","unstructured":"Youn, D. H. et al. Extracellular mitochondrial dysfunction in cerebrospinal fluid of patients with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Neurocrit. Care 33, 422\u2013428 (2020).","journal-title":"Neurocrit. Care"},{"key":"96092_CR16","doi-asserted-by":"publisher","first-page":"2438","DOI":"10.1161\/STROKEAHA.114.005183","volume":"45","author":"SH Baek","year":"2014","unstructured":"Baek, S. H. et al. Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage. Stroke 45, 2438\u20132443 (2014).","journal-title":"Stroke"},{"key":"96092_CR17","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1111\/cns.12325","volume":"20","author":"RY Shi","year":"2014","unstructured":"Shi, R. Y. et al. Bnip3 interacting with lc3 triggers excessive mitophagy in delayed neuronal death in stroke. CNS Neurosci. Ther. 20, 1045\u20131055 (2014).","journal-title":"CNS Neurosci. Ther."},{"key":"96092_CR18","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1007\/s12035-015-9629-9","volume":"54","author":"Y Chen","year":"2017","unstructured":"Chen, Y. et al. Reduction in autophagy by (-)-epigallocatechin-3-gallate (egcg): A potential mechanism of prevention of mitochondrial dysfunction after subarachnoid hemorrhage. Mol. Neurobiol. 54, 392\u2013405 (2017).","journal-title":"Mol. Neurobiol."},{"key":"96092_CR19","doi-asserted-by":"publisher","first-page":"2417","DOI":"10.1038\/s41598-017-02679-z","volume":"7","author":"S Cao","year":"2017","unstructured":"Cao, S. et al. Melatonin-mediated mitophagy protects against early brain injury after subarachnoid hemorrhage through inhibition of nlrp3 inflammasome activation. Sci. Rep. 7, 2417 (2017).","journal-title":"Sci. Rep."},{"key":"96092_CR20","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1073\/pnas.1412833112","volume":"112","author":"JL Leclerc","year":"2015","unstructured":"Leclerc, J. L. et al. Haptoglobin phenotype predicts the development of focal and global cerebral vasospasm and may influence outcomes after aneurysmal subarachnoid hemorrhage. Proc. Natl. Acad. Sci. U S A 112, 1155\u20131160 (2015).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"96092_CR21","doi-asserted-by":"publisher","first-page":"34644","DOI":"10.1074\/jbc.M506466200","volume":"280","author":"T Shang","year":"2005","unstructured":"Shang, T., Joseph, J., Hillard, C. J. & Kalyanaraman, B. Death-associated protein kinase as a sensor of mitochondrial membrane potential: Role of lysosome in mitochondrial toxin-induced cell death. J. Biol. Chem. 280, 34644\u201334653 (2005).","journal-title":"J. Biol. Chem."},{"key":"96092_CR22","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1111\/cns.13140","volume":"25","author":"Y Wang","year":"2019","unstructured":"Wang, Y., Liu, N. & Lu, B. Mechanisms and roles of mitophagy in neurodegenerative diseases. CNS Neurosci. Ther. 25, 859\u2013875 (2019).","journal-title":"CNS Neurosci. Ther."},{"key":"96092_CR23","doi-asserted-by":"publisher","first-page":"4716","DOI":"10.1007\/s12035-016-0008-y","volume":"54","author":"S Wang","year":"2017","unstructured":"Wang, S. et al. Dapk1 signaling pathways in stroke: From mechanisms to therapies. Mol. Neurobiol. 54, 4716\u20134722 (2017).","journal-title":"Mol. Neurobiol."},{"key":"96092_CR24","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.cell.2009.12.055","volume":"140","author":"W Tu","year":"2010","unstructured":"Tu, W. et al. Dapk1 interaction with nmda receptor nr2b subunits mediates brain damage in stroke. Cell 140, 222\u2013234 (2010).","journal-title":"Cell"},{"key":"96092_CR25","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1007\/s10495-013-0933-4","volume":"19","author":"MZ Lai","year":"2014","unstructured":"Lai, M. Z. & Chen, R. H. Regulation of inflammation by dapk. Apoptosis 19, 357\u2013363 (2014).","journal-title":"Apoptosis"},{"key":"96092_CR26","doi-asserted-by":"publisher","first-page":"3238","DOI":"10.4049\/jimmunol.180.5.3238","volume":"180","author":"YT Chuang","year":"2008","unstructured":"Chuang, Y. T. et al. The tumor suppressor death-associated protein kinase targets to tcr-stimulated nf-kappa b activation. J. Immunol. 180, 3238\u20133249 (2008).","journal-title":"J. Immunol."},{"key":"96092_CR27","doi-asserted-by":"publisher","first-page":"17","DOI":"10.2183\/pjab.82.17","volume":"82","author":"T Masaki","year":"2006","unstructured":"Masaki, T. & Sawamura, T. Endothelin and endothelial dysfunction. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 82, 17\u201324 (2006).","journal-title":"Proc. Jpn. Acad. Ser. B Phys. Biol. Sci."},{"key":"96092_CR28","doi-asserted-by":"publisher","first-page":"2353","DOI":"10.1161\/STROKEAHA.110.584995","volume":"41","author":"P Lackner","year":"2010","unstructured":"Lackner, P. et al. Cellular microparticles as a marker for cerebral vasospasm in spontaneous subarachnoid hemorrhage. Stroke 41, 2353\u20132357 (2010).","journal-title":"Stroke"},{"key":"96092_CR29","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.redox.2012.11.008","volume":"1","author":"J Zhang","year":"2013","unstructured":"Zhang, J. Autophagy and mitophagy in cellular damage control. Redox Biol. 1, 19\u201323 (2013).","journal-title":"Redox Biol."},{"key":"96092_CR30","doi-asserted-by":"publisher","first-page":"559","DOI":"10.3340\/jkns.2019.0225","volume":"63","author":"JJ Park","year":"2020","unstructured":"Park, J. J. et al. A preliminary study of the association between sox17 gene variants and intracranial aneurysms using exome sequencing. J. Korean Neurosurg. Soc. 63, 559\u2013565 (2020).","journal-title":"J. Korean Neurosurg. Soc."},{"key":"96092_CR31","doi-asserted-by":"publisher","first-page":"e86017","DOI":"10.1371\/journal.pone.0086017","volume":"8","author":"S Seto","year":"2013","unstructured":"Seto, S., Tsujimura, K., Horii, T. & Koide, Y. Autophagy adaptor protein p62\/sqstm1 and autophagy-related gene atg5 mediate autophagosome formation in response to mycobacterium tuberculosis infection in dendritic cells. PLoS ONE 8, e86017 (2013).","journal-title":"PLoS ONE"},{"key":"96092_CR32","doi-asserted-by":"publisher","first-page":"391","DOI":"10.3390\/ijms18020391","volume":"18","author":"S Comincini","year":"2017","unstructured":"Comincini, S. et al. Identification of autophagy-related genes and their regulatory mirnas associated with celiac disease in children. Int. J. Mol. Sci. 18, 391 (2017).","journal-title":"Int. J. Mol. Sci."},{"key":"96092_CR33","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s40560-018-0297-5","volume":"6","author":"T Okazaki","year":"2018","unstructured":"Okazaki, T. & Kuroda, Y. Aneurysmal subarachnoid hemorrhage: Intensive care for improving neurological outcome. J. Intensive Care. 6, 28 (2018).","journal-title":"J. Intensive Care."},{"key":"96092_CR34","doi-asserted-by":"crossref","first-page":"12","DOI":"10.4103\/joacp.JOACP_192_17","volume":"35","author":"N Samagh","year":"2019","unstructured":"Samagh, N., Bhagat, H. & Jangra, K. Monitoring cerebral vasospasm: How much can we rely on transcranial doppler. J. Anaesthesiol. Clin. Pharmacol. 35, 12\u201318 (2019).","journal-title":"J. Anaesthesiol. Clin. Pharmacol."},{"key":"96092_CR35","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1080\/15548627.2015.1034403","volume":"11","author":"M Mauro-Lizcano","year":"2015","unstructured":"Mauro-Lizcano, M. et al. New method to assess mitophagy flux by flow cytometry. Autophagy 11, 833\u2013843 (2015).","journal-title":"Autophagy"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96092-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96092-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96092-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T05:10:08Z","timestamp":1699333808000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-96092-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,13]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["96092"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-96092-2","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-394833\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,13]]},"assertion":[{"value":"5 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 August 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16512"}}