{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T20:37:02Z","timestamp":1793738222906,"version":"4.6.1"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T00:00:00Z","timestamp":1646265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>\n                    Mitochondrial dysfunction has been regarded as one of the major contributors of ischemic neuronal death after stroke. Recently, intercellular mitochondrial transfer between different cell types has been widely studied and suggested as a potential therapeutic approach. However, whether mitochondria are involved in the neuron-glia cross-talk following ischemic stroke and the underlying mechanisms have not been explored yet. In this study, we demonstrated that under physiological condition, neurons release few mitochondria into the extracellular space, and the mitochondrial release increased when subjected to the challenges of acidosis, hydrogen peroxide (H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    ),\n                    <jats:italic>N<\/jats:italic>\n                    -methyl-\n                    <jats:sc>D<\/jats:sc>\n                    -aspartate (NMDA), or glutamate. Acidosis reduced the mitochondrial basal respiration and lowered the membrane potential in primary-cultured mouse cortical neurons. These defective mitochondria were prone to be expelled to the extracellular space by the injured neurons, and were engulfed by adjacent astrocytes, leading to increased astrocytic expressions of mitochondrial Rho GTPase 1 (Miro 1) and mitochondrial transcription factor A (TFAM) at mRNA level. In mice subjected to transient focal cerebral ischemia, the number of defective mitochondria in the cerebrospinal fluid increased. Our results suggested that the neuron-derived mitochondria may serve as a \u201chelp-me\u201d signaling and mediate the neuron-astrocyte cross-talk following ischemic stroke. Promoting the intercellular mitochondrial transfer by accelerating the neuronal releasing or astrocytic engulfing might be a potential and attractive therapeutic strategy for the treatment of ischemic stroke in the future.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2022.785761","type":"journal-article","created":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T19:58:37Z","timestamp":1646251117000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":53,"title":["Neurons Release Injured Mitochondria as \u201cHelp-Me\u201d Signaling After Ischemic Stroke"],"prefix":"10.3389","volume":"14","author":[{"given":"Li","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin-Pin","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anatol","family":"Manaenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Peng","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Le","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1214","DOI":"10.1007\/s12975-020-00828-7","article-title":"Mitochondrial transfer as a therapeutic strategy against ischemic stroke.","volume":"11","author":"Chen","year":"2020","journal-title":"Transl. Stroke Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1161\/STROKEAHA.117.017758","article-title":"Extracellular mitochondria in cerebrospinal fluid and neurological recovery after subarachnoid hemorrhage.","volume":"48","author":"Chou","year":"2017","journal-title":"Stroke"},{"key":"B3","doi-asserted-by":"publisher","first-page":"9633","DOI":"10.1073\/pnas.1404651111","article-title":"Transcellular degradation of axonal mitochondria.","volume":"111","author":"Davis","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-020-00897-7","article-title":"Astrocytes rescue neuronal health after cisplatin treatment through mitochondrial transfer.","volume":"8","author":"English","year":"2020","journal-title":"Acta Neuropathol. Commun."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.2174\/1570159X18666200914162013","article-title":"The effects and underlying mechanisms of cell therapy on blood-brain barrier integrity after ischemic stroke.","volume":"18","author":"Gao","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.3892\/mmr.2015.4726","article-title":"Bone marrow-derived mesenchymal stem cells rescue injured H9c2 cells via transferring intact mitochondria through tunneling nanotubes in an in vitro simulated ischemia\/reperfusion model.","volume":"13","author":"Han","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"B7","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/nature18928","article-title":"Transfer of mitochondria from astrocytes to neurons after stroke.","volume":"535","author":"Hayakawa","year":"2016","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1016\/j.jstrokecerebrovasdis.2019.01.016","article-title":"Dexmedetomidine protects against neurological dysfunction in a mouse intracerebral hemorrhage model by inhibiting mitochondrial dysfunction-derived oxidative stress.","volume":"28","author":"Huang","year":"2019","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"913","DOI":"10.3727\/096368915X689785","article-title":"Transferring xenogenic mitochondria provides neural protection against ischemic stress in ischemic rat brains.","volume":"25","author":"Huang","year":"2016","journal-title":"Cell Transpl."},{"key":"B10","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1038\/nm.2736","article-title":"Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury.","volume":"18","author":"Islam","year":"2012","journal-title":"Nat. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2896","DOI":"10.1016\/j.cell.2021.04.027","article-title":"Mitocytosis, a migrasome-mediated mitochondrial quality-control process.","volume":"184","author":"Jiao","year":"2021","journal-title":"Cell"},{"key":"B12","doi-asserted-by":"publisher","first-page":"924","DOI":"10.14336\/ad.2017.1126","article-title":"Mitochondria in ischemic stroke: new insight and implications.","volume":"9","author":"Liu","year":"2018","journal-title":"Aging Dis."},{"key":"B13","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.mvr.2019.01.001","article-title":"Mesenchymal stem cells transfer mitochondria into cerebral microvasculature and promote recovery from ischemic stroke.","volume":"123","author":"Liu","year":"2019","journal-title":"Microvasc. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.mvr.2014.01.008","article-title":"Mesenchymal stem cells rescue injured endothelial cells in an in vitro ischemia-reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer.","volume":"92","author":"Liu","year":"2014","journal-title":"Microvasc. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"5986","DOI":"10.7150\/thno.58632","article-title":"Antioxidant activity of mesenchymal stem cell-derived extracellular vesicles restores hippocampal neurons following seizure damage.","volume":"11","author":"Luo","year":"2021","journal-title":"Theranostics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"5007","DOI":"10.1111\/jcmm.15120","article-title":"TAT-dextran-mediated mitochondrial transfer enhances recovery from models of reperfusion injury in cultured cardiomyocytes.","volume":"24","author":"Maeda","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.1038\/cdd.2017.51","article-title":"Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties.","volume":"24","author":"Mahrouf-Yorgov","year":"2017","journal-title":"Cell Death Differ."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.1111\/j.1582-4934.2007.00205.x","article-title":"Cell-to-cell cross-talk between mesenchymal stem cells and cardiomyocytes in co-culture.","volume":"12","author":"Plotnikov","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e344","DOI":"10.1161\/str.0000000000000211","article-title":"Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association\/American Stroke Association.","volume":"50","author":"Powers","year":"2019","journal-title":"Stroke"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201949799","article-title":"Mitochondrial DNA in inflammation and immunity.","volume":"21","author":"Riley","year":"2020","journal-title":"EMBO Rep."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2019.109295","article-title":"Linalool attenuates oxidative stress and mitochondrial dysfunction mediated by glutamate and NMDA toxicity.","volume":"118","author":"Sabogal-Gu\u00e1queta","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"B22","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1111\/jnc.14971","article-title":"ASIC1a channels regulate mitochondrial ion signaling and energy homeostasis in neurons.","volume":"153","author":"Savic Azoulay","year":"2020","journal-title":"J. Neurochem."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21984-w","article-title":"Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs.","volume":"12","author":"Todkar","year":"2021","journal-title":"Nat. Commun."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1111\/j.1471-4159.2007.04634.x","article-title":"Inhibition of mitochondrial function in astrocytes: implications for neuroprotection.","volume":"102","author":"Voloboueva","year":"2007","journal-title":"J. Neurochem."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13873-0","article-title":"Disruption of auto-inhibition underlies conformational signaling of ASIC1a to induce neuronal necroptosis.","volume":"11","author":"Wang","year":"2020","journal-title":"Nat. Commun."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.05682","article-title":"Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction.","volume":"4","author":"Wang","year":"2015","journal-title":"Elife"},{"key":"B27","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1038\/nri2975","article-title":"Mitochondria in innate immune responses.","volume":"11","author":"West","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/j.bbamcr.2018.02.001","article-title":"GRP78 protects CHO cells from ribosylation.","volume":"1865","author":"Wu","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.expneurol.2019.03.017","article-title":"MicroRNA-132 attenuates cerebral injury by protecting blood-brain-barrier in MCAO mice.","volume":"316","author":"Zuo","year":"2019","journal-title":"Exp. Neurol."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2022.785761\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T19:58:41Z","timestamp":1646251121000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2022.785761\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,3]]},"references-count":29,"alternative-id":["10.3389\/fnagi.2022.785761"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2022.785761","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,3]]},"article-number":"785761"}}