{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:53:29Z","timestamp":1785405209294,"version":"3.56.0"},"reference-count":27,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"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","award":["82201500"],"award-info":[{"award-number":["82201500"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82201500"],"award-info":[{"award-number":["82201500"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: Recent studies strongly suggest that low intracranial pressure (ICP) may be involved in the pathogenesis of glaucomatous optic neuropathy. As retinal ganglion cells (RGCs) are highly susceptible to mitochondrial dysfunction, mitochondrial injury may be associated with optic neuropathy related to reduced ICP. In this study, aquaporin-1 (AQP1)-null mice were used to investigate whether reduced ICP is associated with alterations in mitochondrial structure and the release of optic atrophy type 1 (OPA1) and cytochrome c from mitochondria. Methods: Intraocular pressure (IOP) and ICP were measured in AQP1-null mice, and mitochondrial structural changes were examined using transmission electron microscopy (TEM). Total OPA1 and cytochrome c protein levels were evaluated using immunocytochemistry and Western blotting. Cytosolic and mitochondrial fractions were extracted from retinal tissues, and the subcellular distribution of OPA1 and cytochrome c was further analyzed by Western blotting. Bax and Bcl-2 expression levels were also detected. Results: TEM revealed mitochondrial fission, matrix swelling, and abnormal cristae depletion in the retinas of 1-, 3-, and 6-month-old AQP1-null mice. Morphometric quantification further confirmed significantly reduced mitochondrial length across all age groups and increased mitochondrial width at 1 and 6 months in AQP1-null mice compared with wild-type controls. Decreased retinal OPA1 immunoreactivity and protein expression were observed across all age groups of AQP1-null mice compared with age-matched C57BL\/6 control mice. Subcellular fractionation showed increased mitochondrial release of OPA1 (at 3 and 6 months) and cytochrome c (at 1, 3, and 6 months) in the retinas of AQP1-null mice. Altered Bax expression was also detected in the retinas of AQP1-null mice with reduced ICP at all examined ages. Conclusions: Mitochondrial ultrastructural abnormalities, including fission and cristae depletion, altered OPA1 distribution, increased mitochondrial release of OPA1 and cytochrome c, and upregulated Bax expression were observed in the retinas of AQP1-null mice with reduced ICP. These concurrent changes indicate a close association between reduced ICP and retinal mitochondrial dysfunction. Maintaining mitochondrial integrity may therefore serve as a potential protective strategy against optic nerve degeneration in patients with chronic low ICP.<\/jats:p>","DOI":"10.3390\/brainsci16050470","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T15:09:33Z","timestamp":1777388973000},"page":"470","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intracranial Pressure Reduction Is Associated with Mitochondrial OPA1 and Cytochrome c Release in the Retinas of AQP1-Null Mice"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5501-3031","authenticated-orcid":false,"given":"Zheng","family":"Zhang","sequence":"first","affiliation":[{"name":"Beijing Tongren Eye Center, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China"},{"name":"Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing 100005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shen","family":"Wu","sequence":"additional","affiliation":[{"name":"Beijing Tongren Eye Center, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China"},{"name":"Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing 100005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kegao","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Tongren Eye Center, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Tongren Eye Center, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China"},{"name":"Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing 100005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3007-4898","authenticated-orcid":false,"given":"Qian","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Tongren Eye Center, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China"},{"name":"Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing 100005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8933-4482","authenticated-orcid":false,"given":"Ningli","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Tongren Eye Center, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China"},{"name":"Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing 100005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1016\/S0140-6736(17)31469-1","article-title":"Glaucoma","volume":"390","author":"Jonas","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1016\/S0140-6736(04)16257-0","article-title":"Primary open-angle glaucoma","volume":"363","author":"Weinreb","year":"2004","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.ophtha.2008.01.013","article-title":"Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma","volume":"115","author":"Berdahl","year":"2008","journal-title":"Ophthalmology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.ophtha.2009.06.058","article-title":"Cerebrospinal fluid pressure in glaucoma: A prospective study","volume":"117","author":"Ren","year":"2010","journal-title":"Ophthalmology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5189","DOI":"10.1167\/iovs.03-0174","article-title":"Anatomic relationship between lamina cribrosa, intraocular space, and cerebrospinal fluid space","volume":"44","author":"Jonas","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1097\/IJG.0000000000001421","article-title":"The influence of translaminar pressure gradient and intracranial pressure in glaucoma: A review","volume":"29","author":"Price","year":"2020","journal-title":"J. Glaucoma"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ajo.2013.03.003","article-title":"Senescent changes in cerebrospinal fluid circulatory physiology and their role in the pathogenesis of normal-tension glaucoma","volume":"156","author":"Wostyn","year":"2013","journal-title":"Am. J. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Tripathi, K., and Ben-Shachar, D. (2024). Mitochondria in the central nervous system in health and disease: The puzzle of the therapeutic potential of mitochondrial transplantation. Cells, 13.","DOI":"10.3390\/cells13050410"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1016\/j.biocel.2009.04.013","article-title":"OPA1 functions in mitochondria and dysfunctions in optic nerve","volume":"41","author":"Lenaers","year":"2009","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/j.exer.2006.06.004","article-title":"OPA1 expression in the human retina and optic nerve","volume":"83","author":"Wang","year":"2006","journal-title":"Exp. Eye Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/cne.20586","article-title":"OPA1 expression in the normal rat retina and optic nerve","volume":"488","author":"Ju","year":"2005","journal-title":"J. Comp. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Guo, Y., Chen, X., Zhang, H., Li, N., Yang, X., Cheng, W., and Zhao, K. (2012). Association of OPA1 polymorphisms with NTG and HTG: A meta-analysis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042387"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4903","DOI":"10.1167\/iovs.07-1661","article-title":"Intraocular pressure elevation induces mitochondrial fission and triggers OPA1 release in glaucomatous optic nerve","volume":"49","author":"Ju","year":"2008","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_14","first-page":"120","article-title":"Elevated hydrostatic pressure triggers release of OPA1 and cytochrome C, and induces apoptotic cell death in differentiated RGC-5 cells","volume":"15","author":"Ju","year":"2009","journal-title":"Mol. Vis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"35742","DOI":"10.1074\/jbc.M505970200","article-title":"Release of OPA1 during apoptosis participates in the rapid and complete release of cytochrome c and subsequent mitochondrial fragmentation","volume":"280","author":"Arnoult","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1096\/fj.04-1711fje","article-title":"Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel aquaporin-1","volume":"19","author":"Oshio","year":"2005","journal-title":"FASEB J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4617","DOI":"10.1167\/iovs.05-0781","article-title":"Noninvasive measurement of rodent intraocular pressure with a rebound tonometer","volume":"46","author":"Wang","year":"2005","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1007\/s00415-025-13304-9","article-title":"A systematic study of the distribution and expression of aquaporin water channels in normal adult human brain","volume":"272","author":"Adiele","year":"2025","journal-title":"J. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Elisabetta, C., Kashi, B., Simona, D.Q., and Davide, C. (2023). Targeting Mitochondrial Dysfunction and Oxidative Stress to Prevent the Neurodegeneration of Retinal Ganglion Cells. Antioxidants, 12.","DOI":"10.3390\/antiox12112011"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4257","DOI":"10.1167\/iovs.14-16045","article-title":"Axonal Transport in the Rat Optic Nerve Following Short-Term Reduction in Cerebrospinal Fluid Pressure or Elevation in Intraocular Pressure","volume":"56","author":"Zhang","year":"2015","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1111\/aos.12768","article-title":"Dynein, kinesin and morphological changes in optic nerve axons in a rat model with cerebrospinal fluid pressure reduction: The Beijing Intracranial and Intraocular Pressure (iCOP) study","volume":"94","author":"Zhang","year":"2016","journal-title":"Acta Ophthalmol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1126\/science.1219855","article-title":"Mitochondrial fission, fusion, and stress","volume":"337","author":"Youle","year":"2012","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Vasileiou, P.V.S., Evangelou, K., Vlasis, K., Fildisis, G., Panayiotidis, M.I., Chronopoulos, E., Passias, P.G., Kouloukoussa, M., Gorgoulis, V.G., and Havaki, S. (2019). Mitochondrial homeostasis and cellular senescence. Cells, 8.","DOI":"10.3390\/cells8070686"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1126\/science.1059108","article-title":"Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death","volume":"292","author":"Wei","year":"2001","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"a011106","DOI":"10.1101\/cshperspect.a011106","article-title":"Where killers meet--permeabilization of the outer mitochondrial membrane during apoptosis","volume":"5","author":"Bender","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1167\/iovs.08-2499","article-title":"Memantine blocks mitochondrial OPA1 and cytochrome c release and subsequent apoptotic cell death in glaucomatous retina","volume":"50","author":"Ju","year":"2008","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"110919","DOI":"10.1016\/j.exger.2020.110919","article-title":"Interplay of mitochondrial fission-fusion with cell cycle regulation: Possible impacts on stem cell and organismal aging","volume":"135","author":"Spurlock","year":"2020","journal-title":"Exp. Gerontol."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/5\/470\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T15:38:25Z","timestamp":1777390705000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/5\/470"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,28]]},"references-count":27,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["brainsci16050470"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16050470","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,28]]}}}