{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T11:40:37Z","timestamp":1784374837267,"version":"3.55.0"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T00:00:00Z","timestamp":1659657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY026662"],"award-info":[{"award-number":["EY026662"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Glaucoma is an optic neuropathy that leads to irreversible blindness, the most common subtype of which is typified by a chronic increase in intraocular pressure that promotes a stretch injury to the optic nerve head. In rodents, the predominant glial cell in this region is the optic nerve head astrocyte that provides axons with metabolic support, likely by releasing lactate produced through astrocytic glycolysis. Our primary hypothesis is that stretching of the optic nerve head astrocytes alters their metabolic activity, thereby advancing glaucoma-associated degeneration by compromising the metabolic support that the astrocytes provide to the axons in the optic nerve head. Metabolic changes in optic nerve head astrocytes were investigated by subjecting them to 24 h of 12% biaxial stretch at 1 Hz then measuring the cells\u2019 bioenergetics using a Seahorse XFe24 Analyzer. We observed significant glycolytic and respiratory activity differences between control and stretched cells, including greater extracellular acidification and lower ATP-linked respiration, yet higher maximal respiration and spare capacity in stretched optic nerve head astrocytes. We also determined that both control and stretched optic nerve head astrocytes displayed a dependency for glutamine over pyruvate or long-chain fatty acids for fuel. The increased use of glycolysis as indicated by the extracellular acidification rate, concomitant with a dependency on glutamine, suggests the need to replenish NAD + for continued glycolysis and provision of carbon for TCA cycle intermediates. Stretch alters optic nerve astrocyte bioenergetics to support an increased demand for internal and external energy.<\/jats:p>","DOI":"10.3389\/fnins.2022.957034","type":"journal-article","created":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T10:52:50Z","timestamp":1659696770000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Stretch stress propels glutamine dependency and glycolysis in optic nerve head astrocytes"],"prefix":"10.3389","volume":"16","author":[{"given":"Nathaniel","family":"Pappenhagen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Autumn B.","family":"Morgan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles C.","family":"Kiehlbauch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise M.","family":"Inman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"227","DOI":"10.3389\/fncel.2017.00227","article-title":"The P2X7 receptor primes IL-1\u03b2 and the NLRP3 inflammasome in astrocytes exposed to mechanical strain.","volume":"11","author":"Albalawi","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1046\/j.1471-4159.2001.00322.x","article-title":"Transfer of glutamine between astrocytes and neurons.","volume":"77","author":"Br\u00f6er","year":"2001","journal-title":"J. Neurochem."},{"key":"B3","first-page":"35","article-title":"S100 immunoreactivity is increased in reactive astrocytes of the visual pathways following a mechanical lesion of the rat occipital cortex.","volume":"24","author":"Cerutti","year":"2000","journal-title":"Cell Biol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1007\/s00401-011-0807-1","article-title":"The optic nerve head is the site of axonal transport disruption, axonal cytoskeleton damage and putative axonal regeneration failure in a rat model of glaucoma.","volume":"121","author":"Chidlow","year":"2011","journal-title":"Acta Neuropathol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3365","DOI":"10.1523\/JNEUROSCI.5427-08.2009","article-title":"Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV \u03b1-synucleinopathy.","volume":"29","author":"Chung","year":"2009","journal-title":"J. Neurosci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1002\/glia.21242","article-title":"Structural basis of glaucoma: the fortified astrocytes of the optic nerve head are the target of raised intraocular pressure.","volume":"60","author":"Dai","year":"2012","journal-title":"Glia"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1093\/jn\/130.4.1026s","article-title":"Compartmentation of brain glutamate metabolism in neurons and glia.","volume":"130","author":"Daikhin","year":"2000","journal-title":"J. Nutr."},{"key":"B8","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1002\/jnr.10079","article-title":"Glucose and lactate metabolism during brain activation.","volume":"66","author":"Dienel","year":"2001","journal-title":"J. Neurosci. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1097\/OPX.0b013e31817841cb","article-title":"Mechanical environment of the optic nerve head in glaucoma.","volume":"85","author":"Downs","year":"2008","journal-title":"Optom. Vis. Sci."},{"key":"B10","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1016\/j.ophtha.2016.02.008","article-title":"In vivo 3-dimensional strain mapping of the optic nerve head following intraocular pressure lowering by trabeculectomy.","volume":"123","author":"Girard","year":"2016","journal-title":"Opthamology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/jbiol63","article-title":"Metabolic reconfiguration is a regulated response to oxidative stress.","volume":"7","author":"Grant","year":"2008","journal-title":"J. Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1136\/bjo.2004.058941","article-title":"En face optical coherence tomography: a new method to analyse structural changes of the optic nerve head in rat glaucoma.","volume":"89","author":"Guo","year":"2005","journal-title":"Br. J. Ophthalmol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/iub.573","article-title":"The monocarboxylate transporter family-structure and functional characterization.","volume":"64","author":"Halestrap","year":"2012","journal-title":"IUBMB Life"},{"key":"B14","doi-asserted-by":"publisher","first-page":"33619","DOI":"10.1073\/pnas.2014213117","article-title":"Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin.","volume":"117","author":"Harder","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B15","doi-asserted-by":"publisher","first-page":"5122","DOI":"10.1523\/JNEUROSCI.3652-17.2018","article-title":"Structural and functional rescue of chronic metabolically stressed optic nerves through respiration.","volume":"38","author":"Harun-or-Rashid","year":"2018","journal-title":"J. Neurosci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"104944","DOI":"10.1016\/j.nbd.2020.104944","article-title":"MCT2 overexpression rescues metabolic vulnerability and protects retinal ganglion cells in two models of glaucoma.","volume":"141","author":"Harun-Or-Rashid","year":"","journal-title":"Neurobiol. Dis."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1101\/2020.02.14.950097","article-title":"MCT2 overexpression rescues metabolic vulnerability and protects retinal ganglion cells in two glaucoma models.","author":"Harun-Or-Rashid","year":"","journal-title":"BioRXiv"},{"key":"B18","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S1350-9462(99)00017-8","article-title":"The optic nerve head in glaucoma: role of astrocytes in tissue remodeling.","volume":"19","author":"Hernandez","year":"","journal-title":"Prog. Retin. Eye Res."},{"key":"B19","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S1350-9462(99)00017-8","article-title":"The optic nerve head in glaucoma: role of astrocytes in tissue remodeling.","volume":"19","author":"Hernandez","year":"","journal-title":"Prog. Retin. Eye Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1083\/jcb.200706181","article-title":"Axons of retinal ganglion cells are insulted in the optic nerve early in DBA\/2J glaucoma.","volume":"179","author":"Howell","year":"2007","journal-title":"J. Cell Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1111\/ceo.13818","article-title":"Improvement in inner retinal function in glaucoma with nicotinamide (vitamin B3) supplementation: a crossover randomized clinical trial.","volume":"48","author":"Hui","year":"2020","journal-title":"Clin. Exp. Ophthalmol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2518","DOI":"10.1007\/s12035-016-9833-2","article-title":"Metabolic and inflammatory adaptation of reactive astrocytes: role of PPARs.","volume":"54","author":"Iglesias","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"B23","doi-asserted-by":"crossref","first-page":"7097","DOI":"10.1007\/s12035-019-1576-4","article-title":"Higher reliance on glycolysis limits glycolytic responsiveness in degenerating glaucomatous optic nerve.","volume":"56","author":"Jassim","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.expneurol.2014.12.014","article-title":"Differential subcellular Ca2+ signaling in a highly specialized subpopulation of astrocytes.","volume":"265","author":"Kaja","year":"2015","journal-title":"Exp. Neurol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1167\/IOVS.61.13.4","article-title":"Reduced oxidative phosphorylation and increased glycolysis in human glaucoma lamina cribrosa cells.","volume":"61","author":"Kamel","year":"2020","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia.","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1167\/iovs.12-10109","article-title":"Morphology of astrocytes in a glaucomatous optic nerve.","volume":"54","author":"Lye-Barthel","year":"2013","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s13024-020-00400-9","article-title":"CNS axonal degeneration and transport deficits at the optic nerve head precede structural and functional loss of retinal ganglion cells in a mouse model of glaucoma.","volume":"15","author":"Maddineni","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1002\/glia.20527","article-title":"Pressure induces loss of gap junction communication and redistribution of connexin 43 in astrocytes.","volume":"55","author":"Malone","year":"2007","journal-title":"Glia"},{"key":"B30","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1046\/j.1471-4159.1996.66010386.x","article-title":"Exogenous glutamate concentration regulates the metabolic fate of glutamate in astrocytes.","volume":"66","author":"McKenna","year":"1996","journal-title":"J. Neurochem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.bbabio.2014.10.005","article-title":"The contributions of respiration and glycolysis to extracellular acid production.","volume":"1847","author":"Mookerjee","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"B32","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1038\/eye.2000.128","article-title":"Optic nerve head structure in glaucoma: astrocytes as mediators of axonal damage.","volume":"14","author":"Morgan","year":"2000","journal-title":"Eye"},{"key":"B33","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1002\/glia.440140107","article-title":"The human blood\u2212brain barrier glucose transporter (GLUT1) is a glucose transporter of gray matter astrocytes.","volume":"14","author":"Morgello","year":"1995","journal-title":"Glia"},{"key":"B34","doi-asserted-by":"publisher","first-page":"108092","DOI":"10.1016\/j.celrep.2020.108092","article-title":"AMPK-regulated astrocytic lactate shuttle plays a non-cell-autonomous role in neuronal survival.","volume":"32","author":"Muraleedharan","year":"2020","journal-title":"Cell Rep."},{"key":"B35","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1177\/1073858403253460","article-title":"Glaucomatous optic neuropathy: when glia misbehave.","volume":"9","author":"Neufeld","year":"2003","journal-title":"Neuroscientist"},{"key":"B36","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/1755-8794-2-24","article-title":"Network analysis of human glaucomatous optic nerve head astrocytes.","volume":"2","author":"Nikolskaya","year":"2009","journal-title":"BMC Med. Genomics"},{"key":"B37","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1007\/s11064-006-9132-9","article-title":"Kinetic parameters and lactate dehydrogenase isozyme activities support possible lactate utilization by neurons.","volume":"32","author":"O\u2019Brien","year":"2007","journal-title":"Neurochem. Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.1007\/s12035-020-01910-9","article-title":"Sub-region-specific optic nerve head glial activation in glaucoma.","volume":"57","author":"Oikawa","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"B39","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1159\/000017324","article-title":"Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle.","volume":"20","author":"Pellerin","year":"1998","journal-title":"Dev. Neurosci."},{"key":"B40","first-page":"582","article-title":"Gap junctions between optic nerve head astrocytes.","volume":"16","author":"Quigley","year":"1977","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B41","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1001\/archopht.1981.03930010635009","article-title":"Optic nerve damage in human glaucomaII. The site of injury and susceptibility to damage.","volume":"99","author":"Quigley","year":"1981","journal-title":"Arch. Ophthalmol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"459","DOI":"10.3389\/fnagi.2020.614410","article-title":"Mitochondrial dynamics and bioenergetic alteration during inflammatory activation of astrocytes.","volume":"12","author":"Rahman","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"B43","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.neuint.2016.03.014","article-title":"Astroglial glutamate transporters coordinate excitatory signaling and brain energetics.","volume":"98","author":"Robinson","year":"2016","journal-title":"Neurochem. Int."},{"key":"B44","doi-asserted-by":"publisher","first-page":"M111.012302","DOI":"10.1074\/mcp.M111.012302","article-title":"Proteomics analyses of human optic nerve head astrocytes following biomechanical.","volume":"11","author":"Rogers","year":"","journal-title":"Mol. Cell Proteomics"},{"key":"B45","doi-asserted-by":"publisher","first-page":"3806","DOI":"10.1167\/iovs.11-8480","article-title":"Proteomics analyses of activated human optic nerve head lamina cribrosa cells following biomechanical strain.","volume":"53","author":"Rogers","year":"","journal-title":"Invest. Opthalmol. Vis. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.neuron.2016.05.016","article-title":"Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism.","volume":"91","author":"Saab","year":"2016","journal-title":"Neuron"},{"key":"B47","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.exer.2015.08.014","article-title":"The role of astrocytes in optic nerve head fibrosis in glaucoma.","volume":"142","author":"Schneider","year":"2015","journal-title":"Exp. Eye Res."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2148","DOI":"10.1007\/s11064-013-1123-z","article-title":"Reactive oxygen species from human astrocytes induced functional impairment and oxidative damage.","volume":"38","author":"Sheng","year":"2013","journal-title":"Neurochem. Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1177\/1073858405278321","article-title":"Reactive astrocytes in neural repair and protection.","volume":"11","author":"Sofroniew","year":"2005","journal-title":"Neuroscientist"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/cne.22058","article-title":"The morphology and spatial arrangement of astrocytes in the optic nerve head of the mouse.","volume":"516","author":"Sun","year":"2009","journal-title":"J. Comp. Neurol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1002\/glia.22507","article-title":"Reversible reactivity by optic nerve astrocytes.","volume":"61","author":"Sun","year":"2013","journal-title":"Glia"},{"key":"B52","doi-asserted-by":"publisher","first-page":"101988","DOI":"10.1016\/j.redox.2021.101988","article-title":"Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction.","volume":"43","author":"Tribble","year":"2021","journal-title":"Redox Biol."},{"key":"B53","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1523\/JNEUROSCI.16-03-00877.1996","article-title":"Metabolic Coupling Glia and Neurons.","volume":"16","author":"Tsacopoulos","year":"1996","journal-title":"J. Neurosci."},{"key":"B54","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1097\/NEN.0b013e31820e1152","article-title":"Neuronal-astrocyte metabolic interactions: understanding the transition into abnormal astrocytoma metabolism.","volume":"70","author":"Turner","year":"2011","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s11064-020-02965-9","article-title":"Intertwined ROS and metabolic signaling at the neuron-astrocyte interface.","volume":"46","author":"Vicente-Guti\u00e9rrez","year":"2021","journal-title":"Neurochem. Res."},{"key":"B56","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/J.SURVOPHTHAL.2012.08.010","article-title":"The role of inflammation in the pathogenesis of glaucoma.","volume":"58","author":"Vohra","year":"2013","journal-title":"Surv. Ophthalmol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.cmet.2015.07.006","article-title":"Glial glycolysis is essential for neuronal survival in drosophila.","volume":"22","author":"Volkenhoff","year":"2015","journal-title":"Cell Metab."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1901","DOI":"10.1001\/jama.2014.3192","article-title":"The pathophysiology and treatment of glaucoma: a review.","volume":"311","author":"Weinreb","year":"2014","journal-title":"JAMA"},{"key":"B59","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1120\/science.aal0092","article-title":"Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice.","volume":"760","author":"Williams","year":"2017","journal-title":"Science"},{"key":"B60","doi-asserted-by":"publisher","first-page":"494","DOI":"10.3389\/fnins.2016.00494","article-title":"Early cytoskeletal protein modifications precede overt structural degeneration in the DBA\/2J mouse model of glaucoma.","volume":"10","author":"Wilson","year":"2016","journal-title":"Front. Neurosci."},{"key":"B61","doi-asserted-by":"publisher","first-page":"C125","DOI":"10.1152\/ajpcell.00247.2006","article-title":"Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells.","volume":"292","author":"Wu","year":"2007","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"5064683","DOI":"10.1155\/2017\/5064683","article-title":"Evaluation of connexin 43 redistribution and endocytosis in astrocytes subjected to ischemia\/reperfusion or oxygen-glucose deprivation and reoxygenation.","volume":"2017","author":"Xie","year":"2017","journal-title":"Biomed Res. Int."},{"key":"B63","doi-asserted-by":"publisher","first-page":"6391","DOI":"10.1523\/JNEUROSCI.6221-11.2012","article-title":"Genomic analysis of reactive astrogliosis.","volume":"32","author":"Zamanian","year":"2012","journal-title":"J. Neurosci."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2022.957034\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T10:53:05Z","timestamp":1659696785000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2022.957034\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,5]]},"references-count":63,"alternative-id":["10.3389\/fnins.2022.957034"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2022.957034","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,5]]},"article-number":"957034"}}