{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T06:22:17Z","timestamp":1773814937268,"version":"3.50.1"},"reference-count":95,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tri-Service General Hospital Research Foundation","award":["TSGH-E-114265"],"award-info":[{"award-number":["TSGH-E-114265"]}]},{"name":"National Defense Medical University (National Defense Medical Center) Foundation","award":["MND-MAB-D-114118"],"award-info":[{"award-number":["MND-MAB-D-114118"]}]},{"name":"Teh-Tzer Study Group for Human Medical Research Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glaucoma is a multifaceted optic neuropathy, characterized by the progressive loss of retinal ganglion cells. This damage frequently continues even after intraocular pressure (IOP) has been effectively lowered. This resistance to conventional IOP-lowering therapy underscores the critical role of interacting IOP-independent mechanisms; specifically metabolic failure and systemic mitochondrial dysfunction have emerged as key parallel drivers. This review analyzes the paradigm shift from a pressure-centric model to a bioenergetic one, focusing on mitochondrial function, peripheral blood mononuclear cell (PBMC) biomarkers, and oxygen consumption dynamics. We synthesize evidence demonstrating that glaucoma patients exhibit a metabolic vulnerability, characterized by lower PBMC oxygen consumption rates and depleted systemic nicotinamide adenine dinucleotide levels relative to healthy individuals. Furthermore, compromised systemic respiratory performance correlates with more rapid worsening of visual fields and structural thinning, independent of IOP status. Moreover, we delineate the role of Complex I defects, SARM1-mediated axonal degeneration, and proteomic alterations, which indicate defective mitophagy. These findings establish systemic metabolic profiling as a valuable supplementary tool for assessing patient risk and support the clinical translation of neuroprotective therapies targeting mitochondrial bioenergetics, specifically nicotinamide, pyruvate, coenzyme Q10, and metformin.<\/jats:p>","DOI":"10.3390\/ijms27062704","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T09:35:57Z","timestamp":1773740157000},"page":"2704","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Peripheral Blood Mononuclear Cell Oxygen Consumption and Systemic Bioenergetics in Glaucoma Management"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5894-3827","authenticated-orcid":false,"given":"Chun","family":"Hsiung","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Tri-Service General Hospital, Taipei 114202, Taiwan"},{"name":"Department of Ophthalmology, College of Medicine, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8263-9607","authenticated-orcid":false,"given":"Ta-Hung","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of General Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1473-2531","authenticated-orcid":false,"given":"Wei-Ting","family":"Yen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tri-Service General Hospital, Taipei 114202, Taiwan"},{"name":"Department of Ophthalmology, College of Medicine, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Da-Wen","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tri-Service General Hospital, Taipei 114202, Taiwan"},{"name":"Department of Ophthalmology, College of Medicine, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"ref_1","unstructured":"(2021). Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: The Right to Sight: An analysis for the Global Burden of Disease Study. Lancet Glob. Health, 9, e144\u2013e160."},{"key":"ref_2","unstructured":"(2024). Global estimates on the number of people blind or visually impaired by glaucoma: A meta-analysis from 2000 to 2020. Eye, 38, 2036\u20132046."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1167\/tvst.13.12.7","article-title":"The Strain Response to Intraocular Pressure Increase in the Lamina Cribrosa of Control Subjects and Glaucoma Patients","volume":"13","author":"Czerpak","year":"2024","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1167\/iovs.66.1.32","article-title":"Relationship Between Intraocular Pressure and the True Rate of Functional and Structural Progression in the United Kingdom Glaucoma Treatment Study","volume":"66","author":"Montesano","year":"2025","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e001609","DOI":"10.1136\/bmjophth-2023-001609","article-title":"Population-based survey of the prevalence and types of glaucoma in Bangladesh","volume":"9","author":"Mannaf","year":"2024","journal-title":"BMJ Open Ophthalmol."},{"key":"ref_6","first-page":"1641","article-title":"The prevalence of primary open-angle glaucoma in Japanese: The Tajimi Study","volume":"111","author":"Iwase","year":"2004","journal-title":"Ophthalmology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.exer.2010.08.004","article-title":"Glaucomatous cupping of the lamina cribrosa: A review of the evidence for active progressive remodeling as a mechanism","volume":"93","author":"Roberts","year":"2011","journal-title":"Exp. Eye Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"101136","DOI":"10.1016\/j.preteyeres.2022.101136","article-title":"Glaucomatous optic neuropathy: Mitochondrial dynamics, dysfunction and protection in retinal ganglion cells","volume":"95","author":"Ju","year":"2023","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1038\/s41591-024-03068-6","article-title":"Peripheral blood mononuclear cell respiratory function is associated with progressive glaucomatous vision loss","volume":"30","author":"Petriti","year":"2024","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Petriti, B., Williams, P.A., Lascaratos, G., Chau, K.Y., and Garway-Heath, D.F. (2021). Neuroprotection in Glaucoma: NAD(+)\/NADH Redox State as a Potential Biomarker and Therapeutic Target. Cells, 10.","DOI":"10.3390\/cells10061402"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"109500","DOI":"10.1016\/j.exer.2023.109500","article-title":"Low mitochondrial DNA copy number in buffy coat DNA of primary open-angle glaucoma patients","volume":"232","author":"Hamers","year":"2023","journal-title":"Exp. Eye Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1074\/jbc.M209909200","article-title":"How does the eye breathe? Evidence for neuroglobin-mediated oxygen supply in the mammalian retina","volume":"278","author":"Schmidt","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Solar Fernandez, V., Marino, M., and Fiocchetti, M. (2021). Neuroglobin in Retinal Neurodegeneration: A Potential Target in Therapeutic Approaches. Cells, 10.","DOI":"10.3390\/cells10113200"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1136\/bjo.2006.093930","article-title":"Neuroglobin in normal retina and retina from eyes with advanced glaucoma","volume":"91","author":"Rajendram","year":"2007","journal-title":"Br. J. Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.ejphar.2004.06.067","article-title":"Effects of neurosteroids on ischemia-reperfusion injury in the rat retina: Role of sigma1 recognition sites","volume":"498","author":"Bucolo","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Choi, E.H., Kim, M.H., and Park, S.J. (2024). Targeting Mitochondrial Dysfunction and Reactive Oxygen Species for Neurodegenerative Disease Treatment. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25147952"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1016\/j.neuron.2021.02.009","article-title":"SARM1 is a metabolic sensor activated by an increased NMN\/NAD(+) ratio to trigger axon degeneration","volume":"109","author":"Figley","year":"2021","journal-title":"Neuron"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.coph.2012.09.008","article-title":"Oxidative stress and mitochondrial dysfunction in glaucoma","volume":"13","author":"Chrysostomou","year":"2013","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1136\/bjo.2003.027664","article-title":"The distributions of mitochondria and sodium channels reflect the specific energy requirements and conduction properties of the human optic nerve head","volume":"88","author":"Barron","year":"2004","journal-title":"Br. J. Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1167\/iovs.07-1361","article-title":"Mitochondrial complex I defect induces ROS release and degeneration in trabecular meshwork cells of POAG patients: Protection by antioxidants","volume":"49","author":"He","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Izzotti, A., Longobardi, M., Cartiglia, C., and Sacc\u00e0, S.C. (2011). Mitochondrial damage in the trabecular meshwork occurs only in primary open-angle glaucoma and in pseudoexfoliative glaucoma. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0014567"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1001\/archophthalmol.2010.87","article-title":"Mitochondrial damage in the trabecular meshwork of patients with glaucoma","volume":"128","author":"Izzotti","year":"2010","journal-title":"Arch. Ophthalmol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Banerjee, D., Banerjee, A., Mookherjee, S., Vishal, M., Mukhopadhyay, A., Sen, A., Basu, A., and Ray, K. (2013). Mitochondrial genome analysis of primary open angle glaucoma patients. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070760"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.mito.2017.05.004","article-title":"Mitochondrial dysfunction in ocular disease: Focus on glaucoma","volume":"35","author":"Kamel","year":"2017","journal-title":"Mitochondrion"},{"key":"ref_25","doi-asserted-by":"crossref","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":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Irnaten, M., and O\u2019Brien, C.J. (2023). Calcium-Signalling in Human Glaucoma Lamina Cribrosa Myofibroblasts. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021287"},{"key":"ref_27","first-page":"1182","article-title":"Oxidative stress, mitochondrial dysfunction and calcium overload in human lamina cribrosa cells from glaucoma donors","volume":"17","author":"McElnea","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1167\/iovs.17-22531","article-title":"Activation of the NFAT-Calcium Signaling Pathway in Human Lamina Cribrosa Cells in Glaucoma","volume":"59","author":"Irnaten","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Strat, A.N., Patel, S., Thanh, M.H., Kirschner, A., Ghosh, S., Geiss, M.P., Venkatesan, A., Bernstein, A.M., Viapiano, M., and Liu, Y. (2025). Compression injury regulates astrocyte morphology, metabolic function, and extracellular matrix modification in a 3D hydrogel. bioRxiv.","DOI":"10.1101\/2025.06.20.660800"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100953","DOI":"10.1016\/j.preteyeres.2021.100953","article-title":"Adaptive responses to neurodegenerative stress in glaucoma","volume":"84","author":"Calkins","year":"2021","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Yang, T.H., Kang, E.Y., Lin, P.H., Yu, B.B., Wang, J.H., Chen, V., and Wang, N.K. (2024). Mitochondria in Retinal Ganglion Cells: Unraveling the Metabolic Nexus and Oxidative Stress. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25168626"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.preteyeres.2013.07.001","article-title":"Retinal ganglion cells: Energetics, compartmentation, axonal transport, cytoskeletons and vulnerability","volume":"36","author":"Yu","year":"2013","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1126\/science.aal0092","article-title":"Vitamin B(3) modulates mitochondrial vulnerability and prevents glaucoma in aged mice","volume":"355","author":"Williams","year":"2017","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.1167\/iovs.12-9596","article-title":"Impaired complex-I-linked respiration and ATP synthesis in primary open-angle glaucoma patient lymphoblasts","volume":"53","author":"Lee","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/gim.2014.121","article-title":"Whole-mitochondrial genome sequencing in primary open-angle glaucoma using massively parallel sequencing identifies novel and known pathogenic variants","volume":"17","author":"Sundaresan","year":"2015","journal-title":"Genet. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1167\/iovs.05-1639","article-title":"Mitochondrial abnormalities in patients with primary open-angle glaucoma","volume":"47","author":"Morales","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Vallbona-Garcia, A., Lindsey, P.J., Kamps, R., Stassen, A.P.M., Nguyen, N., van Tienen, F.H.J., Hamers, I.H.J., Hardij, R., van Gisbergen, M.W., and Benedikter, B.J. (2023). Mitochondrial DNA D-loop variants correlate with a primary open-angle glaucoma subgroup. Front. Ophthalmol., 3.","DOI":"10.3389\/fopht.2023.1309836"},{"key":"ref_38","doi-asserted-by":"crossref","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":"ref_39","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1016\/j.ymthe.2022.01.035","article-title":"NMNAT2 is downregulated in glaucomatous RGCs, and RGC-specific gene therapy rescues neurodegeneration and visual function","volume":"30","author":"Fang","year":"2022","journal-title":"Mol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Gilley, J., and Coleman, M.P. (2010). Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000300"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"E6271","DOI":"10.1073\/pnas.1601506113","article-title":"SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation","volume":"113","author":"Summers","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s40478-024-01736-9","article-title":"Loss of Sarm1 reduces retinal ganglion cell loss in chronic glaucoma","volume":"12","author":"Zeng","year":"2024","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6256","DOI":"10.1038\/s41467-024-50354-5","article-title":"NMNAT2 is a druggable target to drive neuronal NAD production","volume":"15","author":"Tribble","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_44","first-page":"41","article-title":"Oxidative DNA damage and total antioxidant status in glaucoma patients","volume":"17","author":"Sorkhabi","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"983","DOI":"10.3109\/02713683.2013.800889","article-title":"Increased urinary 8-hydroxy-2\u2032-deoxyguanosine (8-OHdG)\/creatinine level is associated with the progression of normal-tension glaucoma","volume":"38","author":"Yuki","year":"2013","journal-title":"Curr. Eye Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Stavropoulos, D., Grewal, M.K., Petriti, B., Chau, K.Y., Hammond, C.J., Garway-Heath, D.F., and Lascaratos, G. (2023). The Role of Mitophagy in Glaucomatous Neurodegeneration. Cells, 12.","DOI":"10.3390\/cells12151969"},{"key":"ref_47","first-page":"2905","article-title":"Systemic mitochondrial function tests as a biomarker for susceptibility to glaucoma and neurodegeneration in an unselected ageing twin population","volume":"64","author":"Ansari","year":"2023","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_48","first-page":"895","article-title":"Lack of blood-brain barrier properties in microvessels of the prelaminar optic nerve head","volume":"42","author":"Hofman","year":"2001","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"S115","DOI":"10.1016\/j.survophthal.2007.08.005","article-title":"Does the blood-brain barrier play a role in Glaucoma?","volume":"52","author":"Grieshaber","year":"2007","journal-title":"Surv. Ophthalmol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"14866","DOI":"10.1021\/acsomega.4c10035","article-title":"Profiling of the Peripheral Blood Mononuclear Cells Proteome by Shotgun Proteomics Identifies Alterations of Immune System Components, Proteolytic Balance, Autophagy, and Mitochondrial Metabolism in Glaucoma Subjects","volume":"10","author":"Giammaria","year":"2025","journal-title":"ACS Omega"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Chiu, T.H., Hung, S.H., Lan, C.H., Yen, W.T., and Lu, D.W. (2025). Update on Nicotinamide and Its Application in the Management of Glaucoma. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262110789"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"108059","DOI":"10.1016\/j.celrep.2020.108059","article-title":"Mitochondrial Regulation of the 26S Proteasome","volume":"32","author":"Meul","year":"2020","journal-title":"Cell Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e105268","DOI":"10.15252\/embj.2020105268","article-title":"Mitochondrial translation deficiency impairs NAD(+)-mediated lysosomal acidification","volume":"40","author":"Yagi","year":"2021","journal-title":"EMBO J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/s41419-024-06770-y","article-title":"Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models","volume":"15","author":"Kataura","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/s41420-018-0077-y","article-title":"Contribution of autophagy to ocular hypertension and neurodegeneration in the DBA\/2J spontaneous glaucoma mouse model","volume":"4","author":"Hirt","year":"2018","journal-title":"Cell Death Discov."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"100916","DOI":"10.1016\/j.preteyeres.2020.100916","article-title":"Inflammation in Glaucoma: From the back to the front of the eye, and beyond","volume":"83","author":"Baudouin","year":"2021","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3530","DOI":"10.1073\/pnas.1812941116","article-title":"Loss of MPC1 reprograms retinal metabolism to impair visual function","volume":"116","author":"Grenell","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Tessema, B., Riemer, J., Sack, U., and K\u00f6nig, B. (2022). Cellular Stress Assay in Peripheral Blood Mononuclear Cells: Factors Influencing Its Results. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232113118"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"103516","DOI":"10.1016\/j.redox.2025.103516","article-title":"Poor glycaemic control in type 2 diabetes compromises leukocyte oxygen consumption rate, OXPHOS complex content and neutrophil-endothelial interactions","volume":"81","author":"Cacace","year":"2025","journal-title":"Redox Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"17012","DOI":"10.1038\/s41598-020-73896-2","article-title":"Simvastatin improves mitochondrial respiration in peripheral blood cells","volume":"10","author":"Durhuus","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Repas, J., Peternel, L., Sourij, H., and Pavlin, M. (2023). Low glucose availability potentiates the effects of metformin on model T cell activation and exhaustion markers in vitro. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1216193"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s12974-025-03638-6","article-title":"NAD(+) depletion drives age-related monocyte hyperinflammation after stroke and is reversed by nicotinamide riboside","volume":"23","author":"Cabrera","year":"2025","journal-title":"J. Neuroinflamm."},{"key":"ref_63","first-page":"1765","article-title":"Preliminary data show normal tension glaucoma patients have lower systemic nicotinamide adenine dinucleotide (NAD+) levels and mitochondrial function compared to controls","volume":"62","author":"Petriti","year":"2021","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.freeradbiomed.2022.07.009","article-title":"Evidence of impaired mitochondrial cellular bioenergetics in ocular fibroblasts derived from glaucoma patients","volume":"189","author":"Vallabh","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jprot.2013.01.008","article-title":"MALDI MS imaging analysis of apolipoprotein E and lysyl oxidase-like 1 in human lens capsules affected by pseudoexfoliation syndrome","volume":"82","author":"Ronci","year":"2013","journal-title":"J. Proteom."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.exer.2009.05.001","article-title":"Identification of LOXL1 protein and Apolipoprotein E as components of surgically isolated pseudoexfoliation material by direct mass spectrometry","volume":"89","author":"Sharma","year":"2009","journal-title":"Exp. Eye Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.freeradbiomed.2025.03.046","article-title":"Mitochondrial and microtubule defects in Exfoliation Glaucoma","volume":"233","author":"Venkatesan","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Venkatesan, A., and Bernstein, A.M. (2025). Protein misfolding and mitochondrial dysfunction in glaucoma. Front. Cell Dev. Biol., 13.","DOI":"10.3389\/fcell.2025.1595121"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"RP105576","DOI":"10.7554\/eLife.105576","article-title":"Pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucoma","volume":"14","author":"Li","year":"2025","journal-title":"eLife"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/s41588-019-0556-y","article-title":"Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression","volume":"52","author":"Craig","year":"2020","journal-title":"Nat. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4764","DOI":"10.1016\/S0021-9258(17)30079-0","article-title":"Oxidation-reduction ratio studies of mitochondria in freeze-trapped samples. NADH and flavoprotein fluorescence signals","volume":"254","author":"Chance","year":"1979","journal-title":"J. Biol. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/0304-4165(85)90064-9","article-title":"Contribution of different enzymes to flavoprotein fluorescence of isolated rat liver mitochondria","volume":"841","author":"Kunz","year":"1985","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/s41433-020-1110-y","article-title":"Functional imaging of mitochondria in retinal diseases using flavoprotein fluorescence","volume":"35","author":"Chen","year":"2021","journal-title":"Eye"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.ogla.2021.12.006","article-title":"Mitochondrial Dysfunction in Primary Open-Angle Glaucoma Characterized by Flavoprotein Fluorescence at the Optic Nerve Head","volume":"5","author":"Zhou","year":"2022","journal-title":"Ophthalmol. Glaucoma"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Caro, R., Chen, A., Mudumbai, R., Duerr, E., Chen, P.P., and Bojikian, K.D. (2025). In vivo imaging of mitochondrial function in normal, glaucoma suspect, and glaucoma eyes. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0317354"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.nbd.2015.05.012","article-title":"Resistance to the most common optic neuropathy is associated with systemic mitochondrial efficiency","volume":"82","author":"Lascaratos","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1080\/15384101.2017.1285631","article-title":"NAD(+) in DNA repair and mitochondrial maintenance","volume":"16","author":"Croteau","year":"2017","journal-title":"Cell Cycle"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1001\/jamaophthalmol.2021.4576","article-title":"Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma: A Phase 2 Randomized Clinical Trial","volume":"140","author":"John","year":"2022","journal-title":"JAMA Ophthalmol."},{"key":"ref_79","doi-asserted-by":"crossref","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":"ref_80","unstructured":"National Library of Medicine (2025, December 28). A Phase III, Double-masked, Randomised, Placebo-controlled Trial Investigating the Safety and Efficacy of Nicotinamide (NAM) to Slow Visual Field Loss in Adults with Open-Angle Glaucoma, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05405868."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1056\/NEJM197311292892208","article-title":"Hepatic toxicity from large doses of vitamin B3 (nicotinamide)","volume":"289","author":"Winter","year":"1973","journal-title":"N. Engl. J. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.ogla.2025.01.002","article-title":"American Glaucoma Society-American Academy of Ophthalmology Position Statement on Nicotinamide Use for Glaucoma Neuroprotection","volume":"8","author":"Shukla","year":"2025","journal-title":"Ophthalmol. Glaucoma"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Paradies, G., Paradies, V., Ruggiero, F.M., and Petrosillo, G. (2019). Role of Cardiolipin in Mitochondrial Function and Dynamics in Health and Disease: Molecular and Pharmacological Aspects. Cells, 8.","DOI":"10.3390\/cells8070728"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1167\/iovs.66.15.66","article-title":"Mitochondrial-Targeted HDAP2 Preserves Retinal Ganglion Cells and Increases Pressure Tolerance in DBA\/2J Mice","volume":"66","author":"MacNeil","year":"2025","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.addr.2018.01.008","article-title":"Ocular delivery of proteins and peptides: Challenges and novel formulation approaches","volume":"126","author":"Mandal","year":"2018","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1016\/j.bbrc.2018.08.016","article-title":"Ubiquinol promotes retinal ganglion cell survival and blocks the apoptotic pathway in ischemic retinal degeneration","volume":"503","author":"Ju","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Al-Megrin, W.A., Soliman, D., Kassab, R.B., Metwally, D.M., Ahmed, E.A.M., and El-Khadragy, M.F. (2020). Coenzyme Q10 Activates the Antioxidant Machinery and Inhibits the Inflammatory and Apoptotic Cascades Against Lead Acetate-Induced Renal Injury in Rats. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.00064"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"104720","DOI":"10.1016\/j.pdpdt.2025.104720","article-title":"Effects of topical coenzyme Q10 in conjunction with vitamin e on the pattern visual evoked potential, visual field, retinal ganglion cell layer and retinal nerve fibre layer thickness in patients with primary open-angle glaucoma","volume":"55","author":"Dogan","year":"2025","journal-title":"Photodiagn. Photodyn. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e81198","DOI":"10.7554\/eLife.81198","article-title":"Metformin protects trabecular meshwork against oxidative injury via activating integrin\/ROCK signals","volume":"12","author":"Xu","year":"2023","journal-title":"eLife"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e002027","DOI":"10.1136\/bmjophth-2024-002027","article-title":"Association of metformin use with primary open-angle glaucoma using data from the National Institutes of Health All of Us Program","volume":"10","author":"Sidhu","year":"2025","journal-title":"BMJ Open Ophthalmol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Toppila, M., Ranta-Aho, S., Kaarniranta, K., Hytti, M., and Kauppinen, A. (2024). Metformin Alleviates Inflammation and Induces Mitophagy in Human Retinal Pigment Epithelium Cells Suffering from Mitochondrial Damage. Cells, 13.","DOI":"10.3390\/cells13171433"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/s41420-025-02824-y","article-title":"Metformin protects retinal ganglion cells in a preclinical model of retinal ischemia\/reperfusion injury and stabilizes visual field in diabetic patients with glaucoma","volume":"11","author":"Satriano","year":"2025","journal-title":"Cell Death Discov."},{"key":"ref_93","unstructured":"National Library of Medicine (2025, December 28). Metformin as a Neuroprotective Therapy for Glaucoma\u2014A Randomized Controlled Trial, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05426044."},{"key":"ref_94","first-page":"1365","article-title":"Loxl1 protein aggregation and impaired mitochondrial bioenergetics in exfoliation glaucoma","volume":"64","author":"Venkatesan","year":"2023","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.exer.2019.02.004","article-title":"Altered unfolded protein response and proteasome impairment in pseudoexfoliation pathogenesis","volume":"181","author":"Hayat","year":"2019","journal-title":"Exp. Eye Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2704\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T05:29:18Z","timestamp":1773811758000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2704"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,16]]},"references-count":95,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062704"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062704","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,16]]}}}