ABSTRACT
Purpose: The lamina cribrosa (LC) is a key site of damage in glaucomatous optic neuropathy. We previously found that glaucoma LC cells have an increased profibrotic gene expression, with mitochondrial dysfunction in the form of decreased mitochondrial membrane potential. Altered cell bioenergetics have recently been reported in organ fibrosis and in cancer. In this study, we carried out a systematic mitochondrial bioenergetic assessment and measured markers of alternative sources of cellular energy in normal and glaucoma LC cells. Methods: LC cells from three glaucoma donors and three age-matched normal controls were assessed using VICTOR X4 Perkin Elmer (Waltham, MA) plate reader with different phosphorescent and luminescent probes. adenosine triphosphate levels, oxygen consumption rate, and extracellular acidification were measured and normalized to total protein content. RNA and protein expression levels of MCT1, MCT4, MTFHD2, and GLS2 were quantified using real-time RT-PCR and Western blotting. Results: Glaucoma LC cells contain significantly less adenosine triphosphate (P < .05) when supplied with either glucose or galactose. They also showed significantly diminished oxygen consumption in both basal and maximal respiration with more lactic acid contribution in ECA. Both mRNA and protein expression levels of MCT1, MCT4, MTHFD2, and GLS2 were significantly increased in glaucoma LC cells. Conclusions: We demonstrate evidence of metabolic reprogramming (The Warburg effect) in glaucoma LC cells. Expression of markers of glycolysis, glutamine, and one carbon metabolism are elevated in glaucoma cells at both the mRNA and protein levels. A better understanding of bioenergetics in glaucoma may help in the development of new therapeutics.
Subject(s)
Glaucoma, Open-Angle/metabolism , Glycolysis/physiology , Mitochondrial Diseases/metabolism , Optic Disk/metabolism , Optic Nerve Diseases/metabolism , Oxidative Phosphorylation , Adenosine Triphosphate/metabolism , Aminohydrolases/genetics , Aminohydrolases/metabolism , Biomarkers , Blotting, Western , Cells, Cultured , Gene Expression Profiling , Glaucoma, Open-Angle/pathology , Glial Fibrillary Acidic Protein/metabolism , Glutaminase/genetics , Glutaminase/metabolism , Humans , Methylenetetrahydrofolate Dehydrogenase (NADP)/genetics , Methylenetetrahydrofolate Dehydrogenase (NADP)/metabolism , Mitochondrial Diseases/pathology , Monocarboxylic Acid Transporters/genetics , Monocarboxylic Acid Transporters/metabolism , Multifunctional Enzymes/genetics , Multifunctional Enzymes/metabolism , Muscle Proteins/genetics , Muscle Proteins/metabolism , Optic Disk/pathology , Optic Nerve Diseases/pathology , Oxygen Consumption/physiology , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Symporters/genetics , Symporters/metabolism , Tissue DonorsABSTRACT
BACKGROUND: Patients at glaucoma risk are commonly identified by optometrists and subsequently referred to glaucoma specialists. Optometrists mainly use non-contact tonometry (NCT) for intraocular pressure (IOP) measurement. AIMS: To investigate the role of differences in IOP measurement between NCT and Goldmann applanation tonometry (GAT) and the effect of central corneal thickness (CCT) on these differences in optometrist referrals METHODS: Details of the initial clinical visit of patients referred with IOP > 21 mmHg in either eye as measured by NCT to a consultant glaucoma specialist were retrospectively reviewed. Demographic and referral data, IOP, CCT, and glaucoma diagnosis were obtained. The main outcome measure was the IOP measurement differences between NCT and GAT. RESULTS: Of the 98 patients referred, only 23% had IOP > 21 mmHg when measured by GAT. NCT (Nidek NT400, Reichert Puff, Pulsair Easy Eye) measured the IOP greater than GAT by a mean of 5.8 mmHg (NCT 24.1 ± 3.5, GAT 18.3 ± 3.0). The effect of CCT on IOP measurement was less for GAT (R2 0.034, p = 0.067) than for NCT (R2 0.088, p = 0.003). The NCT/GAT IOP differences increased with increasing CCT (R2 0.166, p < 0.0001). The NCT/GAT differences decreased with patient age (R2 0.048, p = 0.03). Patients were classified as normal 67% (66/98), ocular hypertension 11% (11/98), glaucoma suspect 14% (14/98), and glaucoma 7% (7/98). CONCLUSIONS: The difference in IOP measurement between NCT and GAT leads to a possible increase in glaucoma referrals, particularly in patients with thicker corneas. Repeat IOP using GAT and CCT measurement would help in triaging referrals.
Subject(s)
Cornea/pathology , Glaucoma/diagnosis , Intraocular Pressure/physiology , Tonometry, Ocular/instrumentation , Adult , Aged , Aged, 80 and over , Corneal Pachymetry , Female , Humans , Male , Middle Aged , Organ Size , Referral and Consultation , Retrospective Studies , Tonometry, Ocular/methodsABSTRACT
In this review, we present an update on biomarkers (both clinical and laboratory) on the basis of recent peer-reviewed publications relating to pseudoexfoliation syndrome and pseudoexfoliation glaucoma.
Subject(s)
Biomarkers/metabolism , Exfoliation Syndrome/metabolism , Glaucoma, Open-Angle/metabolism , Actins/metabolism , Collagen Type I/metabolism , Collagen Type I, alpha 1 Chain , Connective Tissue Growth Factor/metabolism , Fibrillin-1/metabolism , Fibronectins/metabolism , Humans , Intraocular PressureABSTRACT
Mitochondrial dysfunction commonly presents with ocular findings as a part of a systemic disorder. These ophthalmic manifestations can be the first sign of a mitochondrial abnormality, which highlights the key role of a comprehensive ophthalmic assessment. On the other hand, a number of visually disabling genetic and acquired eye diseases with no curative treatment show abnormal mitochondrial function. Recent advances in mitochondrial research have improved our understanding of previously unexplained ocular disorders utilising better diagnostic approaches. Further studies on mitochondrial dysfunction and novel modalities of treatment will help to improve outcomes of these conditions. In this review article we discuss the clinical picture of common mitochondrial-related eye diseases, diagnostic approaches and possible treatment options including a very recent interesting report about gene therapy, with a particular focus on glaucoma.
