title: Resistance to the most common optic neuropathy is associated with systemic mitochondrial efficiency.
abstract: Glaucomatous optic neuropathy, an important neurodegenerative condition and the commonest optic neuropathy in humans, is the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with ageing and raised intraocular pressure (IOP). Using glaucomatous optic neuropathy as an exemplar for neurodegeneration, this study investigates putative factors imparting resistance to neurodegeneration. Systemic mitochondrial function, oxidative stress and vascular parameters were compared from isolated lymphocytes, whole blood and urine samples between 30 patients who have not developed the neuropathy despite being exposed for many years to very high IOP ('resistant'), 30 fast deteriorating glaucoma patients despite having low IOP ('susceptible'), and 30 age-similar controls. We found that 'resistant' individuals showed significantly higher rates of ADP phosphorylation by mitochondrial respiratory complexes I, II and IV, hyperpolarised mitochondrial membrane potential, higher levels of mitochondrial DNA, and enhanced capacity to deal with cytosolic calcium overload and exogenous oxidative stress, as compared to both controls and glaucoma patients. While it has been known for some years that mitochondrial dysfunction is implicated in neurodegeneration, this study provides a fresh perspective to the field of neurodegeneration by providing, for the first time, evidence that systemic mitochondrial efficiency above normal healthy levels is associated with an enhanced ability to withstand optic nerve injury. These results demonstrate the importance of cellular bioenergetics in glaucomatous disease progression, with potential relevance for other neurodegenerative disorders, and raise the possibility for new therapeutic targets in the field of neurodegeneration.
authors.affiliation: NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK. Electronic address: glascaratos@gmail.com.
authors.forename: Gerassimos
authors.initials: G
authors.lastname: Lascaratos
authors.affiliation: Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK.
authors.forename: Kai-Yin
authors.initials: KY
authors.lastname: Chau
authors.affiliation: Department of Optometry and Visual Science, City University, London, UK.
authors.forename: Haogang
authors.initials: H
authors.lastname: Zhu
authors.affiliation: NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
authors.forename: Despoina
authors.initials: D
authors.lastname: Gkotsi
authors.affiliation: Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK.
authors.forename: Rosalind
authors.initials: R
authors.lastname: King
authors.affiliation: UCL Institute of Structural and Molecular Biology, London, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Gout
authors.affiliation: NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Kamal
authors.affiliation: NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK; Department of Pathology, UCL Institute of Ophthalmology, London, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Luthert
authors.affiliation: Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK.
authors.forename: Anthony H V
authors.initials: AHV
authors.lastname: Schapira
authors.affiliation: NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
authors.forename: David F
authors.initials: DF
authors.lastname: Garway-Heath
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D004272:DNA, Mitochondrial; D005260:Female; D005901:Glaucoma / Q000150:complications / Q000378:metabolism*; D006801:Humans; D007429:Intraocular Pressure / Q000502:physiology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D009901:Optic Nerve Diseases / Q000209:etiology / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D011446:Prospective Studies
chemical_list: D004272:DNA, Mitochondrial
keywords: Glaucoma; Intraocular pressure; Mitochondria; Neurodegeneration; Normal tension glaucoma; Ocular hypertension