Evidence of impaired mitochondrial cellular bioenergetics in ocular fibroblasts derived from glaucoma patients

Neeru A. Vallabh, Jane Armstrong, Gabriela Czanner, Brian Mc Donagh, Anshoo Choudhary, David N. Criddle, Colin E. Willoughby

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5 Citations (Scopus)
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Abstract

Glaucoma is a progressive optic neuropathy characterized by the neurodegeneration of the retinal ganglion cells (RGCs) resulting in irreversible visual impairment and eventual blindness. RGCs are extremely susceptible to mitochondrial compromise due to their marked bioenergetic requirements and morphology. There is increasing interest in therapies targeting mitochondrial health as a method of preventing visual loss in managing glaucoma. The bioenergetic profile of Tenon's ocular fibroblasts from glaucoma patients and controls was investigated using the Seahorse XF24 analyser. Impaired mitochondrial cellular bioenergetics was detected in glaucomatous ocular fibroblasts including basal respiration, maximal respiration and spare capacity. Spare respiratory capacity levels reflect mitochondrial bio-energetic adaptability in response to pathophysiological stress. Basal oxidative stress was elevated in glaucomatous Tenon's ocular fibroblasts and hydrogen peroxide (H2O2) induced reactive oxygen species (ROS) simulated the glaucomatous condition in normal Tenon's ocular fibroblasts. This work supports the role of therapeutic interventions to target oxidative stress or provide mitochondrial energetic support in glaucoma.
Original languageEnglish
Pages (from-to)102-110
Number of pages9
JournalFree Radical Biology and Medicine
Volume189
Early online date22 Jul 2022
DOIs
Publication statusPublished online - 22 Jul 2022

Bibliographical note

Funding Information:
This work was supported by Glaucoma UK (formerly known as International Glaucoma Association ), Fight for Sight (UK) , and the Royal Liverpool University Hospital Charitable Funds .

Funding Information:
Glaucoma is a progressive optic neuropathy characterized by the neurodegeneration of the retinal ganglion cells (RGCs) resulting in irreversible visual impairment and eventual blindness [1]. In glaucoma, damage and degeneration of RGCs and their axons result in characteristic changes in the appearance of the optic nerve head and patterns of visual field loss [2]. Glaucoma is the leading cause of irreversible blindness worldwide and is estimated to affect over 60 million people globally of which approximately 10% are estimated to be blind from this disease [3]. Glaucoma is an umbrella term for a heterogenous group of optic neuropathies of which primary open angle glaucoma (POAG) is the most prevalent [4]. The pathogenesis of POAG is multifactorial and complex [5,6] but currently lowering intra-ocular pressure (IOP) medically or surgically is the only modifiable risk factor [7]. POAG can be clinically sub-divided into patients with normal IOP, termed normal-tension glaucoma, and those with raised IOP, termed high-tension glaucoma [2,4]. Given that POAG can develop with a normal IOP, and even when IOP is adequately treated and controlled POAG patients can still progress to blindness [8–10], supports the concept that other non-IOP mechanisms can drive glaucoma development and progression.Spare capacity depends on the functional integrity of the electron transport chain and the inner mitochondrial potential, the availability of energetic substrates for oxidation and the maintenance of mitochondrial homeostasis via biogenesis and mitophagy [57]. Oxidative stress has a significant impact on mitochondrial spare capacity [59,60]. Under conditions of oxidative stress, the spare capacity of cells is further depleted, and if the basal respiratory threshold is breached, cell death occurs [59–62]. Spare respiratory capacity levels correlate with the degree of mitochondrial plasticity, allowing bio-energetic adaptability in response to pathophysiological stress, and hence inadequate levels are associated with pathological conditions [57]. In GTFs there was elevated basal oxidative stress compared to NTFs which could represent one mechanism resulting in a reduced spare capacity. Oxidative stress and ageing can induce mitochondrial DNA (mtDNA) mutations impacting mitochondrial bioenergetics including spare capacity, in addition, to contributing to further ROS production [63]. Previous work by our group has demonstrated pathogenic variants in mtDNA extracted from peripheral blood leucocytes and Tenon's ocular fibroblasts from glaucoma patients [30,64]. The results demonstrate that the source of ROS in glaucomatous TFs is not mitochondrial in origin. In this paper we demonstrate elevated ROS and impaired mitochondrial bioenergetics in glaucoma, but the underlying mechanism of ROS induced mitochondrial dysfunction requires further investigation. The mechanistic basis is important to identify therapeutic strategies to reduce ROS, and mitigate impaired mitochondrial bioenergetics, to prevent or reduce RGC loss and protect vision in glaucoma. Several antioxidant-based therapies have been evaluated in experimental glaucoma models and clinical trials [65,66]. Coenzyme Q10 (ubiquinone) is a molecule that shuttles electrons from complex I and I to complex III which maintains the mitochondrial membrane potential, supporting ATP synthesis and inhibiting reactive oxygen species generation [67]. Improvements in retinal ganglion cell health following the topical administration of coenzyme Q10 have been demonstrated in rodent glaucoma models [67–70].This work was supported by Glaucoma UK (formerly known as International Glaucoma Association), Fight for Sight (UK), and the Royal Liverpool University Hospital Charitable Funds.

Publisher Copyright:
© 2022 The Authors

Keywords

  • Tenon's fibroblast
  • Glaucoma
  • Mitochondria
  • Seahorse XF analyserq
  • Oxidative stress
  • Bioenergetics
  • Seahorse XF analyser

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