Destabilizing COXIV in Müller Glia Increases Retinal Glycolysis and Alters Scotopic Electroretinogram
Nana Yaa Nsiah1, Denise M Inman1
1Department of Pharmaceutical Sciences, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Abstract:
Müller glia (MG), the principal glial cell of the retina, have a metabolism that defies categorization into glycolytic versus oxidative. We showed that MG mount a strong hypoxia response to ocular hypertension, raising the question of their relative reliance on mitochondria for function. To explore the role of oxidative phosphorylation (OXPHOS) in MG energy production in vivo, we generated and characterized adult mice in which MG have impaired cytochrome c oxidase (COXIV) activity through knockout of the COXIV constituent COX10. Histochemistry and protein analysis showed that COXIV protein levels were significantly lower in knockout mouse retina compared to control. Loss of COXIV activity in MG did not induce structural abnormalities, though oxidative stress was increased. Electroretinography assessment showed that knocking out COX10 significantly impaired scotopic a- and b-wave responses. Inhibiting mitochondrial respiration in MG also altered the retinal glycolytic profile. However, blocking OXPHOS in MG did not significantly exacerbate retinal ganglion cell (RGC) loss or photopic negative response after ocular hypertension (OHT). These results suggest that MG were able to compensate for reduced COXIV stability by maintaining fundamental processes, but changes in retinal physiology and metabolism-associated proteins indicate subtle changes in MG function.
Insights
Müller glia (MG) in the retina utilize oxidative phosphorylation (OXPHOS) for energy. Impairing this function affects retinal responses but does not worsen glaucoma damage, suggesting MG metabolic flexibility.
Area of Science:
- Ophthalmology
- Neuroscience
- Cellular Metabolism
Background:
- Müller glia (MG) are crucial retinal cells with an unusual metabolism.
- MG exhibit a strong hypoxia response to ocular hypertension, prompting investigation into their mitochondrial reliance.
- Understanding MG energy metabolism is vital for retinal health and disease.
Purpose of the Study:
- To investigate the role of oxidative phosphorylation (OXPHOS) in Müller glia energy production in vivo.
- To determine the functional consequences of impaired OXPHOS in MG on retinal physiology and disease progression.
Main Methods:
- Generated and characterized adult mice with impaired cytochrome c oxidase (COXIV) activity in MG via COX10 knockout.
- Utilized histochemistry, protein analysis, electroretinography, and ocular hypertension models.
- Assessed retinal structure, oxidative stress, electrophysiological responses, and retinal ganglion cell (RGC) survival.
Main Results:
- Reduced COXIV protein levels and increased oxidative stress in MG lacking COX10.
- Significant impairment of scotopic electroretinogram responses (a- and b-waves).
- Altered retinal glycolytic profile and subtle changes in MG function, despite no exacerbated RGC loss under ocular hypertension.
Conclusions:
- Müller glia can compensate for reduced COXIV activity, maintaining fundamental processes.
- Impaired OXPHOS in MG impacts retinal physiology and metabolism but does not worsen glaucomatous damage.
- MG exhibit metabolic flexibility, adapting to reduced mitochondrial respiration.
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