Exacerbated mitochondrial fusion abrogates mitophagy and leads to pro‐inflammatory signalling in Müller glia during diabetic retinopathy

Purpose: To determine how the dysregulated interplay between mitochondrial dynamics and mitophagy contribute to the progression of diabetic retinopathy [DR]. Methods: 3‐months and 9‐month‐old diabetic mitophagy reporter (MitoQC‐Ins2Akita) mice and their non‐diabetic siblings, were used to evaluate t...

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Bibliographic Details
Published in:Acta ophthalmologica (Oxford, England) England), 2022-12, Vol.100 (S275), p.n/a
Main Authors: Anderson, Aidan, Alfahad, Nada, Ganley, Ian G., Rauz, Saaeha, Wallace, Graham, Curtis, Tim M., Romero, Jose M.
Format: Article
Language:English
Subjects:
Cell fusion
Diabetes
Diabetes mellitus
Diabetic retinopathy
Fitness
Hyperglycemia
Inflammation
Membrane potential
Metabolic flux
Mitochondria
Mitophagy
Monocyte chemoattractant protein 1
Morphometry
Mueller cells
Peptides
Quality control
Retina
Retinopathy
Secretome
Vascular endothelial growth factor
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Summary:Purpose: To determine how the dysregulated interplay between mitochondrial dynamics and mitophagy contribute to the progression of diabetic retinopathy [DR]. Methods: 3‐months and 9‐month‐old diabetic mitophagy reporter (MitoQC‐Ins2Akita) mice and their non‐diabetic siblings, were used to evaluate the interplay between mitochondrial dynamics and mitophagy by confocal morphometry. To model the dysregulation of mitochondrial quality control processes in vitro, mitochondrial fission was antagonized in retinal Müller cells (mouse primary and MIO‐M1 cell‐line) using a Drp1 inhibitor peptide (P110), under physiological (5.5 mM) and elevated glucose (30.5 mM) conditions. Mitochondrial fitness was assessed via metabolic flux (Seahorse) along with mitochondrial membrane potential (JC‐1), while the Müller glia inflammatory secretome was determined using Luminex. Results: In contrast to younger ages, 9‐month‐old diabetic mice displayed exacerbated mitochondrial fusion at the outer retina (e.g., increased interconnectivity and mitochondrial aspect ratios), which was strongly associated with impaired mitophagy levels (r2 = 0.7, p 
ISSN:1755-375X
1755-3768
DOI:10.1111/j.1755-3768.2022.0350