The Foundation of Decay: Characterizing aging and retinal degeneration with mitochondrial DNA mutation burden.

Abstract

Purpose : Somatic mitochondrial DNA (mtDNA) mutation accumulation has been observed in individuals with retinal degenerative disorders. This study aims to better understand how these mutations are correlated with the onset and progression of retinal degeneration, and to also distinguish these from physiological aging.

Methods : This study utilizes a mouse model of Polymerase gamma (PolgD257A) to evaluate accelerated aging and mtDNA mutation accumulation in the retina. This model has a rapid systemic accumulation of mtDNA mutations due to the inability of PolgD257A to perform the corrective base-excision repair process on mtDNA. 3-, 6-, and 9-month-old PolgD257A mutant, heterozygous, and wild-type (WT) mice were analyzed both functionally and morphologically using in vivo and ex vivo techniques including optical coherence tomography, electroretinography (ERG), histology, immunohistochemistry, electron microscopy, and various other biochemical strategies.

Results : PolgD257A showed a significant reduction in thickness of several retinal layers. In addition, the mutant mouse retina displayed ERG deficits in all recorded responses. Both findings were age-dependent, with the most severe phenotypes observed at 9-months. Analysis of PolgD257A retinal pigment epithelium (RPE) showed an increased abundance in autofluorescent granule formation. In addition, at the ultrastructural level, the PolgD257A RPE showed disordered pigment, disorganized microvilli, improper basal infoldings density, and smaller mitochondria with dilated cristae in comparison to WT cells. Interestingly, there was no significant difference in several measures of oxidative stress analyzed between WT and PolgD257A retina or RPE. However, there was an age-dependent increase in oxidative marker 8-OHdG in the RPE. Polg protein levels remained unchanged in both tissues between genotype and age groups analyzed. Finally, complex proteins of the electron transport chain showed tissue-specific loss in this model as early as 3-months of age, with the loss of complex I and IV appearing preferentially depleted in the retinas and complex I in the RPE.

Conclusions : By identifying and characterizing the contribution of mtDNA mutations in the aging retina, this study suggests that the accumulation of these mutations leads to impaired mitochondrial function and accelerated aging, resulting in retinal degeneration.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.