Increase In Mitochondrial DNA Mutations Impairs Retinal Function And Increase Retinal Ganglion Cell Susceptibility To Injury

Abstract

 

Purpose:

 

Acquired mitochondrial DNA (mtDNA) mutations in neurons and other tissues are a hallmark of biological aging. This study determined whether mtDNA mutations impact on retinal ganglion cell (RGC) function and the RGC response to intraocular pressure (IOP) elevation.

 

Methods:

 

We employed a transgenic mouse model with a neural-targeted proof-reading defect in mitochondrial polymerase gamma that acquires mtDNA mutations at a faster rate than normal. Transgenic (POLG) and wildtype littermate (WT) at 3 and 12 months of age were dark adapted for measurement of baseline retinal function using the full-field scotopic electroretinogram (ERG). Retinal response to progressive IOP elevation (12 - 80 mmHg) via anterior chamber cannulation was examined on 12-month old POLG and WT mice. ERG was analyzed in terms of retinal ganglion cell (positive scotopic threshold response, pSTR), ON-bipolar cell (b-wave) and photoreceptor (a-wave) responses. Statistical comparisons were performed using Student’s t-test.

 

Results:

 

Three month old POLG mice(n=7) showed no differences in retinal response compared with controls (n=10). However at 12 months of age, POLG mice (n=13) showed 43±9% reduction in pSTR amplitude (RGC,P<0.01) and a 29±8% reduction in b-wave amplitude (bipolar cells, P<0.05) compared with controls(n=8), despite having normal a-wave. POLG mice also showed increased susceptibility to IOP elevation(Figure); IOP required to cause 50% reduction in pSTR was significantly lower for POLG mice (31 mmHg,95% CI[27,34]) than controls (42 mmHg,95% CI[38,46]). These changes correlated with mtDNA mutations and reduced mitochondrial enzyme activity (by 36±9%) in the retina.

 

Conclusions:

 

The accumulation of mtDNA mutations leads to accelerated loss of retinal function and reduced capacity to withstand IOP stress, providing a potential mechanism whereby increasing age predisposes to glaucoma.  

 

Keywords: aging • mitochondria • ganglion cells