Diet Restriction Improves Inner Retinal Recovery Following IOP Injury In Mice With Mitochondrial Dysfunction

Abstract

 

Purpose:

 

Accumulation of mitochondrial DNA mutations may render the aging optic nerve vulnerable to injury by external stressors such as IOP elevation. We have shown that alternate day fasting, improves functional optic nerve recovery after IOP elevation in healthy aging mice. As patients with glaucoma may have additional mitochondrial dysfunction over and above that associated with normal aging, we sought to determine whether DR also protects the retinas of transgenic mice with additional mitochondrial dysfunction.

 

Methods:

 

Two transgenic mouse lines with impaired mitochondrial function due to: mismatch in nuclear and mitochondrial encoded OXPHOS complex proteins (xenomitochondrial mouse) or a neuron-specific mutation in mtDNA polymerase proof reading (POLG mouse) were subject to alternate day fasting from 6 to 12months of age(n=6). Ad libitum fed age-matched littermates served as controls. One eye of each mouse was then subject IOP elevation (50mmHg, 30 mins). Inner retinal function was determined at day 1 and 7 post injury and compared to the fellow eye. Oxidative stress was also quantified by western blot.

 

Results:

 

Both mitochondrial transgenic lines had less recovery compared to wildtype mice (p<0.01). Diet restriction led to a significant improvement in inner retina recovery in all mice, such that recovery was similar to that seen in ad libitum fed wildtype mice (53.6 ± 8.2, see table below). The xenomitochondrial mouse had an overall significant increase in oxidative stress, which was not observed in the POLG mouse. Oxidative stress was ameliorated by DR for all strains.

 

Conclusions:

 

Alternate day fasting improves inner retinal recovery in mice with pathological mitochondrial dysfunction due to distinct causes, one with elevated oxidative stress, the other with normal levels of oxidative stress (for age). Mimetics of caloric restriction may thus provide avenues for protecting vulnerable optic nerves with mitochondrial dysfunction.  

 

Keywords: aging • mitochondria • electroretinography: non-clinical