Characterization of Mitochondrial and Metabolic Changes Following Retinal Detachment
Authors: Diaz‐Aguilar Daniel , LI Zhaohui , Khadka Arogya , Jacobo Sarah , Connor Kip , Saint‐Geniez Magali 
Published: November 2023

Retinal detachment (RD) is a leading cause of photoreceptor (PR) degeneration and vision loss. RD is thought to induce rapid retinal degeneration by separating the highly metabolic PRs from their main source of oxygen and metabolites, RPE and choroidal vasculature. Despite the compelling evidences that PR cell death secondary to RD is caused by metabolic alterations and oxidative damage, the effect of RD‐dependent energetic failure on PR function and survival has not been investigated. The proposed study is designed to characterize the effect of RD on PR metabolism using vivo and vitro models.

Using a mouse model of RD, we observed significant changes in expression of the transcriptional co‐activators, PGC‐1α and PGC‐1β following injury. The PGC‐1 isoforms are transcriptional co‐activators that powerfully regulate mitochondrial biogenesis and oxidative metabolism in many tissues. However, little is known of their functions in PR biology under normal and pathological conditions. Gene expression analysis in a mouse model of retinal detachment showed significant upregulation of PGC‐1α and PGC‐1β expression as early as 3 hours retinal post‐injury. Consistent with these results, several downstream genes involved in redox homeostasis and mitochondrial biosynthesis, including superoxide dismutase 2 and estrogen‐related receptor α, were also induced. Cytochrome oxidase subunit IV staining indicated increase in retinal mitochondrial content at 48 hours post‐detachment that was most prominent within the PR inner segments. Characterization of specific effects of RD‐induced hypoxia and hypoglycemia on PR metabolism was conducted using the mouse cone‐like 661w cell line under conditions of relative glucose and/or oxygen depletion. High‐resolution respirometry demonstrated an increase in 661w basal respiration, ATP leak, maximal respiration and non‐mitochondrial respiration after 3 hours of low glucose (LG) exposure and continuing for up to 18 hours. In concordance with these results, we show that LG leads to a reduction in mitochondrial DNA lesions after 48 hours of exposure when compared to normal conditions.

In summary, we demonstrate a change in metabolic RNA expression as well as functional mitochondrial count and activity following retinal detachment or decreased glucose availability. Contrary to RD, low glucose alone shows reduced mitochondrial DNA damage, suggesting that the hypoxic insult or the combination of LG and low O2 is required for PR oxidative stress and degeneration. Further characterization of the combined effects of these stressors are needed to fully evaluate the protective role of Pgc1α and may lead to beneficial therapeutic options for patients with RD and other ocular diseases.

Support or Funding Information

Funded by the National Institutes of Health (1R01EY023682, M.S.G.), a Research to Prevent Blindness Dolly Green Special Scholar Award (M.S.G), and a Research to Prevent Blindness Medical Student Eye Research Fellowship (D.D.A)