Metformin protects against retinal ischemia/reperfusion injury through AMPK-mediated mitochondrial fusion

by Selleckchem | Sep 22 2023

Retinal ischemia/reperfusion (I/R) injury is a common pathological process responsible for cellular damage in glaucoma, diabetic retinopathy and hypertensive retinopathy. Metformin is a biguanide drug that exerts strong effects on multiple diseases. This study aims to evaluate the protective effect of metformin against retinal I/R injury and its underlying mechanism. I/R induced reduction in retina thickness and cell number in ganglion cell layer, and metformin alleviated I/R-induced retinal injury. Both retinal I/R and simulated ischemia/reperfusion (SIR) in R28 cells down-regulated expression of mitochondrial fusion protein Mfn2 and OPA1, which led to mitochondrial fission. Metformin also alleviated damage in R28 cells, and reversed the alteration in Mfn2 and OPA1, mitochondrial fission and mitochondrial membrane potential (MMP) disruption-induced by I/R or SIR as well. Intriguingly, inhibition of AMPK by compound C or siRNA prevented metformin-mediated up-regulation of Mfn2 and OPA1. Compound C and knockdown of Mfn2 or OPA1 dramatically alleviated the protective effect of metformin against intracellular ROS generation, MMP disruption, mitochondrial fission and loss of RGCs in ganglion cell layer induced by SIR or I/R. Moreover, scavenging mitochondrial ROS (mito-ROS) by mito-TEMPO exerted the similar protection against I/R-induced retinal injury or SIR-induced damage in R28 cells as metformin. Our data show for the first time that metformin protects against retinal I/R injury through AMPK-mediated mitochondrial fusion and the decreased mito-ROS generation. These findings might also repurpose metformin as a therapeutic agent for retinal I/R injury.

Comments:

The study you mentioned aimed to investigate the protective effects of metformin against retinal ischemia/reperfusion (I/R) injury and its underlying mechanisms. Retinal I/R injury is a common pathological process that contributes to cellular damage in conditions such as glaucoma, diabetic retinopathy, and hypertensive retinopathy.

The researchers observed that retinal I/R led to a reduction in retina thickness and the number of cells in the ganglion cell layer. However, treatment with metformin alleviated the retinal injury induced by I/R. The study also used simulated ischemia/reperfusion (SIR) in R28 cells, which are a commonly used retinal cell line.

Both retinal I/R and SIR in R28 cells resulted in a down-regulation of the expression of mitochondrial fusion proteins called Mfn2 and OPA1. This down-regulation led to mitochondrial fission, a process where mitochondria undergo fragmentation. Metformin treatment reversed the alterations in Mfn2 and OPA1 expression, inhibited mitochondrial fission, and prevented mitochondrial membrane potential (MMP) disruption induced by I/R or SIR.

Interestingly, the study found that the protective effects of metformin on mitochondrial fusion and function were mediated through the activation of AMP-activated protein kinase (AMPK), a cellular energy sensor. Inhibition of AMPK using a compound called compound C or small interfering RNA (siRNA) prevented the up-regulation of Mfn2 and OPA1 by metformin.

To further investigate the role of mitochondrial fusion in the protective effects of metformin, the researchers used compound C and knockdown techniques to inhibit Mfn2 or OPA1. They observed that inhibiting AMPK or suppressing Mfn2 or OPA1 significantly reduced the protective effect of metformin against intracellular reactive oxygen species (ROS) generation, MMP disruption, mitochondrial fission, and loss of retinal ganglion cells (RGCs) in the ganglion cell layer induced by SIR or I/R.

Moreover, the study demonstrated that scavenging mitochondrial ROS (mito-ROS) using a compound called mito-TEMPO exerted similar protective effects against I/R-induced retinal injury or SIR-induced damage in R28 cells, as observed with metformin treatment.

In summary, this study provides evidence that metformin protects against retinal I/R injury through AMPK-mediated mitochondrial fusion and the suppression of mito-ROS generation. These findings suggest that metformin could potentially be repurposed as a therapeutic agent for retinal I/R injury in conditions such as glaucoma, diabetic retinopathy, and hypertensive retinopathy. However, further research is needed to validate these findings and evaluate the potential clinical application of metformin in the context of retinal I/R injury.