Inhibition of mitochondrial VDAC1 oligomerization alleviates apoptosis and necroptosis of retinal neurons following OGD/R injury

by Selleckchem | Oct 26 2023

Ischemia-reperfusion (I/R) injury is a common pathological mechanism in many retinal diseases, which can lead to cell death via mitochondrial dysfunction. Voltage-dependent anion channel 1 (VDAC1), which is mainly located in the outer mitochondrial membrane, is the gatekeeper of mitochondria. The permeability of mitochondrial membrane can be regulated by controlling the oligomerization of VDAC1. However, the functional mechanism of VDAC1 in retinal I/R injury was unclear. Our results demonstrate that oxygen-glucose deprivation and re-oxygenation (OGD/R) injury leads to apoptosis, necroptosis, and mitochondrial dysfunction of R28 cells. The OGD/R injury increases the levels of VDAC1 oligomerization. Inhibition of VDAC1 oligomerization by VBIT-12 rescued mitochondrial dysfunction by OGD/R and also reduced apoptosis/necroptosis of R28 cells. In vivo, the use of VBIT-12 significantly reduced aHIOP-induced neuronal death (apoptosis/necroptosis) in the rat retina. Our findings indicate that VDAC1 oligomers may open and enlarge mitochondrial membrane pores during OGD/R injury, leading to the release of death-related factors in mitochondria, resulting in apoptosis and necroptosis. This study provides a potential therapeutic strategy against ocular diseases caused by I/R injury.Ischemia-reperfusion (I/R) injury is a common pathological mechanism in many retinal diseases, which can lead to cell death via mitochondrial dysfunction. Voltage-dependent anion channel 1 (VDAC1), which is mainly located in the outer mitochondrial membrane, is the gatekeeper of mitochondria. The permeability of mitochondrial membrane can be regulated by controlling the oligomerization of VDAC1. However, the functional mechanism of VDAC1 in retinal I/R injury was unclear. Our results demonstrate that oxygen-glucose deprivation and re-oxygenation (OGD/R) injury leads to apoptosis, necroptosis, and mitochondrial dysfunction of R28 cells. The OGD/R injury increases the levels of VDAC1 oligomerization. Inhibition of VDAC1 oligomerization by VBIT-12 rescued mitochondrial dysfunction by OGD/R and also reduced apoptosis/necroptosis of R28 cells. In vivo, the use of VBIT-12 significantly reduced aHIOP-induced neuronal death (apoptosis/necroptosis) in the rat retina. Our findings indicate that VDAC1 oligomers may open and enlarge mitochondrial membrane pores during OGD/R injury, leading to the release of death-related factors in mitochondria, resulting in apoptosis and necroptosis. This study provides a potential therapeutic strategy against ocular diseases caused by I/R injury.

Comments:

Your provided information describes a study that investigated the role of Voltage-dependent anion channel 1 (VDAC1) in retinal ischemia-reperfusion (I/R) injury. Ischemia-reperfusion injury occurs when blood supply to a tissue, in this case, the retina, is temporarily blocked and then restored. This process can lead to cellular damage and dysfunction. The study focused on the effects of oxygen-glucose deprivation and re-oxygenation (OGD/R) injury on retinal cells (R28 cells) and the potential therapeutic strategy to mitigate the damage caused by I/R injury.

The results of the study showed that OGD/R injury caused apoptosis (programmed cell death), necroptosis (a form of programmed necrosis), and mitochondrial dysfunction in R28 cells. The researchers also observed an increase in the levels of VDAC1 oligomerization, which refers to the formation of complexes or clusters of VDAC1 proteins.

VDAC1 is a protein primarily located in the outer mitochondrial membrane and plays a crucial role in regulating the permeability of the mitochondrial membrane. The researchers hypothesized that the oligomerization of VDAC1 may affect the permeability of the mitochondrial membrane and contribute to mitochondrial dysfunction during OGD/R injury.

To test this hypothesis, the researchers used a compound called VBIT-12, which inhibits VDAC1 oligomerization. They found that treatment with VBIT-12 rescued mitochondrial dysfunction caused by OGD/R injury and also reduced apoptosis and necroptosis in R28 cells.

Additionally, the researchers conducted in vivo experiments using rats. They induced retinal ischemia-reperfusion injury in the rats (aHIOP-induced neuronal death) and treated them with VBIT-12. The use of VBIT-12 significantly reduced the neuronal death (apoptosis/necroptosis) in the rat retina.

Based on these findings, the study suggests that VDAC1 oligomerization plays a role in opening and enlarging mitochondrial membrane pores during OGD/R injury. This process may lead to the release of death-related factors from the mitochondria, ultimately resulting in apoptosis and necroptosis. The inhibition of VDAC1 oligomerization by VBIT-12 showed promising results in rescuing mitochondrial dysfunction and reducing cell death in both in vitro and in vivo models.

The study's implications propose a potential therapeutic strategy for treating ocular diseases caused by ischemia-reperfusion injury by targeting VDAC1 oligomerization. Further research and clinical trials would be necessary to validate the efficacy and safety of this therapeutic approach in humans.