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Evaluating Cell Death Signaling by Immunofluorescence in a Rat Model of Ischemic Stroke
Published on: January 3, 2025
Inhibiting VDAC1 oligomerization attenuated cerebral ischemia-reperfusion injury by promoting mitophagy via reduced
Xiangna Guo1, Huiyi Jiang2, Yitian Lu3
1Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China; Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510510, China; Department of Sleep and Brain Medicine Center, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, 518000, China.
Abstract:
Increasing evidence highlights the protective role of mitophagy in eliminating damaged mitochondria during ischemic stroke. As a mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1) mediates the elimination of damaged mitochondria through mitophagy. However, whether VDAC1 contributes to cerebral ischemia-reperfusion (I/R) injury and the underlying mechanisms remain unexplored. In this study, we demonstrated that inhibiting VDAC1 oligomerization reduced infarct volume and improved neurological function following cerebral I/R. We further confirmed that inhibiting VDAC1 oligomerization promoted mitophagy, thereby exerting neuroprotective effects. Additionally, VDAC1 knockdown restored mitochondrial membrane potential and decreased mitochondrial reactive oxygen species generation, thereby alleviating mitochondrial damage in neurons subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Mechanistically, we identified the interaction between VDAC1 oligomers and Lon protease 1 (LONP1) as a critical regulator of mitophagy during cerebral I/R injury. Taken together, our findings provide novel insights into the regulation of mitophagy in cerebral I/R injury and suggest that VDAC1 represents a promising therapeutic target for ischemic stroke.
Insights
Inhibiting voltage-dependent anion channel 1 (VDAC1) oligomerization protects the brain from ischemic stroke by enhancing mitophagy, reducing damage, and improving neurological function.
Area of Science:
- Neuroscience
- Cell Biology
- Mitochondrial Biology
Background:
- Mitophagy is crucial for removing damaged mitochondria during ischemic stroke.
- Voltage-dependent anion channel 1 (VDAC1) acts as a gatekeeper for mitophagy.
- The role of VDAC1 in cerebral ischemia-reperfusion (I/R) injury is not well understood.
Purpose of the Study:
- To investigate the role of VDAC1 in cerebral I/R injury.
- To explore the underlying mechanisms by which VDAC1 influences mitophagy and neuroprotection.
Main Methods:
- Inhibition of VDAC1 oligomerization in a cerebral I/R injury model.
- VDAC1 knockdown in neurons subjected to oxygen-glucose deprivation/reoxygenation (OGD/R).
- Assessment of infarct volume, neurological function, mitophagy, mitochondrial membrane potential, and reactive oxygen species (ROS) generation.
- Identification of interacting proteins using co-immunoprecipitation.
Main Results:
- Inhibiting VDAC1 oligomerization reduced infarct volume and improved neurological outcomes after cerebral I/R.
- Promoting mitophagy via VDAC1 inhibition conferred neuroprotective effects.
- VDAC1 knockdown preserved mitochondrial membrane potential and decreased ROS production in OGD/R-treated neurons.
- The interaction between VDAC1 oligomers and Lon protease 1 (LONP1) was identified as a key regulator of mitophagy.
Conclusions:
- VDAC1 oligomerization plays a significant role in cerebral I/R injury.
- Targeting VDAC1 oligomerization enhances mitophagy and offers neuroprotection.
- VDAC1 is a potential therapeutic target for treating ischemic stroke.
