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Updated: Jul 10, 2026
10:50
Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons
Published on: April 24, 2021
IP3R1-mediated Ca2+ overload promotes SAH-induced neuron apoptosis through MAMs
Zhonghua Zhang1, Peipei Shen1, Lin Zong1
1Department of Anesthesiology, Jinling Hospital, Jinling School of Clinical Medicine, Nanjing Medical University, Jiangsu 210000, China.
Cellular Signalling
|July 8, 2026
Summary
Aneurysmal subarachnoid hemorrhage (SAH) disrupts brain cell connections, causing injury. Targeting the IP3R1/GRP75/VDAC1 complex can restore cell communication and protect against SAH-induced brain damage.
Area of Science:
- Neuroscience
- Cell Biology
- Stroke Research
Background:
- Aneurysmal subarachnoid hemorrhage (SAH) is a severe stroke type.
- Mitochondria-associated membranes (MAMs) regulate communication between the endoplasmic reticulum (ER) and mitochondria, crucial for neuronal health.
- Disrupted ER-mitochondrial coupling at MAMs may contribute to early brain injury (EBI) after SAH.
Purpose of the Study:
- Investigate if altered ER-mitochondrial coupling at MAMs contributes to EBI after SAH.
- Examine the role of the IP3R1/GRP75/VDAC1 complex in pathological calcium (Ca2+) transfer.
- Explore therapeutic strategies targeting this complex for SAH treatment.
Main Methods:
- Utilized primary cortical neurons and a mouse SAH model.
- Assessed dynamic changes in MAM structure, ER stress, and Ca2+ handling.
- Employed shRNA-mediated knockdown and lentiviral overexpression of IP3R1 to evaluate its functional role.
Main Results:
- SAH induced decreased ER-mitochondria distance and increased MAM contact area, with upregulated IP3R1/GRP75/VDAC1.
- These changes correlated with heightened ER stress and elevated cytosolic/mitochondrial Ca2+ levels.
- IP3R1 knockdown mitigated SAH-induced damage, reduced ER stress and Ca2+ overload, and decreased neuronal apoptosis.
Conclusions:
- Pathological ER-mitochondria coupling via IP3R1/GRP75/VDAC1 drives Ca2+-mediated neuronal apoptosis in SAH-induced EBI.
- Targeting IP3R1 downregulation offers a potential therapeutic approach to restore MAM homeostasis and reduce brain injury.
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