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Targeting VDAC1 to protect against mitochondria-linked cell death pathways: apoptosis, pyroptosis, ferroptosis, and
A Shteinfer-Kuzmine1, A Karunanithi Nivedita2, M Santhanam2
1National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, 84105, Beer-Sheva, Israel.
Abstract:
The pathways of programmed cell death (PCD), including apoptosis, pyroptosis, and ferroptosis, are interconnected. They can be activated simultaneously within tissues or cell lines and are often associated with various diseases. Thus, identifying a common player and inhibitor targeting several PCD types is essential. Here, we show that overexpression and oligomerization of the mitochondrial gatekeeper voltage-dependent anion channel 1 (VDAC1) is involved in apoptosis, pyroptosis, and ferroptosis, and specific VDAC1 oligomerization inhibitors, VBIT-4 and VBIT-12, prevented multiple forms of PCD triggered by various stimuli. In addition, they mitigated mitochondrial dysfunction, reduced reactive oxygen species production and intracellular Ca2⁺ levels, preserved mitochondrial-associated hexokinase, and inhibited assembly/activation of the NLRP3 inflammasome. In Alzheimer's disease and inflammatory bowel disease mouse models, VBIT-4 and VBIT-12, respectively, protected against apoptosis, pyroptosis, ferroptosis, and disease-associated pathologies. Thus, we show that VDAC1 oligomerization represents a prime target for VBIT-4 and VBIT-12 that can simultaneously inhibit various PCD forms and diseases associated with enhanced PCD and/or inflammation.
Insights
Targeting voltage-dependent anion channel 1 (VDAC1) oligomerization with VBIT-4 and VBIT-12 offers a novel approach to simultaneously inhibit multiple programmed cell death (PCD) pathways, including apoptosis, pyroptosis, and ferroptosis, and mitigate associated diseases.
Area of Science:
- Cell Biology
- Biochemistry
- Pathology
Background:
- Programmed cell death (PCD) pathways like apoptosis, pyroptosis, and ferroptosis are interconnected and implicated in various diseases.
- A common therapeutic target for multiple PCD types is crucial for disease intervention.
Purpose of the Study:
- To investigate the role of mitochondrial VDAC1 oligomerization in diverse PCD pathways.
- To evaluate VDAC1 oligomerization inhibitors (VBIT-4, VBIT-12) as potential treatments for multiple PCD forms and associated pathologies.
Main Methods:
- Overexpression and oligomerization studies of VDAC1.
- Treatment with VBIT-4 and VBIT-12 in cellular and mouse models.
- Assessment of PCD markers, mitochondrial function, reactive oxygen species (ROS), intracellular calcium, hexokinase association, and inflammasome activation.
- Evaluation in Alzheimer's disease and inflammatory bowel disease mouse models.
Main Results:
- VDAC1 overexpression and oligomerization were found to be involved in apoptosis, pyroptosis, and ferroptosis.
- VBIT-4 and VBIT-12 effectively inhibited these PCD pathways across various stimuli.
- Inhibitors mitigated mitochondrial dysfunction, reduced ROS and Ca2+ levels, preserved hexokinase, and inhibited NLRP3 inflammasome activation.
- VBIT-4 and VBIT-12 demonstrated therapeutic effects in Alzheimer's and inflammatory bowel disease models, respectively.
Conclusions:
- VDAC1 oligomerization is a common mechanism underlying multiple PCD pathways.
- VBIT-4 and VBIT-12 are potent inhibitors of VDAC1 oligomerization, offering a dual therapeutic strategy.
- Targeting VDAC1 oligomerization presents a promising approach for treating PCD-associated diseases and inflammation.
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