Vdac1-KO Mouse

Vdac1, also known as voltage-dependent anion channel 1, is a crucial regulator of mitochondrial function, acting as a mitochondrial gatekeeper. It is located in the outer mitochondrial membrane and is involved in multiple key cellular processes, such as controlling energy sources, metabolism, epigenomic elements, apoptosis, endoplasmic reticulum-mitochondria cross-talk, autophagy, and inflammation [1]. It interacts with over 100 proteins, orchestrating mitochondrial and cellular activities through various signaling pathways.

In Alzheimer's disease (AD), Vdac1 is overexpressed post-mortem in patients' brains and in amyloid precursor protein (APP) transgenic mice. Targeting Vdac1 with VBIT-4 in a 5×FAD mouse model of AD prevented associated pathophysiological changes like neuronal cell death, neuroinflammation, and cognitive decline, suggesting Vdac1 as a potential therapeutic target for AD [2,5]. In liver fibrosis, Parkin-mediated site-specific ubiquitination of Vdac1 at lysine 53 interrupted Vdac1 oligomerization and mitochondrial DNA release, with Parkin knockout aggravating the effects, indicating the importance of Vdac1 regulation in liver fibrosis [3]. In inflammatory bowel disease, Vdac1 is overexpressed in the colon of patients and DSS-treated mice. Treatment with VBIT-12, a Vdac1-interacting molecule, suppressed various symptoms of inflammation and apoptosis in DSS-treated mice [4].

In conclusion, Vdac1 is essential for maintaining mitochondrial function and is involved in numerous cellular processes. Model-based research, especially using mouse models, has revealed its significance in diseases such as Alzheimer's disease, liver fibrosis, and inflammatory bowel disease. These studies suggest that targeting Vdac1 could be a promising strategy for treating these diseases.

References:

1. Shoshan-Barmatz, Varda, Shteinfer-Kuzmine, Anna, Verma, Ankit. 2020. VDAC1 at the Intersection of Cell Metabolism, Apoptosis, and Diseases. In Biomolecules, 10, . doi:10.3390/biom10111485. https://pubmed.ncbi.nlm.nih.gov/33114780/

2. Shoshan-Barmatz, Varda, Nahon-Crystal, Edna, Shteinfer-Kuzmine, Anna, Gupta, Rajeev. 2018. VDAC1, mitochondrial dysfunction, and Alzheimer's disease. In Pharmacological research, 131, 87-101. doi:10.1016/j.phrs.2018.03.010. https://pubmed.ncbi.nlm.nih.gov/29551631/

3. Wu, Ne N, Wang, Lifeng, Wang, Lu, Zhang, Yingmei, Ren, Jun. 2023. Site-specific ubiquitination of VDAC1 restricts its oligomerization and mitochondrial DNA release in liver fibrosis. In Experimental & molecular medicine, 55, 269-280. doi:10.1038/s12276-022-00923-9. https://pubmed.ncbi.nlm.nih.gov/36658227/

4. Verma, Ankit, Pittala, Srinivas, Alhozeel, Belal, Chung, Jay H, Shoshan-Barmatz, Varda. 2021. The role of the mitochondrial protein VDAC1 in inflammatory bowel disease: a potential therapeutic target. In Molecular therapy : the journal of the American Society of Gene Therapy, 30, 726-744. doi:10.1016/j.ymthe.2021.06.024. https://pubmed.ncbi.nlm.nih.gov/34217890/

5. Verma, Ankit, Shteinfer-Kuzmine, Anna, Kamenetsky, Nikita, Knafo, Shira, Shoshan-Barmatz, Varda. 2022. Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer's disease protects against mitochondrial dysfunction and mitigates brain pathology. In Translational neurodegeneration, 11, 58. doi:10.1186/s40035-022-00329-7. https://pubmed.ncbi.nlm.nih.gov/36578022/