Shteinfer-Kuzmine Anna, Moyal Meital M, Karunanithi Nivedita Aditya, Trishna Sweta, Nadir Almog, Tripathi Shubhandra, Shoshan-Barmatz Varda
National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Pharmaceuticals (Basel). 2025 May 20;18(5):757. doi: 10.3390/ph18050757.
Besides diabetes mellitus, metformin has been identified as a potential therapeutic agent for treating various other conditions that include various cancers, cardiovascular diseases, neurodegenerative diseases, and aging. In cancer, metformin increased apoptotic cell death, while inhibiting it in neurodegenerative diseases. Thus, different modes of metformin action at the molecular level have been proposed. In this study, we present the mitochondria and the VDAC1 (voltage-dependent anion channel) as a potential target of metformin. Metformin induces VDAC1 overexpression, its oligomerization, and subsequent apoptosis. Metformin analogs phenformin and buformin at much lower concentrations also induce VDAC1 overexpression, oligomerization, and cell death. We demonstrate the interaction of metformin with purified VDAC1, which inhibited its channel conduction in a voltage-dependent manner. Metformin bound to the synthetic VDAC1--terminal peptide and binding to this domain was also found by its molecular docking with VDAC1. Moreover, we demonstrated metformin binding to purified hexokinases (HK-I) with a 400-fold lower metformin concentration than that required for cell death induction. In cells, metformin induced HK-I detachment from the mitochondrial VDAC1. Lastly, metformin increased the expression of NLRP3 and ASC and induced their co-localization, suggesting inflammasome activation. The results suggest that VDAC1 is a target for metformin and its analogs, and this is associated with metformin's adverse effects on many diseases.
除糖尿病外，二甲双胍已被确定为一种潜在的治疗药物，可用于治疗包括各种癌症、心血管疾病、神经退行性疾病和衰老在内的多种其他病症。在癌症中，二甲双胍增加凋亡细胞死亡，而在神经退行性疾病中则抑制凋亡细胞死亡。因此，人们提出了二甲双胍在分子水平上的不同作用模式。在本研究中，我们提出线粒体和电压依赖性阴离子通道1（VDAC1）是二甲双胍的潜在靶点。二甲双胍诱导VDAC1过表达、寡聚化及随后的细胞凋亡。二甲双胍类似物苯乙双胍和丁双胍在低得多的浓度下也诱导VDAC1过表达、寡聚化和细胞死亡。我们证明了二甲双胍与纯化的VDAC1相互作用，其以电压依赖性方式抑制其通道传导。二甲双胍与合成的VDAC1末端肽结合，并且通过其与VDAC1的分子对接也发现其与该结构域结合。此外，我们证明二甲双胍与纯化的己糖激酶（HK-I）结合，其浓度比诱导细胞死亡所需的浓度低400倍。在细胞中，二甲双胍诱导HK-I从线粒体VDAC1上脱离。最后，二甲双胍增加NLRP3和ASC的表达并诱导它们共定位，提示炎性小体激活。结果表明，VDAC1是二甲双胍及其类似物的靶点，这与二甲双胍对许多疾病的不良反应有关。
