Institute for Genetics, CECAD Research Center, University of Cologne, Cologne 50931, Germany.
J Cell Sci. 2023 Nov 15;136(22). doi: 10.1242/jcs.260790. Epub 2023 Nov 23.
The proteins of the BCL-2 family are known as key regulators of apoptosis, with interactions between family members determining permeabilisation of the mitochondrial outer membrane (MOM) and subsequent cell death. However, the exact mechanism through which they form the apoptotic pore responsible for MOM permeabilisation (MOMP), the structure and specific components of this pore, and what roles BCL-2 proteins play outside of directly regulating MOMP are incompletely understood. Owing to the link between apoptosis dysregulation and disease, the BCL-2 proteins are important targets for drug development. With the development and clinical use of drugs targeting BCL-2 proteins showing success in multiple haematological malignancies, enhancing the efficacy of these drugs, or indeed developing novel drugs targeting BCL-2 proteins is of great interest to treat cancer patients who have developed resistance or who suffer other disease types. Here, we review our current understanding of the molecular mechanism of MOMP, with a particular focus on recently discovered roles of BCL-2 proteins in apoptosis and beyond, and discuss what implications these functions might have in both healthy tissues and disease.
BCL-2 家族蛋白是细胞凋亡的关键调节因子，家族成员之间的相互作用决定了线粒体外膜（MOM）的通透性和随后的细胞死亡。然而，它们形成负责 MOM 通透性（MOMP）的凋亡孔的确切机制、该孔的结构和特定成分，以及 BCL-2 蛋白在直接调节 MOMP 之外所起的作用，尚不完全清楚。由于细胞凋亡失调与疾病之间存在联系，BCL-2 蛋白是药物开发的重要靶点。随着针对 BCL-2 蛋白的药物的开发和临床应用在多种血液恶性肿瘤中取得成功，提高这些药物的疗效，或者开发针对 BCL-2 蛋白的新型药物，对于治疗已经产生耐药性或患有其他疾病类型的癌症患者具有重要意义。在这里，我们回顾了我们对 MOMP 分子机制的现有理解，特别关注 BCL-2 蛋白在凋亡及其他方面的新发现作用，并讨论这些功能在健康组织和疾病中的可能影响。
