Mitobridge, Inc. (a Subsidiary of Astellas Pharma, Inc.), Cambridge, MA 02138 USA.
Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616 USA.
Biochem Biophys Res Commun. 2018 May 15;499(3):556-562. doi: 10.1016/j.bbrc.2018.03.189. Epub 2018 Apr 4.
Balanced rates of mitochondrial division and fusion are required to maintain mitochondrial function, as well as cellular and organismal homeostasis. In mammals, the cellular machines that mediate these processes are dynamin-related GTPases; the cytosolic DRP1 mediates division, while the outer membrane MFN1/2 and inner membrane OPA1 mediate fusion. Unbalanced mitochondrial dynamics are linked to varied pathologies, including cell death and neurodegeneration, raising the possibility that small molecules that target the division and fusion machines to restore balance may have therapeutic potential. Here we describe the discovery of novel small molecules that directly and selectively inhibit assembly-stimulated GTPase activity of the division dynamin, DRP1. In addition, these small molecules restore wild type mtDNA copy number in MFN1 knockout mouse embryonic fibroblast cells, a phenotype linked to deficient mitochondrial fusion activity. Thus, these compounds are unique tools to explore the roles of mitochondrial division in cells, and to assess the potential therapeutic efficacy of rebalancing mitochondrial dynamics in pathologies associated with excessive mitochondrial division.
线粒体分裂和融合的平衡速率对于维持线粒体功能以及细胞和机体的内稳态是必需的。在哺乳动物中，介导这些过程的细胞机器是与 dynamin 相关的 GTP 酶；胞质中的 DRP1 介导分裂，而外膜的 MFN1/2 和内膜的 OPA1 则介导融合。线粒体动力学的不平衡与多种病理有关，包括细胞死亡和神经退行性变，这增加了靶向分裂和融合机器以恢复平衡的小分子可能具有治疗潜力的可能性。在这里，我们描述了新型小分子的发现，这些小分子可直接且选择性地抑制分裂 dynamin，DRP1 的组装刺激 GTPase 活性。此外，这些小分子可恢复 MFN1 敲除的鼠胚胎成纤维细胞中的野生型 mtDNA 拷贝数，这一表型与线粒体融合活性缺陷有关。因此，这些化合物是探索线粒体分裂在细胞中的作用以及评估通过重新平衡与过度线粒体分裂相关的病理中的线粒体动力学的潜在治疗效果的独特工具。
