Kamerkar Sukrut C, Liu Ao, Higgs Henry N
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH 03755, USA.
J Cell Sci. 2025 May 1;138(9). doi: 10.1242/jcs.263640. Epub 2025 Mar 19.
Mitochondrial fission is important for many aspects of cellular homeostasis, including mitochondrial distribution, stress response, mitophagy, mitochondrially derived vesicle production and metabolic regulation. Several decades of research has revealed much about fission, including identification of a key division protein - the dynamin Drp1 (also known as DNM1L) - receptors for Drp1 on the outer mitochondrial membrane (OMM), including Mff, MiD49 and MiD51 (also known as MIEF2 and MIEF1, respectively) and Fis1, and important Drp1 regulators, including post-translational modifications, actin filaments and the phospholipid cardiolipin. In addition, it is now appreciated that other organelles, including the endoplasmic reticulum, lysosomes and Golgi-derived vesicles, can participate in mitochondrial fission. However, a more holistic understanding of the process is lacking. In this Review, we address three questions that highlight knowledge gaps. First, how do we quantify mitochondrial fission? Second, how does the inner mitochondrial membrane (IMM) divide? Third, how many 'types' of fission exist? We also introduce a model that integrates multiple regulatory factors in mammalian mitochondrial fission. In this model, three possible pathways (cellular stimulation, metabolic switching or mitochondrial dysfunction) independently initiate Drp1 recruitment at the fission site, followed by a shared second step in which Mff mediates subsequent assembly of a contractile Drp1 ring. We conclude by discussing some perplexing issues in fission regulation, including the effects of Drp1 phosphorylation and the multiple Drp1 isoforms.
线粒体分裂对细胞内稳态的许多方面都很重要，包括线粒体分布、应激反应、线粒体自噬、线粒体衍生囊泡的产生以及代谢调节。几十年的研究已经揭示了很多关于分裂的知识，包括鉴定出一种关键的分裂蛋白——动力蛋白Drp1（也称为DNM1L）、线粒体外膜（OMM）上Drp1的受体，包括Mff、MiD49和MiD51（也分别称为MIEF2和MIEF1）以及Fis1，还有重要的Drp1调节因子，包括翻译后修饰、肌动蛋白丝和磷脂心磷脂。此外，现在人们认识到其他细胞器，包括内质网、溶酶体和高尔基体衍生的囊泡，也可以参与线粒体分裂。然而，目前仍缺乏对这一过程更全面的理解。在这篇综述中，我们提出了三个突出知识空白的问题。第一，我们如何量化线粒体分裂？第二，线粒体内膜（IMM）是如何分裂的？第三，存在多少种“类型”的分裂？我们还介绍了一个整合了哺乳动物线粒体分裂中多种调节因子的模型。在这个模型中，三种可能的途径（细胞刺激、代谢转换或线粒体功能障碍）独立地在分裂位点启动Drp1的募集，随后是一个共同的第二步，其中Mff介导后续收缩性Drp1环的组装。我们通过讨论分裂调节中的一些令人困惑的问题来结束本文，包括Drp1磷酸化的影响和多种Drp1亚型。
