Institute of Molecular Medicine, University Medical Center of the Johannes-Gutenberg University Mainz, 55131 Mainz, Germany.
Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093, USA.
Cells. 2020 Mar 27;9(4):815. doi: 10.3390/cells9040815.
Mitochondrial fusion and fission tailors the mitochondrial shape to changes in cellular homeostasis. Players of this process are the mitofusins, which regulate fusion of the outer mitochondrial membrane, and the fission protein DRP1. Upon specific stimuli, DRP1 translocates to the mitochondria, where it interacts with its receptors FIS1, MFF, and MID49/51. Another fission factor of clinical relevance is GDAP1. Here, we identify and discuss cysteine residues of these proteins that are conserved in phylogenetically distant organisms and which represent potential sites of posttranslational redox modifications. We reveal that worms and flies possess only a single mitofusin, which in vertebrates diverged into MFN1 and MFN2. All mitofusins contain four conserved cysteines in addition to cysteine 684 in MFN2, a site involved in mitochondrial hyperfusion. DRP1 and FIS1 are also evolutionarily conserved but only DRP1 contains four conserved cysteine residues besides cysteine 644, a specific site of nitrosylation. MFF and MID49/51 are only present in the vertebrate lineage. GDAP1 is missing in the nematode genome and contains no conserved cysteine residues. Our analysis suggests that the function of the evolutionarily oldest proteins of the mitochondrial fusion and fission machinery, the mitofusins and DRP1 but not FIS1, might be altered by redox modifications.
线粒体融合和裂变根据细胞内稳态的变化来调整线粒体的形状。这个过程的参与者是调节外膜融合的线粒体融合蛋白（mitofusins），以及分裂蛋白 DRP1。在特定刺激下，DRP1 易位到线粒体，在那里与它的受体 FIS1、MFF 和 MID49/51 相互作用。另一个具有临床相关性的分裂因子是 GDAP1。在这里，我们确定并讨论了这些蛋白质中在进化上相距较远的生物体中保守的半胱氨酸残基，这些残基代表潜在的翻译后氧化还原修饰位点。我们揭示了线虫和果蝇只拥有一种线粒体融合蛋白，而在脊椎动物中，这种蛋白分化为 MFN1 和 MFN2。除了 MFN2 中参与线粒体过度融合的 684 位半胱氨酸外，所有的线粒体融合蛋白都包含四个保守的半胱氨酸。DRP1 和 FIS1 也是进化上保守的，但只有 DRP1 除了 644 位半胱氨酸外还包含四个保守的半胱氨酸残基，这是一个特定的亚硝基化位点。MFF 和 MID49/51 仅存在于脊椎动物谱系中。GDAP1 在线虫基因组中缺失，并且不包含保守的半胱氨酸残基。我们的分析表明，线粒体融合和裂变机械中进化最古老的蛋白质，即线粒体融合蛋白和 DRP1（而非 FIS1）的功能可能会被氧化还原修饰改变。
