Adhikary Ankita, Joseph Vivian Francis, Banerjee Riddhi, Nagotu Shirisha
Organelle Biology and Cellular Ageing Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India.
Organelle Biology and Cellular Ageing Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India.
Mitochondrion. 2025 Mar;81:102006. doi: 10.1016/j.mito.2025.102006. Epub 2025 Jan 7.
Mitochondrial morphology is a result of regulated opposite events called fission and fusion and requires the GTPase, dynamin-related protein 1 (DRP1/Dnm1), or its homologs. A recent clinical report identified a heterozygous missense mutation in the human DRP1 that replaces Glycine (G) 149 with Arginine (R) and results in debilitating conditions in the patient. In this study, we mimicked this mutation in yeast Dnm1 (G178R) and investigated the impact of the pathogenic mutation on the protein's function. We provide evidence that the substitution of G with R in the G3 motif of the GTPase domain, renders the protein non-functional and in a dominant-negative way. The mutation hampers the distribution, localization, and function of the protein. Cells expressing the mutant variant exhibit a block in mitochondrial fission and altered peroxisome morphology and number.
线粒体形态是由称为裂变和融合的相反调节事件所导致的结果，并且需要GTP酶、动力相关蛋白1（DRP1/Dnm1）或其同源物。最近一份临床报告在人类DRP1中鉴定出一种杂合错义突变，该突变将甘氨酸（G）149替换为精氨酸（R），并导致患者出现衰弱症状。在本研究中，我们在酵母Dnm1（G178R）中模拟了这种突变，并研究了该致病突变对蛋白质功能的影响。我们提供的证据表明，在GTP酶结构域的G3基序中，G被R取代使该蛋白质失去功能，并以显性负性方式发挥作用。该突变阻碍了蛋白质的分布、定位和功能。表达突变体变体的细胞表现出线粒体裂变受阻以及过氧化物酶体形态和数量改变。
