Mitochondria are double-membrane organelles with varying shapes influenced by metabolic conditions, developmental stage, and environmental stimuli1–4. Their dynamic morphology is realized through regulated and balanced fusion and fission processes5, 6. Fusion is crucial for the health and physiological functions of mitochondria, including complementation of damaged mitochondrial DNAs and maintenance of membrane potential6–8. Mitofusins (Mfns) are dynamin-related GTPases essential for mitochondrial fusion9, 10. They are embedded in the mitochondrial outer membrane and thought to fuse adjacent mitochondria via concerted oligomerization and GTP hydrolysis11–13. However, the molecular mechanisms behind this process remains elusive. Here we present crystal structures of engineered human Mfn1 containing the GTPase domain and a helical domain in different stages of GTP hydrolysis. The helical domain is composed of elements from widely dispersed sequence regions of Mfn1 and resembles the Neck of the bacterial dynamin-like protein. The structures reveal unique features of its catalytic machinery and explain how GTP binding induces conformational changes to promote G domain dimerization in the transition state. Disruption of G domain dimerization abolishes the fusogenic activity of Mfn1. Moreover, a conserved aspartate trigger was found in Mfn1 to affect mitochondrial elongation, likely through a GTP-loading-dependent domain rearrangement. Based on these results, we propose a mechanistic model for Mfn1-mediated mitochondrial tethering. Our study provides important insights in the molecular basis of mitochondrial fusion and mitofusin-related human neuromuscular disorders14.

The cell is constructed by higher-order structures and organelles through complex interactions among distinct structural constituents. The centrosome is a membraneless organelle composed of two microtubule-derived structures called centrioles and an amorphous mass of pericentriolar material. Super-resolution microscopic analyses in various organisms revealed that diverse pericentriolar material proteins are concentrically localized around a centriole in a highly organized manner. However, the molecular nature underlying these organizations remains unknown. Here we show that two human pericentriolar material scaffolds, Cep63 and Cep152, cooperatively generate a heterotetrameric α-helical bundle that functions in conjunction with its neighboring hydrophobic motifs to self-assemble into a higher-order cylindrical architecture capable of recruiting downstream components, including Plk4, a key regulator for centriole duplication. Mutations disrupting the self-assembly abrogate Plk4-mediated centriole duplication. Because pericentriolar material organization is evolutionarily conserved, this work may offer a paradigm for investigating the assembly and function of centrosomal scaffolds in various organisms.

A retrospective analysis of 123 postpartum choriocarcinoma cases treated at the Peking Union Medical College Hospital between December 1985 and December 2006 was performed. All the patients with postpartum choriocarcinoma received chemotherapy, combined with comprehensive therapy. The total number of chemotherapy cycles was 1041 (8.5 for every patient on average). The complete remission (CR) was achieved in 108 patients (87.8%), whereas five patients had partial remission and ten died. Of the 26 patients who became resistant to 5-fluorouracil combined chemotherapy, 18 achieved CR. Of the four cases who had recurrence, three achieved CR. The patients were divided into high- and low-risk groups, based on the new FIGO 2000 risk factor scoring system. Seventy-five patients were in high-risk group, with a score of 7 or more. Among them, 62 achieved CR (82.7%). The remaining 48 patients were in the low-risk group, with a score of 6 or less, among whom 46 patients achieved CR (95.8%). There is a significant difference in CR rate between the two groups. Based on the FIGO staging and scoring system, 24 patients were diagnosed as FIGO stage I, 9 stage II, 66 stage III, and 24 stage IV. The rate of CR was 100%, 100%, 91%, and 62.5%, respectively. Our experience shows that prognosis of postpartum choriocarcinoma is good when multiagent systemic chemotherapy is applied. Shortened time interval between the antecedent pregnancy and the treatment will lead to better prognosis.