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Molecular mechanism of mitochondrial tethering revealed by Professor Song Gao’s team from Sun Yat-sen University Cancer Center

Last updated :2017-02-27

Source: Sun Yat-sen University Cancer Center
Written by: Sun Yat-sen University Cancer Center
Edited by: Wang Dongmei

The research team led by Prof. Song Gao (高嵩) from the State Key laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, recently revealed the molecular mechanism of mitochondrial tethering by dynamin-related GTPase MFN1 upon GTP binding and hydrolysis. Their work appears on the Feb 16 issue of Nature.

Mitochondria are double-membraned organelles with variable shapes influenced by metabolic conditions, developmental stage, and environmental stimuli. Their dynamic morphology is a result of regulated and balanced fusion and fission processes. Fusion is crucial for the health and physiological functions of mitochondria, including complementation of damaged mitochondrial DNAs and the maintenance of membrane potential. Mitofusins, belonging to dynamin superfamily of GTPases, play an important role in this process. Mammalians have two mitofusin analogues called MFN1 and MFN2. They are thought to fuse adjacent mitochondria via orchestrated oligomerization and GTP hydrolysis. However, the molecular mechanisms of how mitofusins regulate fusion of mitochondrial outer membrane are still unknown.

The Gao team carefully designed the constructs of human MFN1 for crystallization experiments, and successfully determined their crystal structures in different stages of GTP hydrolysis. The engineered MFN1 contains the GTPase domain and a helical domain, and the latter is composed of four α-helices from widely dispersed sequence regions. The structures reveal unique features of its catalytic machinery and explain how GTP binding induces conformational changes to promote GTPase domain dimerization in the transition state. Moreover, based on the similarity with a bacterial-dynamin-like protein, MFN1 may experience domain rearrangements during the GTP turnover cycle, which might be controlled by a conserved aspartate trigger. Finally, the Gao team proposes a mechanistic model for MFN1-mediated mitochondrial tethering.

Figure 1: MFN1 mediated mitochondrial tethering. a, Construct design for crystallization. b, Overall structure of engineered MFN1. c, Dimerization of GTPase domain in the transition state of GTP hydrolysis. d, Conformational rearrangements of MFN1 in the GTP turnover cycle.
This study sheds light on the molecular basis of mitochondrial fusion and mitofusin-related human diseases and contribute to the development of clinical approaches against these diseases, including several types of neuromuscular disorders, cancers, and diabetes.

Figure 2: The Gao team in 2016. From left to right: Xiao-Yan Ma, Jin-Yu Yang, Dong-Dong Gu, Yang Chen, Jian-Xiong Feng, Prof. Li-Wu Fu (head of the research department), Prof. Song Gao, Bing Yu, Yu-Lu Cao, Hong Zhang. Jia-Li Hu is not in the photo.
This study was published in Nature 2017, 542(7641):372-376, entitled “MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion”. The first author is PhD student Yu-Lu Cao (曹雨露) who is graduating this year, the corresponding author is Prof. Song Gao. Professor David Chan and Shuxia Meng from California Institute of Technology (Caltech) contributed to this study. This work was supported by grants of National Basic Research Program of China, National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, New Century Excellent Talents in University and the Recruitment Program of Global Youth Experts.

Link to the publication: http://www.nature.com/nature/journal/v542/n7641/full/nature21077.html