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Properties of mitochondrial fusion-mediating protein MFN2 resolved

Last updated :2020-01-08

Source: Cancer Center
Written by: Cancer Center
Edited by: Wang Dongmei

Recently, Professor Song Gao’s research group in Sun Yat-sen University Cancer Center has reported crystal structures of truncated human MFN2 protein, the key mitochondrial fusion mediator. Based on the structural and functional studies, the mechanism of MFN2-mediated mitochondrial tethering and the molecular basis of MFN2 mutation-related occurrence of CMT2A (an inherited neuromuscular disorder) are proposed. This study has expanded the understanding of the pivotal mitochondrial fusion process in high eukaryotes, and shed light on the development of diagnosis, prognosis and individualized treatment of related diseases. This work was published in Nature Communications entitled "Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset" on Oct. 29, 2019.

Mitochondria are essential double-membrane organelles in most of the eukaryotic cells. In order to adapt to environmental change, mitochondria constantly undergo a dynamic balance of fusion and division. Disrupted mitochondrial fusion is associated with a number of human diseases, including neurodegenerative diseases, diabetes, and cancer. In mammals, mitochondrial outer membrane fusion is mediated by MFN1 and MFN2 that belong to the dynamin superfamily of large GTPases. The two proteins share similar structures and cellular functions, but also bear significant differences. In addition, the cooperation between the two proteins is also important for the fusion of mitochondrial outer membrane.

In their earlier studies, Professor Gao’s group has reported the structures of truncated MFN1 and the preliminary mechanism of mitochondrial outer membrane fusion (Cao et al. Nature 2017). However, the structural difference and functional cooperation between MFN2 and MFN1 remain elusive, and the molecular mechanism of MFN2 mutation-related occurrence of CMT2A is unclear.

The molecular basis of MFN2-mediated mitochondrial tethering and MFN2 mutation-related occurrence of CMT2A disease
To answer these questions, Professor Gao's team has conducted an in-depth study on the structure of human MFN2 and its functional relevance in mitochondrial outer membrane fusion. The group members have solved crystal structures of an internally truncated human MFN2 in different GTP hydrolysis states. Biochemical study revealed that MFN2 forms a tight homodimer at the transition state of GTP hydrolysis. Unlike MFN1, this MFN2 dimer sustains even after the GTP hydrolysis process is completed, which explains the observation that MFN2 has stronger membrane tethering ability than MFN1. This prominent difference between MFN2 and MFN1 is largely determined by a primate-only single amino acid variation. In addition, MFN2 and MFN1 can form heterodimers via the GTPase domain in a nucleotide-dependent manner. In terms of efficiency, the formation of MFN1-MFN2 heterodimer is comparable to that of MFN1 or MFN2 homodimers, suggesting that this heterodimer may play an important role in mitochondrial fusion. Mutations in MFN2 are associated with CMT2A, an inherited neurodegenerative disease that is currently incurable. Professor Gao’s group further examined the impact of pathogenic MFN2 mutations on its biochemical properties, and found that the mutants led to distinct effects on GTPase activity. With these results and the structures of engineered MFN2, two possible mechanisms are proposed for how different MFN2 mutations may cause CMT2A.

This work was funded by the National Key Research and Development Program and the National Natural Science Foundation of China.

Link to the paper: https://www.nature.com/articles/s41467-019-12912-0