A special latch in yeast mitofusin guarantees mitochondrial fusion by stabilizing self-assembly
The mitochondrion is a highly dynamic organelle, constantly undergoing fusion and fission, which are critical processes for the health of cells. Fusion of the outer mitochondrial membrane (OMM) is mediated by the mitofusins belonging to the dynamin superfamily of GTPases. Most eukaryotic organisms possess two cooperatively functioning mitofusins, but yeast has only one mitofusin (Fzo1). How Fzo1 solely catalyzes OMM fusion is unclear. Here, we present crystal structures of truncated Fzo1 (Fzo1<sub>IM</sub>) in different nucleotide-loading states and report a special mechanistic feature of Fzo1 through systematic functional studies. Differing from mammalian mitofusins, Fzo1 contains an extra latch bulge (LB) that is essential for the viability of yeast. Upon GTP loading, Fzo1<sub>IM</sub> dimerizes via the GTPase domain and prefers the closed conformation. This state is then locked by the subsequent trans interaction mediated by the LB of each protomer, so that Fzo1<sub>IM</sub> remains dimerized in the closed conformation even after GTP hydrolysis. This special mechanistic feature may be relevant to the previous observation that degradation of Fzo1 by the ubiquitin-proteasome system is required for mitochondrial fusion. Our study reveals how mitochondrial fusion in yeast is efficiently ensured with limited GTP consumption, which broadens current understanding of this fundamental biological process.
Authors
- Song Gao (ORCID: https://orcid.org/0000-0001-7427-6681)
- Shujing Huang (ORCID: https://orcid.org/0009-0008-9408-3420)
- Junjie Hu (ORCID: https://orcid.org/0000-0003-4712-2243)
- Xinyu Tu (ORCID: https://orcid.org/0000-0003-3213-7290)
- Jia‐Xing Yue (ORCID: https://orcid.org/0000-0002-2122-9221)
- Bing Yu (ORCID: https://orcid.org/0000-0001-6013-5220)
- Liming Yan (ORCID: https://orcid.org/0000-0003-0648-9604)
- Jun-Ying Ou
- Yuanbo Qi (ORCID: https://orcid.org/0000-0002-6589-3677)
- Jian-Xiong Feng
- Ying Lü (ORCID: https://orcid.org/0000-0002-8421-7228)
- Yu-Lu Cao (ORCID: https://orcid.org/0000-0002-5239-1184)
- Jing Li (ORCID: https://orcid.org/0000-0001-5697-9527)
- Ming Li (ORCID: https://orcid.org/0000-0002-5328-5826)
- Dongfei Ma
- Caiting Yu
- Z. Huang (ORCID: https://orcid.org/0000-0002-3187-5681)
Institutions
- Sun Yat-sen University (CN)
- Chinese Academy of Sciences (CN)
- Nankai University (CN)
- Institute of Biophysics (CN)
- Songshan Lake Materials Laboratory (CN)
- FZU ‒ Institute of Physics of the Academy of Sciences of the Czech Republic (CZ)
- Sun Yat-sen University Cancer Center (CN)
- Institute of Physics (CN)
- National Laboratory for Superconductivity (CN)
- University of Chinese Academy of Sciences (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-31
- DOI
- https://doi.org/10.1038/s41467-025-64646-x
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Salt Science Research Foundation
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Sun Yat-sen University
- Natural Science Foundation of Guangdong Province
- Sun Yat-sen University Cancer Center