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<p>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 <i>trans</i> 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.</p>

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A special latch in yeast mitofusin guarantees mitochondrial fusion by stabilizing self-assembly

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月31日

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  • Shu-Jing Huang,
  • Dong-Fei Ma,
  • Caiting Yu,
  • Jing Li,
  • Xinyu Tu,
  • Zi Huang,
  • Yuanbo Qi,
  • Jun-Ying Ou,
  • Jian-Xiong Feng,
  • Bing Yu,
  • Yu-Lu Cao,
  • Jia-Xing Yue,
  • Junjie Hu,
  • Ming Li,
  • Ying Lu,
  • Liming Yan,
  • Song Gao

摘要

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 (Fzo1IM) 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, Fzo1IM 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 Fzo1IM 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.