Medical Biochemistry & Molecular Biology, Center for Molecular Signaling, PZMS, Saarland University Medical School, Homburg, Germany.
Department of Biochemistry, University of Colorado Boulder, Boulder, CO, USA.
Nature. 2023 Aug;620(7976):1101-1108. doi: 10.1038/s41586-023-06441-6. Epub 2023 Aug 23.
Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate. The mechanochemical GTPase optic atrophy 1 (OPA1) influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane. Despite its fundamental importance, the molecular mechanisms by which OPA1 modulates mitochondrial morphology are unclear. Here, using a combination of cellular and structural analyses, we illuminate the molecular mechanisms that are key to OPA1-dependent membrane remodelling and fusion. Human OPA1 embeds itself into cardiolipin-containing membranes through a lipid-binding paddle domain. A conserved loop within the paddle domain inserts deeply into the bilayer, further stabilizing the interactions with cardiolipin-enriched membranes. OPA1 dimerization through the paddle domain promotes the helical assembly of a flexible OPA1 lattice on the membrane, which drives mitochondrial fusion in cells. Moreover, the membrane-bending OPA1 oligomer undergoes conformational changes that pull the membrane-inserting loop out of the outer leaflet and contribute to the mechanics of membrane remodelling. Our findings provide a structural framework for understanding how human OPA1 shapes mitochondrial morphology and show us how human disease mutations compromise OPA1 functions.
线粒体网络的不同形态支持决定细胞功能和命运的不同代谢和调节过程。机械化学 GTP 酶视神经萎缩 1（OPA1）影响嵴的结构并催化线粒体内膜的融合。尽管 OPA1 至关重要，但调节线粒体形态的分子机制尚不清楚。在这里，我们使用细胞和结构分析的组合，阐明了 OPA1 依赖性膜重塑和融合的关键分子机制。人 OPA1 通过含有脂酰甘油的膜中的脂质结合桨叶域嵌入其中。桨叶域内的保守环深入插入双层，进一步稳定了与富含心磷脂的膜的相互作用。通过桨叶域的 OPA1 二聚化促进了灵活的 OPA1 晶格在膜上的螺旋组装，从而促进细胞中的线粒体融合。此外，膜弯曲的 OPA1 寡聚体发生构象变化，将插入膜的环从外叶层中拉出，并有助于膜重塑的力学。我们的发现为理解人 OPA1 如何塑造线粒体形态提供了一个结构框架，并展示了人类疾病突变如何破坏 OPA1 的功能。
