美国科罗拉多大学Halil Aydin等研究人员合作揭示人类OPA1重塑线粒体膜的结构机制。该研究于2023年8月23日在线发表于国际一流学术期刊《自然》。

研究人员结合细胞和结构分析来阐明了OPA1依赖性膜重塑和融合的关键分子机制。人类OPA1通过一个脂质结合桨状结构域嵌入含心磷脂的膜中。桨状结构域内的一个保守环深入双分子层，并进一步稳定了与富含心磷脂膜的相互作用。通过桨状结构域的OPA1二聚化促进了膜上柔性OPA1晶格的螺旋组装，从而推动了细胞内线粒体的融合。

此外，膜弯曲的OPA1寡聚体发生构象变化，将膜插入环拉出外叶，促进了膜的力学重塑。这些发现为理解人类OPA1如何塑造线粒体形态提供了一个结构框架，并向人们展示了人类疾病突变如何损害OPA1的功能。

据介绍，线粒体网络的不同形态支持着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OPA1（optic atrophy 1）影响嵴的结构，并催化线粒体内膜的融合。尽管OPA1至关重要，但其调节线粒体形态的分子机制尚不清楚。

附：英文原文

Title: Structural mechanism of mitochondrial membrane remodelling by human OPA1

Author: von der Malsburg, Alexander, Sapp, Gracie M., Zuccaro, Kelly E., von Appen, Alexander, Moss, Frank R., Kalia, Raghav, Bennett, Jeremy A., Abriata, Luciano A., Dal Peraro, Matteo, van der Laan, Martin, Frost, Adam, Aydin, Halil

Issue&Volume: 2023-08-23

Abstract: Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate1,2,3. The mechanochemical GTPase optic atrophy 1 (OPA1) influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane4,5. 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.

DOI: 10.1038/s41586-023-06441-6

Source: https://www.nature.com/articles/s41586-023-06441-6