韦斯特莱克大学研究小组揭示了人线粒体丙酮酸载体的结构与机制。相关论文于2025年3月18日发表于国际顶尖学术期刊《自然》杂志上。

研究团队报道了人类MPC在三种不同状态下的六种低温电镜结构：在膜间空间（IMS）的不同条件下获得的三种结构-开放状态，最高分辨率为3.2°，丙酮酸处理的MPC在3.7°的封闭状态下的结构，以及在基质侧与抑制剂UK5099或抑制纳米体结合的两种面向基质状态的结构在3.2°和3.0 MPC被分配到由MPC1和MPC2组成的异源二聚体中，跨膜结构域采用伪C2对称。近似刚体运动发生在IMS开放状态和封闭状态之间，而主要发生在基质侧的结构变化促进了封闭状态和面向基质状态之间的过渡，揭示了丙酮酸转运过程中的交替进入机制。在UK5099结合结构中，抑制剂配合良好，并与向基质一侧开放的口袋广泛相互作用。他们的发现为MPC介导的底物转运机制以及UK5099的识别和抑制提供了重要的见解，这将有助于未来针对MPC的药物开发。

据悉，线粒体丙酮酸载体（Mitochondrial pyruvate carrier， MPC）是一种线粒体内膜蛋白复合物，对丙酮酸作为三羧酸（TCA）循环的主要碳载体摄取到基质中至关重要。

附：英文原文

Title: Structures and mechanism of human mitochondrial pyruvate carrier

Author: Liang, Jiaming, Shi, Junhui, Song, Ailong, Lu, Meihua, Zhang, Kairan, Xu, Meng, Huang, Gaoxingyu, Lu, Peilong, Wu, Xudong, Ma, Dan

Issue&Volume: 2025-03-18

Abstract: Mitochondrial pyruvate carrier (MPC) is a mitochondrial inner membrane protein complex essential for uptake of pyruvate into matrix as the primary carbon source for tricarboxylic acid (TCA) cycle1,2. Here, we report six cryo-EM structures of human MPC in three different states: three structures obtained at different conditions in intermembrane space (IMS)-open state with highest resolution of 3.2 , a structure of pyruvate-treated MPC in occluded state at 3.7 , and two structures in matrix-facing state bound with the inhibitor UK5099 or an inhibitory nanobody on the matrix side at 3.2 and 3.0 , respectively. MPC is assigned into a heterodimer consisting of MPC1 and MPC2, with the transmembrane domain adopting pseudo-C2-symmetry. Approximate rigid body movements occur between the IMS-open state and the occluded state, while structural changes primarily on the matrix side facilitate the transition between the occluded state and the matrix-facing state, revealing the alternating access mechanism during pyruvate transport. In the UK5099-bound structure, the inhibitor fits well and interacts extensively with a pocket that opens to the matrix side. Our findings provide important insights into the mechanisms underlying MPC-mediated substrate transport, and the recognition and inhibition by UK5099, which will facilitate future drug development targeting MPC.

DOI: 10.1038/s41586-025-08873-8

Source: https://www.nature.com/articles/s41586-025-08873-8