近日，美国杜克大学医学院教授Hui-Kuan Lin及其小组的最新研究提出了ALDH4A1作为MPC复合物的活性成分，维持线粒体丙酮酸的输入，用于TCA循环进入和肿瘤抑制。该项研究成果发表在2025年5月12日出版的《自然—细胞生物学》上。

在这里，研究组发现ALDH4A1，一种定位于线粒体的脯氨酸代谢酶，作为一种以前未被识别的MPC成分，维持丙酮酸线粒体进口和TCA循环独立于其酶活性。哺乳动物细胞中ALDH4A1的缺失会损害丙酮酸进入线粒体，导致TCA循环进入缺陷。ALDH4A1与MPC1-MPC2形成活性三聚体复合物，维持MPC1-MPC2的完整性和寡聚化，促进丙酮酸在体外系统中的转运。ALDH4A1通过维持MPC复合物活性来抑制肿瘤。他们的研究确定ALDH4A1是MPC中丙酮酸线粒体输入、TCA循环进入和肿瘤抑制的重要组成部分。

据介绍，MPC1和MPC2是两个众所周知的线粒体丙酮酸载体（MPC）复合物的组成部分，维持MPC的活性，将丙酮酸转运到线粒体中，以进入哺乳动物细胞的三羧酸（TCA）循环。目前尚不清楚是否有一种额外的MPC成分对丙酮酸线粒体进口至关重要地维持MPC复合物的活性。

附：英文原文

Title: ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression

Author: Hsu, Che-Chia, Wang, Chi-Yun, Manne, Rajesh Kumar, Cai, Zhen, Penugurti, Vasudevarao, Kant, Rajni, Bai, Ling, Pan, Bo-Syong, Chen, Tingjin, Chen, Yuan-Ru, Wu, Hsin-En, Jin, Yan, Gu, Haiwei, Li, Chia-Yang, Lin, Hui-Kuan

Issue&Volume: 2025-05-12

Abstract: MPC1 and MPC2 are two well-known components of the mitochondrial pyruvate carrier (MPC) complex maintaining MPC activity to transport pyruvate into mitochondria for tricarboxylic acid (TCA) cycle entry in mammalian cells. It is currently unknown whether there is an additional MPC component crucially maintaining MPC complex activity for pyruvate mitochondrial import. Here we show that ALDH4A1, a proline-metabolizing enzyme localized in mitochondria, serves as a previously unrecognized MPC component maintaining pyruvate mitochondrial import and the TCA cycle independently of its enzymatic activity. Loss of ALDH4A1 in mammalian cells impairs pyruvate entry to mitochondria, resulting in defective TCA cycle entry. ALDH4A1 forms an active trimeric complex with MPC1–MPC2 to maintain the integrity and oligomerization of MPC1–MPC2 and facilitates pyruvate transport in an in vitro system. ALDH4A1 displays tumour suppression by maintaining MPC complex activity. Our study identifies ALDH4A1 as an essential component of MPC for pyruvate mitochondrial import, TCA cycle entry and tumour suppression.

DOI: 10.1038/s41556-025-01651-8

Source: https://www.nature.com/articles/s41556-025-01651-8