新加坡Duke-NUS医学院Lena Ho团队发现，I₂+III₂超复合物的形成可以挽救呼吸链缺陷。2025年1月8日出版的《细胞—代谢》发表了这项成果。

线粒体电子传递链（ETC）复合物在游离复合物，和被称为超复合物（SCs）的四聚体组装体之间分布。然而，超复合物的生理学需求及其形成的调控机制仍然存在争议。

该课题组发现哺乳动物电子传递链（ETC）复合物III（CIII）生物发生的基因扰动，能够刺激形成一种特殊的大型超复合物（SC-XL），其结构为I₂+III₂。SC-XL的形成增加了线粒体嵴密度，减少了CIII引起的活性氧（ROS），并在CIII活性减少70%的情况下维持了正常的呼吸功能，从而有效地拯救了CIII缺陷。因此，使用Uqcrc1^{DEL:E258-D260}接触位点突变抑制SC-XL的形成，会导致CIII突变体的呼吸衰竭。

最后，SC-XL的形成促进了脂肪酸氧化（FAO），并保护小鼠免受缺血性心力衰竭的影响。研究揭示了哺乳动物ETC中的一种意外可塑性，其中结构适应有助于缓解内在扰动，并提出操控SC-XL形成可能是，治疗线粒体功能障碍的潜在策略。

附：英文原文

Title: Formation of I2+III2 supercomplex rescues respiratory chain defects

Author: Chao Liang, Abhilash Padavannil, Shan Zhang, Sheryl Beh, David R.L. Robinson, Jana Meisterknecht, Alfredo Cabrera-Orefice, Timothy R. Koves, Chika Watanabe, Miyuki Watanabe, María Illescas, Radiance Lim, Jordan M. Johnson, Shuxun Ren, Ya-Jun Wu, Dennis Kappei, Anna Maria Ghelli, Katsuhiko Funai, Hitoshi Osaka, Deborah Muoio, Cristina Ugalde, Ilka Wittig, David A. Stroud, James A. Letts, Lena Ho

Issue&Volume: 2025-01-08

Abstract: Mitochondrial electron transport chain (ETC) complexes partition between free complexes and quaternary assemblies known as supercomplexes (SCs). However, the physiological requirement for SCs and the mechanisms regulating their formation remain controversial. Here, we show that genetic perturbations in mammalian ETC complex III (CIII) biogenesis stimulate the formation of a specialized extra-large SC (SC-XL) with a structure of I2+III2, resolved at 3.7 by cryoelectron microscopy (cryo-EM). SC-XL formation increases mitochondrial cristae density, reduces CIII reactive oxygen species (ROS), and sustains normal respiration despite a 70% reduction in CIII activity, effectively rescuing CIII deficiency. Consequently, inhibiting SC-XL formation in CIII mutants using the Uqcrc1DEL:E258-D260 contact site mutation leads to respiratory decompensation. Lastly, SC-XL formation promotes fatty acid oxidation (FAO) and protects against ischemic heart failure in mice. Our study uncovers an unexpected plasticity in the mammalian ETC, where structural adaptations mitigate intrinsic perturbations, and suggests that manipulating SC-XL formation is a potential therapeutic strategy for mitochondrial dysfunction.

DOI: 10.1016/j.cmet.2024.11.011

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00457-1