Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine (CMMC), University of Cologne, Germany.
FEBS J. 2022 Nov;289(22):7128-7146. doi: 10.1111/febs.15964. Epub 2021 May 19.
To ensure correct function, mitochondria have developed several mechanisms of protein quality control (QC). Protein homeostasis highly relies on chaperones and proteases to maintain proper folding and remove damaged proteins that might otherwise form cell-toxic aggregates. Besides quality control, mitochondrial proteases modulate and regulate many essential functions, such as trafficking, processing and activation of mitochondrial proteins, mitochondrial dynamics, mitophagy and apoptosis. Therefore, the impaired function of mitochondrial proteases is associated with various pathological conditions, including cancer, metabolic syndromes and neurodegenerative disorders. This review recapitulates and discusses the emerging roles of two major proteases of the mitochondrial matrix, LON and ClpXP. Although commonly acknowledge for their protein quality control role, recent advances have uncovered several highly regulated processes controlled by the LON and ClpXP connected to mitochondrial gene expression and respiratory chain function maintenance. Furthermore, both proteases have been lately recognized as potent targets for anticancer therapies, and we summarize those findings.
为了确保正常功能，线粒体已经开发出几种蛋白质质量控制（QC）机制。蛋白质动态平衡高度依赖于伴侣蛋白和蛋白酶来维持适当的折叠和清除可能形成细胞毒性聚集的受损蛋白质。除了质量控制，线粒体蛋白酶还调节和调节许多基本功能，如线粒体蛋白的运输、加工和激活、线粒体动力学、线粒体自噬和细胞凋亡。因此，线粒体蛋白酶功能受损与各种病理状况有关，包括癌症、代谢综合征和神经退行性疾病。本综述总结并讨论了线粒体基质中两种主要蛋白酶 LON 和 ClpXP 的新兴作用。尽管它们通常被认为具有蛋白质质量控制作用，但最近的进展揭示了由 LON 和 ClpXP 控制的与线粒体基因表达和呼吸链功能维持相关的几个高度调控过程。此外，这两种蛋白酶最近都被认为是癌症治疗的有效靶点，我们总结了这些发现。
