线粒体是真核细胞提供能量的主要来源，在线粒体中存在1000多种蛋白质，与细胞的发育密切相关。然而，受损的蛋白质会损害线粒体功能，进一步促进多种人类疾病的发生。证据表明，线粒体蛋白酶对蛋白质维护至关重要。最重要的是，质量控制酶通过降解错误折叠、老化或过多的蛋白质，在调节线粒体功能方面发挥关键作用。有趣的是，癌细胞能在损害蛋白质的压力下茁壮成长，因此，针对线粒体质量控制蛋白酶作为癌细胞的新型调节剂具有重要意义。此外，研究表明，通过调节视神经萎缩1 (OPA1)的形态，线粒体质量控制蛋白酶还影响着线粒体动力学，这与癌症的发生和发展密切相关。在本综述中，我们介绍了线粒体质量控制蛋白酶如凝乳蛋白酶P（ClpP）、Lon蛋白酶（LonP1）、高温需求蛋白A2（HrtA2）和OMA-1作为癌症治疗中有前途的靶点和相关调节剂。此外，我们还总结了目前有关线粒体质量控制蛋白酶调节剂的临床试验进展的最新知识。总的来说，上述内容有助于为新型抗肿瘤药物的开发提供方向。©2022 Wiley Periodicals LLC.

Mitochondria, the main provider of energy in eukaryotic cells, contains more than 1000 different proteins and is closely related to the development of cells. However, damaged proteins impair mitochondrial function, further contributing to several human diseases. Evidence shows mitochondrial proteases are critically important for protein maintenance. Most importantly, quality control enzymes exert a crucial role in the modulation of mitochondrial functions by degrading misfolded, aged, or superfluous proteins. Interestingly, cancer cells thrive under stress conditions that damage proteins, so targeting mitochondrial quality control proteases serves as a novel regulator for cancer cells. Not only that, mitochondrial quality control proteases have been shown to affect mitochondrial dynamics by regulating the morphology of optic atrophy 1 (OPA1), which is closely related to the occurrence and progression of cancer. In this review, we introduce mitochondrial quality control proteases as promising targets and related modulators in cancer therapy with a focus on caseinolytic protease P (ClpP), Lon protease (LonP1), high-temperature requirement protein A2 (HrtA2), and OMA-1. Further, we summarize our current knowledge of the advances in clinical trials for modulators of mitochondrial quality control proteases. Overall, the content proposed above serves to suggest directions for the development of novel antitumor drugs.© 2022 Wiley Periodicals LLC.