Johann Wolfgang Goethe University, Faculty for Biosciences and Cluster of Excellence Macromolecular Complexes, Institute of Molecular Biosciences, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Adv Exp Med Biol. 2010;694:108-25. doi: 10.1007/978-1-4419-7002-2_9.
Preserving the integrity of proteins, biomolecules prone to molecular damage, is a fundamental function of all biological systems. Impairments in protein quality control (PQC) may lead to degenerative processes, such as aging and various disorders and diseases. Fortunately, cells contain a hierarchical system of pathways coping protein damage. Specific molecular pathways detect misfolded proteins and act either to unfold or degrade them. Degradation of proteins generates peptides and amino acids that can be used for remodelling of impaired pathways and cellular functions. At increased levels of cellular damage whole organelles can be removed via autophagy, a process that depends on the activity oflysosomes. In addition, cells may undergo apoptosis, a form of programmed cell death, which in single-cellular and lower multicellular organisms can lead to death of the individual. Molecular damage of cellular compartments is mainly caused by reactive oxygen species (ROS). ROS is generated via different cellular pathways and frequently arises in the mitochondrial electron transport chain as a by-product of oxygenic energy transduction. Consequently, mitochondrial proteins are under high risk to become damaged. Perhaps for this reason mitochondria contain a very efficient PQC system that keeps mitochondrial proteins functional as long as damage does not reach a certain threshold and the components of this system themselves are not excessively damaged. The mitochondrial PQC system consists of chaperones that counteract protein aggregation through binding and refolding misfolded polypeptides and of membrane-bound and soluble ATP-dependent proteases that are involved in degradation of damaged proteins. During aging and in neurodegenerative diseases components of this PQC system, including Lon protease present in the mitochondrial matrix, become functionally impaired. In this chapter we summarise the current knowledge of cellular quality control systems with special emphasis on the role of the mitochondrial PQC system and its impact on biological aging and disease.
保护蛋白质的完整性，这些容易受到分子损伤的生物分子，是所有生物系统的基本功能。蛋白质质量控制（PQC）的损伤可能导致退行性过程，如衰老和各种障碍和疾病。幸运的是，细胞中存在着一种应对蛋白质损伤的分层途径系统。特定的分子途径检测到错误折叠的蛋白质，并采取展开或降解它们的措施。蛋白质的降解产生肽和氨基酸，可用于重塑受损的途径和细胞功能。在细胞损伤增加的水平上，可以通过自噬来去除整个细胞器，自噬过程依赖于溶酶体的活性。此外，细胞可能会经历细胞凋亡，这是一种程序性细胞死亡的形式，在单细胞和低等多细胞生物中，可能导致个体死亡。细胞区室的分子损伤主要是由活性氧（ROS）引起的。ROS 通过不同的细胞途径产生，并且经常在线粒体电子传递链中作为产氧能量转导的副产物出现。因此，线粒体蛋白处于受损的高风险之中。也许是出于这个原因，线粒体含有一个非常有效的 PQC 系统，只要损伤没有达到一定的阈值，并且该系统自身的组件没有过度受损，就可以保持线粒体蛋白的功能。线粒体 PQC 系统由伴侣蛋白组成，伴侣蛋白通过结合和重折叠错误折叠的多肽来对抗蛋白质聚集，以及膜结合和可溶性 ATP 依赖性蛋白酶，它们参与受损蛋白质的降解。在衰老和神经退行性疾病中，包括存在于线粒体基质中的 Lon 蛋白酶在内的这个 PQC 系统的组件的功能会受损。在这一章中，我们总结了细胞质量控制系统的最新知识，特别强调了线粒体 PQC 系统的作用及其对生物衰老和疾病的影响。
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