Mitochondrial protein quality control systems in aging and disease.

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.