Quality Control and Quality Assurance in the Mitochondrion

This chapter charts out the diverse pathways by which the mediators of quality control determine cellular and organismal physiology. Inherited human diseases linked to defects in mitochondrial ATP dependent proteases and chaperones reveal how protein quality control extends beyond the boundaries of the mitochondrion. Mutations in the human gene encoding paraplegin, a subunit of the m-AAA protease, cause an autosomal recessive form of hereditary spastic paraplegia (HSP), resulting in neurodegeneration. Whether HSP is caused by a general defect in paraplegin dependent proteolysis, or by defects in the turnover or processing of cell specific substrates remains unknown. In addition, loss of function mutations in the human gene encoding DDP1/TIMM8a, which are homologs of yeast Tim8–13 that chaperone the import of carrier proteins to the inner membrane, are associated with Mohr-Tranebjaerg syndrome, leading to deafness, dystonia, mental deficiency, and blindness. The potential functions of other quality control proteins in stress and disease related processes await further elucidation. In many solid tumors, these transcriptional pathways are activated to promote tumor survival and metastasis. Future work holds the promise of delineating the roles of mitochondrial ATP dependent proteases and chaperones not only in cellular metabolism and general physiology, but also in disease states such as neurodegeneration and cancer, or aging.