The Proteasome is an unusually large and complex proteinase found in the cytoplasm and nucleus of all eucaryotic cells. Proteasome has been shown to play several key roles in the appropriate turnover of normal proteins and the selective degradation of abnormal and damaged proteins. These activities give the Proteasome a vital place in cell cycle progression, protection from protein aggregation, antigen presentation, and maintenance of cellular homeostasis. In the mitochondrial matrix another large and complex proteolytic enzyme, the Lon protease, is responsible for the selective recognition and proteolytic removal of damaged proteins, and for a good deal of the normal turnover of matrix proteins. In addition, the Lon protease has other vital intramitochondrial roles as a chaperone, as a transcriptional activator (or de-repressor), and as a stabilizing agent for the mitochondrial genome.
Studies in the last few years have revealed an age-dependent, progressive accumulation of oxidized and cross-linked proteins within eucaryotic cells. Such oxidized and cross-linked protein aggregates appear to inhibit the Proteasome, resulting in an exponential decline in proteasome activity with age. For the most part, the transcription and translation of Proteasome subunits appears to be unaffected by aging, and old cells, especially non-dividing cells and tissues from old animals, appear to contain normal levels of Proteasome protein. Thus, the accumulation of non-degradable Proteasome inhibitors (both competitive and non-competitive) appears to explain the age-dependent loss of vital proteasome functions.
In contrast, both transcription and translation of the Lon protease appear to decline with age in mammalian tissues, such as skeletal muscles. The activity of the Lon protease also declines in rough proportion to transcription and translation, indicating that lower rates of Lon synthesis may be the main factor responsible for decreased Lon activity.
These very different patterns of proteolytic activity decreases with age, suggest that equally different treatment strategies will have to be pursued for age-related proteolytic disorders of the Proteasome and the Lon protease.