Influence of Oxidative Stress on D‐Aspartyl Endopeptidase Activity

Abstract

It is strongly suggested that D-aspartic acid (D-Asp)-containing proteins are spontaneously generated by oxidative stress and would cause many aging-related misfolding diseases, such as cataracts, prion disease, and Alzheimer's disease. We have identified a D-Asp-containing protein-specific protease, D-aspartyl endopeptidase (DAEP), from mammalian mitochondria, serving as a scavenger against the noxious D-Asp-containing protein. Recently, it has been shown that the activity of Lon, an ATP-dependent protease degrading oxidatively damaged proteins in mitochondria, decreases with aging by oxidative stress. However, an obvious relation between DAEP activity and oxidative stress with aging remains to be demonstrated. In the present study, we showed that there was a remarkable decrease in DAEP activity in superoxide dismutase-deficient mice, which formed excess reactive oxygen species (ROS). Our result suggests that a decrease in DAEP activity by oxidative stress may cause the accumulation of D-Asp-containing protein, leading to mitochondria-associated diseases.

Substrate stereoselectivity of mammalian d-aspartyl endopeptidase

“…This would be consistent with our previous study in which, in the liver of mice, DAEP activity was 2.5-fold higher in middle-aged mice (69-weeks-old) than in young mice (12-weeks-old) [17].…”