Unlike HSP90b, which is expressed constitutively, HSP90a is a chaperone that is expressed in response to stress. Threonine 5 and 7 (T5,7) are phosphorylated by DNA-PK, which is activated by reactive oxygen species and DNA-breaks. We found that T5,7 phosphorylation is increased with aging in multiple tissues. We also found that this occurs in non-human primates as well as in rodents. Inhibiting this phosphorylation increases chaperoning function of some kinases, including AMPK, which is important for insulin sensitivity, mitochondrial biogenesis and energy metabolism. Indeed, we found that inhibiting DNA-PK activates AMPK at old age and prevents decline in mitochondrial biogenesis. Moreover, obese and older mice treated with DNA-PK inhibitor has greater physical endurance. These findings indicate that DNA-PK has an unexpected metabolic function related to aging.
|Chung, Jay H (2018) The role of DNA-PK in aging and energy metabolism. FEBS J 285:1959-1972|
|Park, Sung-Jun; Gavrilova, Oksana; Brown, Alexandra L et al. (2017) DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging. Cell Metab 25:1135-1146.e7|