Acetylation of PGC1 alpha by Histone Deacetylase 1 Downregulation Is Implicated in Radiation-Induced Senescence of Brain Endothelial Cells

摘要

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1 alpha) is a potent transcription factor for mitochondrial function, lipid metabolism, and detoxification in a variety of tissues. PGC1 alpha also promotes brain cell proliferation and memory. However, how PGC1 alpha is involved in aging is not well known. In brain endothelial cells, we found that PGC1 alpha knockdown accelerated DNA damage-induced senescence, evidenced by an increase in senescence-associated beta-galactosidase-positive cells and a decrease in cell proliferation and adenosine triphosphate production. PGC1 alpha knockdown delayed DNA damage repair mechanisms compared with the wild-type condition as shown by gamma-H2AX foci staining assay. Overexpression of PGC1 alpha reduced senescence-associated beta-galactosidase-positive cells and increased the proliferation of senescent cells. Although PGC1 alpha protein levels were not decreased, PGC1 acetylation was increased by ionizing radiation treatment and aging. Histone deacetylase 1 (HDAC1) expression was decreased by ionizing radiation treatment and aging, and downregulation of HDAC1 induced acetylation of PGC1 alpha. HDAC1 knockdown affected sirtuin 1 expression and decreased its deacetylation of PGC1 alpha. In the mouse brain cortex, acetylation of PGC1 alpha was increased by ionizing radiation treatment. These results suggest that acetylation of PGC1 alpha is induced by DNA damage agents such as ionizing radiation, which deregulates mitochondrial mechanisms and metabolism, resulting in acceleration of radiation-induced senescence. Therefore, acetylation of PGC1 alpha may be a cause of brain disorders and has the potential to serve as a therapeutic target for radiation-induced senescence after radiation cancer therapy.