Acetylation of PGC1α by Histone Deacetylase 1 Downregulation Is Implicated in Radiation-Induced Senescence of Brain Endothelial Cells

Su Bin Kim, Jong Ik Heo, Hyunggee Kim, Kwang Seok Kim

Research output: Contribution to journalArticle

Abstract

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) is a potent transcription factor for mitochondrial function, lipid metabolism, and detoxification in a variety of tissues. PGC1α also promotes brain cell proliferation and memory. However, how PGC1α is involved in aging is not well known. In brain endothelial cells, we found that PGC1α knockdown accelerated DNA damage-induced senescence, evidenced by an increase in senescence-associated β-galactosidase-positive cells and a decrease in cell proliferation and adenosine triphosphate production. PGC1α knockdown delayed DNA damage repair mechanisms compared with the wild-type condition as shown by γ-H2AX foci staining assay. Overexpression of PGC1α reduced senescence-associated β-galactosidase-positive cells and increased the proliferation of senescent cells. Although PGC1α 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 PGC1α. HDAC1 knockdown affected sirtuin 1 expression and decreased its deacetylation of PGC1α. In the mouse brain cortex, acetylation of PGC1α was increased by ionizing radiation treatment. These results suggest that acetylation of PGC1α 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 PGC1α 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.

Original languageEnglish
Pages (from-to)787-793
Number of pages7
JournalThe journals of gerontology. Series A, Biological sciences and medical sciences
Volume74
Issue number6
DOIs
Publication statusPublished - 2019 May 16

Fingerprint

Histone Deacetylase 1
Acetylation
Ionizing Radiation
Down-Regulation
Endothelial Cells
Radiation
Galactosidases
Brain
DNA Damage
Cell Proliferation
Sirtuin 1
Brain Diseases
Therapeutics
Lipid Metabolism
DNA Repair
Transcription Factors
Radiotherapy
Adenosine Triphosphate
Staining and Labeling
Neoplasms

Keywords

  • Brain disorder
  • Cellular senescence
  • HDAC1
  • Ionizing radiation
  • PGC1α

ASJC Scopus subject areas

  • Ageing
  • Geriatrics and Gerontology

Cite this

@article{78f1fb1c7d0f48539bb4998bf742a49d,
title = "Acetylation of PGC1α by Histone Deacetylase 1 Downregulation Is Implicated in Radiation-Induced Senescence of Brain Endothelial Cells",
abstract = "Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) is a potent transcription factor for mitochondrial function, lipid metabolism, and detoxification in a variety of tissues. PGC1α also promotes brain cell proliferation and memory. However, how PGC1α is involved in aging is not well known. In brain endothelial cells, we found that PGC1α knockdown accelerated DNA damage-induced senescence, evidenced by an increase in senescence-associated β-galactosidase-positive cells and a decrease in cell proliferation and adenosine triphosphate production. PGC1α knockdown delayed DNA damage repair mechanisms compared with the wild-type condition as shown by γ-H2AX foci staining assay. Overexpression of PGC1α reduced senescence-associated β-galactosidase-positive cells and increased the proliferation of senescent cells. Although PGC1α 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 PGC1α. HDAC1 knockdown affected sirtuin 1 expression and decreased its deacetylation of PGC1α. In the mouse brain cortex, acetylation of PGC1α was increased by ionizing radiation treatment. These results suggest that acetylation of PGC1α 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 PGC1α 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.",
keywords = "Brain disorder, Cellular senescence, HDAC1, Ionizing radiation, PGC1α",
author = "Kim, {Su Bin} and Heo, {Jong Ik} and Hyunggee Kim and Kim, {Kwang Seok}",
year = "2019",
month = "5",
day = "16",
doi = "10.1093/gerona/gly167",
language = "English",
volume = "74",
pages = "787--793",
journal = "Journals of Gerontology - Series A Biological Sciences and Medical Sciences",
issn = "1079-5006",
publisher = "Oxford University Press",
number = "6",

}

TY - JOUR

T1 - Acetylation of PGC1α by Histone Deacetylase 1 Downregulation Is Implicated in Radiation-Induced Senescence of Brain Endothelial Cells

AU - Kim, Su Bin

AU - Heo, Jong Ik

AU - Kim, Hyunggee

AU - Kim, Kwang Seok

PY - 2019/5/16

Y1 - 2019/5/16

N2 - Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) is a potent transcription factor for mitochondrial function, lipid metabolism, and detoxification in a variety of tissues. PGC1α also promotes brain cell proliferation and memory. However, how PGC1α is involved in aging is not well known. In brain endothelial cells, we found that PGC1α knockdown accelerated DNA damage-induced senescence, evidenced by an increase in senescence-associated β-galactosidase-positive cells and a decrease in cell proliferation and adenosine triphosphate production. PGC1α knockdown delayed DNA damage repair mechanisms compared with the wild-type condition as shown by γ-H2AX foci staining assay. Overexpression of PGC1α reduced senescence-associated β-galactosidase-positive cells and increased the proliferation of senescent cells. Although PGC1α 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 PGC1α. HDAC1 knockdown affected sirtuin 1 expression and decreased its deacetylation of PGC1α. In the mouse brain cortex, acetylation of PGC1α was increased by ionizing radiation treatment. These results suggest that acetylation of PGC1α 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 PGC1α 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.

AB - Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) is a potent transcription factor for mitochondrial function, lipid metabolism, and detoxification in a variety of tissues. PGC1α also promotes brain cell proliferation and memory. However, how PGC1α is involved in aging is not well known. In brain endothelial cells, we found that PGC1α knockdown accelerated DNA damage-induced senescence, evidenced by an increase in senescence-associated β-galactosidase-positive cells and a decrease in cell proliferation and adenosine triphosphate production. PGC1α knockdown delayed DNA damage repair mechanisms compared with the wild-type condition as shown by γ-H2AX foci staining assay. Overexpression of PGC1α reduced senescence-associated β-galactosidase-positive cells and increased the proliferation of senescent cells. Although PGC1α 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 PGC1α. HDAC1 knockdown affected sirtuin 1 expression and decreased its deacetylation of PGC1α. In the mouse brain cortex, acetylation of PGC1α was increased by ionizing radiation treatment. These results suggest that acetylation of PGC1α 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 PGC1α 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.

KW - Brain disorder

KW - Cellular senescence

KW - HDAC1

KW - Ionizing radiation

KW - PGC1α

UR - http://www.scopus.com/inward/record.url?scp=85066854334&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066854334&partnerID=8YFLogxK

U2 - 10.1093/gerona/gly167

DO - 10.1093/gerona/gly167

M3 - Article

C2 - 30016403

AN - SCOPUS:85066854334

VL - 74

SP - 787

EP - 793

JO - Journals of Gerontology - Series A Biological Sciences and Medical Sciences

JF - Journals of Gerontology - Series A Biological Sciences and Medical Sciences

SN - 1079-5006

IS - 6

ER -