Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation

Xuan Fu, Shan Wan, Yi Lisa Lyu, Leroy-Fong Liu, Haiyan Qi

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

Background: DNA damage such as double-stranded DNA breaks (DSBs) has been reported to stimulate mitochondrial biogenesis. However, the underlying mechanism is poorly understood. The major player in response to DSBs is ATM (ataxia telangiectasia mutated). Upon sensing DSBs, ATM is activated through autophosphorylation and phosphorylates a number of substrates for DNA repair, cell cycle regulation and apoptosis. ATM has been reported to phosphorylate the α subunit of AMP-activated protein kinase (AMPK), which senses AMP/ATP ratio in cells, and can be activated by upstream kinases. Here we provide evidence for a novel role of ATM in mitochondrial biogenesis through AMPK activation in response to etoposide-induced DNA damage. Methodology/Principal Findings: Three pairs of human ATM+ and ATM- cells were employed. Cells treated with etoposide exhibited an ATM-dependent increase in mitochondrial mass as measured by 10-N-Nonyl-Acridine Orange and MitoTracker Green FM staining, as well as an increase in mitochondrial DNA content. In addition, the expression of several known mitochondrial biogenesis regulators such as the major mitochondrial transcription factor NRF-1, PGC-1α and TFAM was also elevated in response to etoposide treatment as monitored by RT-PCR. Three pieces of evidence suggest that etoposide-induced mitochondrial biogenesis is due to ATM-dependent activation of AMPK. First, etoposide induced ATM-dependent phosphorylation of AMPK α subunit at Thr172, indicative of AMPK activation. Second, inhibition of AMPK blocked etoposide-induced mitochondrial biogenesis. Third, activation of AMPK by AICAR (an AMP analogue) stimulated mitochondrial biogenesis in an ATM-dependent manner, suggesting that ATM may be an upstream kinase of AMPK in the mitochondrial biogenesis pathway. Conclusions/Significance: These results suggest that activation of ATM by etoposide can lead to mitochondrial biogenesis through AMPK activation. We propose that ATM-dependent mitochondrial biogenesis may play a role in DNA damage response and ROS regulation, and that defect in ATM-dependent mitochondrial biogenesis could contribute to the manifestations of A-T disease.

Original languageEnglish
Article numbere2009
JournalPLoS One
Volume3
Issue number4
DOIs
Publication statusPublished - Apr 23 2008
Externally publishedYes

Fingerprint

AMP-activated protein kinase
Ataxia Telangiectasia
AMP-Activated Protein Kinases
Organelle Biogenesis
Etoposide
Chemical activation
DNA
DNA damage
Adenosine Monophosphate
Double-Stranded DNA Breaks
DNA Damage
phosphotransferases (kinases)
Acridine Orange
Phosphorylation
etoposide
biogenesis
Mitochondrial DNA
acridine orange
protein phosphorylation
cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation. / Fu, Xuan; Wan, Shan; Lyu, Yi Lisa; Liu, Leroy-Fong; Qi, Haiyan.

In: PLoS One, Vol. 3, No. 4, e2009, 23.04.2008.

Research output: Contribution to journalArticle

Fu, Xuan ; Wan, Shan ; Lyu, Yi Lisa ; Liu, Leroy-Fong ; Qi, Haiyan. / Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation. In: PLoS One. 2008 ; Vol. 3, No. 4.
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