Transient mitochondrial DNA double strand breaks in mice cause accelerated aging phenotypes in a ROS-dependent but p53/p21-independent manner

Milena Pinto, Alicia M. Pickrell, Xiao Wang, Sandra R. Bacman, Aixin Yu, Aline Hida, Lloye M. Dillon, Paul D. Morton, Thomas Malek, Sion Llewelyn Williams, Carlos T Moraes

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

We observed that the transient induction of mtDNA double strand breaks (DSBs) in cultured cells led to activation of cell cycle arrest proteins (p21/p53 pathway) and decreased cell growth, mediated through reactive oxygen species (ROS). To investigate this process in vivo we developed a mouse model where we could transiently induce mtDNA DSBs ubiquitously. This transient mtDNA damage in mice caused an accelerated aging phenotype, preferentially affecting proliferating tissues. One of the earliest phenotypes was accelerated thymus shrinkage by apoptosis and differentiation into adipose tissue, mimicking age-related thymic involution. This phenotype was accompanied by increased ROS and activation of cell cycle arrest proteins. Treatment with antioxidants improved the phenotype but the knocking out of p21 or p53 did not. Our results demonstrate that transient mtDNA DSBs can accelerate aging of certain tissues by increasing ROS. Surprisingly, this mtDNA DSB-associated senescence phenotype does not require p21/p53, even if this pathway is activated in the process.Cell Death and Differentiation advance online publication, 2 December 2016; doi:10.1038/cdd.2016.123.

Original languageEnglish (US)
JournalCell Death and Differentiation
DOIs
StateAccepted/In press - Dec 2 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Transient mitochondrial DNA double strand breaks in mice cause accelerated aging phenotypes in a ROS-dependent but p53/p21-independent manner'. Together they form a unique fingerprint.

  • Cite this