Mitochondrial dysfunction in ataxia-telangiectasia.

Journal Article

Ataxia-telangiectasia mutated (ATM) plays a central role in DNA damage responses, and its loss leads to development of T-cell malignancies. Here, we show that ATM loss also leads to intrinsic mitochondrial abnormalities in thymocytes, including elevated reactive oxygen species, increased aberrant mitochondria, high cellular respiratory capacity, and decreased mitophagy. A fraction of ATM protein is localized in mitochondria, and it is rapidly activated by mitochondrial dysfunction. Unexpectedly, allelic loss of the autophagy regulator Beclin-1 significantly delayed tumor development in ATM-null mice. This effect was not associated with rescue of DNA damage signaling but rather with a significant reversal of the mitochondrial abnormalities. These data support a model in which ATM plays direct roles in modulating mitochondrial homeostasis and suggest that mitochondrial dysfunction and associated increases in mitochondrial reactive oxygen species contribute to the cancer-prone phenotype observed in organisms lacking ATM. Thus, ataxia-telangiectasia should be considered, at least in part, as a mitochondrial disease.

Full Text

Duke Authors

Cited Authors

  • Valentin-Vega, YA; Maclean, KH; Tait-Mulder, J; Milasta, S; Steeves, M; Dorsey, FC; Cleveland, JL; Green, DR; Kastan, MB

Published Date

  • February 9, 2012

Published In

Volume / Issue

  • 119 / 6

Start / End Page

  • 1490 - 1500

PubMed ID

  • 22144182

Electronic International Standard Serial Number (EISSN)

  • 1528-0020

Digital Object Identifier (DOI)

  • 10.1182/blood-2011-08-373639

Language

  • eng

Conference Location

  • United States