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Mitochondrial dysfunction in ataxia-telangiectasia.

Publication ,  Journal Article
Valentin-Vega, YA; Maclean, KH; Tait-Mulder, J; Milasta, S; Steeves, M; Dorsey, FC; Cleveland, JL; Green, DR; Kastan, MB
Published in: Blood
February 9, 2012

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.

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

February 9, 2012

Volume

119

Issue

6

Start / End Page

1490 / 1500

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Thymocytes
  • Reverse Transcriptase Polymerase Chain Reaction
  • Reactive Oxygen Species
  • RNA Interference
  • Protein Serine-Threonine Kinases
  • Oxygen Consumption
  • Mitochondria
  • Microscopy, Electron, Transmission
  • Mice, Knockout
 

Citation

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Valentin-Vega, Y. A., Maclean, K. H., Tait-Mulder, J., Milasta, S., Steeves, M., Dorsey, F. C., … Kastan, M. B. (2012). Mitochondrial dysfunction in ataxia-telangiectasia. Blood, 119(6), 1490–1500. https://doi.org/10.1182/blood-2011-08-373639
Valentin-Vega, Yasmine A., Kirsteen H. Maclean, Jacqueline Tait-Mulder, Sandra Milasta, Meredith Steeves, Frank C. Dorsey, John L. Cleveland, Douglas R. Green, and Michael B. Kastan. “Mitochondrial dysfunction in ataxia-telangiectasia.Blood 119, no. 6 (February 9, 2012): 1490–1500. https://doi.org/10.1182/blood-2011-08-373639.
Valentin-Vega YA, Maclean KH, Tait-Mulder J, Milasta S, Steeves M, Dorsey FC, et al. Mitochondrial dysfunction in ataxia-telangiectasia. Blood. 2012 Feb 9;119(6):1490–500.
Valentin-Vega, Yasmine A., et al. “Mitochondrial dysfunction in ataxia-telangiectasia.Blood, vol. 119, no. 6, Feb. 2012, pp. 1490–500. Pubmed, doi:10.1182/blood-2011-08-373639.
Valentin-Vega YA, Maclean KH, Tait-Mulder J, Milasta S, Steeves M, Dorsey FC, Cleveland JL, Green DR, Kastan MB. Mitochondrial dysfunction in ataxia-telangiectasia. Blood. 2012 Feb 9;119(6):1490–1500.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

February 9, 2012

Volume

119

Issue

6

Start / End Page

1490 / 1500

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Thymocytes
  • Reverse Transcriptase Polymerase Chain Reaction
  • Reactive Oxygen Species
  • RNA Interference
  • Protein Serine-Threonine Kinases
  • Oxygen Consumption
  • Mitochondria
  • Microscopy, Electron, Transmission
  • Mice, Knockout