Journal
BLOOD
Volume 119, Issue 6, Pages 1490-1500Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-08-373639
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Funding
- National Institutes of Health [CA71387, CA157216, CA076379, P30CA21765]
- State of Florida to Scripps-Florida
- American Lebanese Syrian Associated Charities of St Jude Children's Research Hospital
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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. (Blood. 2012; 119(6): 1490-1500)
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