Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Animals
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Ataxia Telangiectasia / genetics
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Ataxia Telangiectasia / metabolism
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Ataxia Telangiectasia / physiopathology
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Ataxia Telangiectasia Mutated Proteins
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Autophagy
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Beclin-1
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Gene Expression
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Humans
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Immunoblotting
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Kaplan-Meier Estimate
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Lymphoma, T-Cell / genetics
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Lymphoma, T-Cell / metabolism
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Membrane Potential, Mitochondrial
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microscopy, Electron, Transmission
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Mitochondria / genetics
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Mitochondria / metabolism*
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Mitochondria / physiology
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Oxygen Consumption
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA Interference
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Reactive Oxygen Species / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Thymocytes / metabolism
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Thymocytes / ultrastructure
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Apoptosis Regulatory Proteins
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BECN1 protein, human
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Beclin-1
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Cell Cycle Proteins
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DNA-Binding Proteins
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Membrane Proteins
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Reactive Oxygen Species
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Tumor Suppressor Proteins
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Adenosine Triphosphate
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases