Mitochondrial dysfunction in ataxia-telangiectasia
Open accessAbstract
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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An ATM mouse model displayed mitochondrial dysfunction, higher ROS, and build-up of damaged mitochondria.
“Analysis of an ATM mouse model showed dysfunctional mitochondria with increased ROS levels and the accumulation of damaged mitochondria87.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [87]
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ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts
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ATM directs DNA damage responses and proteostasis via genetically separable pathways
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The Role of Beclin 1-Dependent Autophagy in Cancer
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ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia
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PINK1/Parkin Influences Cell Cycle by Sequestering TBK1 at Damaged Mitochondria, Inhibiting Mitosis
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Mitochondrial redox sensing by the kinase ATM maintains cellular antioxidant capacity
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“In addition, ATM can be directly activated by ROS, independently from DSB signaling, and has been implicated in mitochondrial quality control, potentially through an ability to localize to mitochondria (Guo et al., 2010; Valentin-Vega et al., 2012).”
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Self-citation
- Authors
- Valentin-Vega, Y. A., MacLean, K. H., Tait-Mulder, J., Milasta, S., Steeves, M., Dorsey, F. C., Cleveland, J. L., Green, D. R., & Kastan, M. B.
- Affiliations
- Departments of Oncology and
- St. Jude Children's Research Hospital (US)
- Scripps Research Institute (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2012-02-09
- Volume
- 119
- Issue
- 6
- Pages
- 1490-1500
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3286212
- OpenAlex
- W2120886826
- Cited by
- 365
- References
- 51
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 20 · 2023: 17 · 2022: 22 · 2021: 46 · 2020: 30 · 2019: 26 · 2018: 15 · 2017: 29 · 2016: 38 · 2015: 25 · 2014: 27 · 2013: 29 · 2012: 17
- FWCI
- 9.47
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA076379, R01CA157216, CA71387, CA157216, R01CA076379, P 30CA 21765, R01CA071387, P30CA021765)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- ataxia telangiectasia, ATM, mitochondrial dysfunction, thymocytes, reactive oxygen species, mitophagy, cellular respiration, Beclin-1, autophagy, DNA damage response, T-cell malignancies, mitochondrial homeostasis, cancer susceptibility
- MeSH terms
- Beclin-1, Adenosine Triphosphate, Animals, Ataxia Telangiectasia, Autophagy, Cells, Cultured, DNA-Binding Proteins, Fibroblasts, Humans, Membrane Proteins, Mice, Inbred C57BL, Mitochondria, Oxygen Consumption, Immunoblotting, Gene Expression, Lymphoma, T-Cell, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Mice, Knockout, Cell Cycle Proteins, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Proteins, RNA Interference, Microscopy, Electron, Transmission, Apoptosis Regulatory Proteins, Mice, Membrane Potential, Mitochondrial, Kaplan-Meier Estimate, Thymocytes, Ataxia Telangiectasia Mutated Proteins
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