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Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells.
Mark Ambrose1, Jimena V Goldstine, Richard A Gatti
1Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095-1732, USA.
Human Molecular Genetics
|July 4, 2007
Summary
Ataxia telangiectasia (A-T) cells exhibit mitochondrial dysfunction, characterized by abnormal structure and reduced respiration. Restoring ATM protein or using antioxidants improves mitochondrial function in these cells.
Area of Science:
- Cell Biology
- Genetics
- Biochemistry
Background:
- Ataxia telangiectasia (A-T) cells experience persistent oxidative stress and activate damage response pathways.
- The role of mitochondrial dysfunction in the A-T oxidative stress phenotype requires further investigation.
Purpose of the Study:
- To determine if intrinsic mitochondrial dysfunction contributes to the oxidative stress observed in A-T cells.
- To investigate the role of the ATM gene in regulating mitochondrial function.
Main Methods:
- Mitochondrial structure and membrane potential (DeltaPsi) were assessed using Mitotracker Red staining.
- Gene expression of nuclear-encoded mitochondrial proteins was analyzed.
- Mitochondrial respiratory activity was measured.
- A-T cells were treated with alpha lipoic acid (ALA); ATM was depleted using siRNA and restored via stable expression.
Main Results:
- A-T cells displayed abnormal mitochondrial structure and increased populations with decreased membrane potential.
- Elevated expression of nuclear-encoded mitochondrial oxidative damage-responsive genes was observed in A-T cells.
- Mitochondrial respiration was diminished in A-T cells, but restored by ALA treatment or ATM re-expression. ATM depletion reduced respiration in wild-type cells.
Conclusions:
- A-T cells exhibit intrinsic mitochondrial dysfunction.
- The ATM protein is crucial for regulating mitochondrial function and preventing oxidative stress in A-T cells.
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