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Published on: January 22, 2017
Reducing mitochondrial ROS improves disease-related pathology in a mouse model of ataxia-telangiectasia
Anthony D D'Souza1, Ian A Parish, Diane S Krause
1Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520-8023, USA.
Abstract:
The disease ataxia-telangiectasia (A-T) has no cure and few treatment options. It is caused by mutations in the ATM kinase, which functions in the DNA-damage response and redox sensing. In addition to severe cerebellar degeneration, A-T pathology includes cancer predisposition, sterility, immune system dysfunction, and bone marrow abnormalities. These latter phenotypes are recapitulated in the ATM null (ATM(-/-)) mouse model of the disease. Since oxidative stress and mitochondrial dysfunction are implicated in A-T, we determined whether reducing mitochondrial reactive oxygen species (ROS) via overexpression of catalase targeted to mitochondria (mCAT) alleviates A-T-related pathology in ATM(-/-) mice. We found that mCAT has many beneficial effects in this context, including reduced propensity to develop thymic lymphoma, improved bone marrow hematopoiesis and macrophage differentiation in vitro, and partial rescue of memory T-cell developmental defects. Our results suggest that positive effects observed on cancer development may be linked to mCAT reducing mitochondrial ROS, lactate production, and TORC1 signaling in transforming double-positive cells, whereas beneficial effects in memory T cells appear to be TORC1-independent. Altogether, this study provides proof-of-principle that reducing mitochondrial ROS production per se may be therapeutic for the disease, which may have advantages compared with more general antioxidant strategies.
Insights
Targeting mitochondrial reactive oxygen species (ROS) with mCAT in ataxia-telangiectasia (A-T) mouse models reduced cancer and improved immune cell function. This suggests reducing mitochondrial ROS may be a viable therapeutic strategy for A-T.
Area of Science:
- Biochemistry
- Genetics
- Immunology
Background:
- Ataxia-telangiectasia (A-T) is a severe genetic disorder caused by mutations in the ATM kinase, leading to DNA damage response defects and increased cancer risk.
- A-T pathology includes cerebellar degeneration, immune dysfunction, and bone marrow abnormalities, which are mirrored in ATM-deficient mice.
- Oxidative stress and mitochondrial dysfunction are implicated in A-T pathogenesis.
Purpose of the Study:
- To investigate if reducing mitochondrial reactive oxygen species (ROS) by overexpressing mitochondrially targeted catalase (mCAT) can alleviate A-T-related pathology in ATM-deficient mice.
- To explore the mechanisms underlying the potential therapeutic effects of mCAT, including its impact on cancer development and immune cell function.
Main Methods:
- Overexpression of catalase targeted to mitochondria (mCAT) in ATM-null (ATM(-/-)) mice.
- Assessment of thymic lymphoma development, bone marrow hematopoiesis, and macrophage differentiation.
- Evaluation of memory T-cell development and associated signaling pathways (e.g., TORC1).
Main Results:
- mCAT overexpression significantly reduced the propensity for thymic lymphoma in ATM(-/-) mice.
- Improved bone marrow hematopoiesis and enhanced macrophage differentiation were observed in vitro.
- Partial rescue of memory T-cell developmental defects was achieved, with some effects being TORC1-independent.
Conclusions:
- Reducing mitochondrial ROS production via mCAT demonstrates therapeutic potential for A-T, particularly in mitigating cancer predisposition and improving immune cell abnormalities.
- The findings provide a proof-of-principle for targeting mitochondrial ROS as a therapeutic strategy in A-T, potentially offering advantages over general antioxidant approaches.
- Mechanisms involve reduced mitochondrial ROS, lactate production, and TORC1 signaling in cancer cells, while immune cell benefits may involve TORC1-independent pathways.
