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. 2013 Jan;21(1):42-8.
doi: 10.1038/mt.2012.203. Epub 2012 Sep 25.

Reducing mitochondrial ROS improves disease-related pathology in a mouse model of ataxia-telangiectasia

Anthony D D'Souza  1 , Ian A Parish, Diane S Krause, Susan M Kaech, Gerald S Shadel
Affiliations

Reducing mitochondrial ROS improves disease-related pathology in a mouse model of ataxia-telangiectasia

Anthony D D'Souza et al. Mol Ther. 2013 Jan.

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.

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Figures

Figure 1
Figure 1
Mitochondrial catalase suppresses thymic lymphomagenesis in ATM−/− mice. (a) Total thymocytes from 12-week-old ATM+/+ (white-filled bar, n = 10), ATM+/+ mCAT+ (gray-filled bar, n = 10), normal ATM−/− (white filled with black diagonal lines, n = 6), lymphomagenic ATM−/− (white filled with black vertical lines, n = 6), normal ATM−/− mCAT+ (gray filled with black diagonal lines, n = 8), and lymphomagenic ATM−/− mCAT+ (gray filled with black vertical lines, n = 4) mice. Analyses of percent CD8+ CD4+ (double-positive), CD8− CD4− (double-negative), CD8+ (single-positive), and CD4+ (single-positive) cells from the mice in a. FACS analyses of (b) mitochondrial ROS (MitoSox), (c) cellular ROS/redox (H2DCFDA), and (d) TORC1 activity (phospho-S6) of CD8+ CD4+ (double-positive) cells from the mice in a. (e) L-lactate measured from 107 thymocytes from 12-week-old ATM+/+ (white-filled bar, n = 3), ATM+/+ mCAT+ (gray-filled bar, n = 3), ATM−/− (white filled with black diagonal lines, n = 3), and ATM−/− mCAT+ (gray filled with black diagonal lines, n = 3) mice. Statistical significance is denoted by *(<0.05), **(<0.005), ***(<0.0005) or ns (not significant). FACS, fluorescence-activated cell sorting; ROS, reactive oxygen species.
Figure 2
Figure 2
Survival Analysis. Kaplan–Meier survival curves for ATM+/+ (n = 9), ATM+/+ mCAT+ (n = 14), ATM−/− (n = 22), and ATM−/− mCAT+ (n = 21) mice. P value was <0.0001 on comparing ATM−/− and ATM−/− mCAT+ curves. The experiment was terminated at 300 days.
Figure 3
Figure 3
Bone marrow analyses of 12-week-old ATM−/− and ATM−/− mCAT+ mice. (a) FACS analyses of total bone marrow cells from femurs of the same mice analyzed in a, followed by (b) total number of hematopoietic stem cells (HSC, Lin− cKit+ Sca-1+), (c) granulocytes-monocytes (Gr-1+ Mac-1+), erythroid cells (Ter119+ CD71+), and lymphoid cells (B220+). (d) Total macrophages obtained upon differentiation in vitro of bone marrow cells from ATM+/+ (n = 4), ATM+/+ mCAT+ (n = 4), ATM−/− (n = 4), and ATM−/− mCAT+ (n = 4) mice. Statistical significance is denoted by *(<0.05), **(<0.005), ***(<0.0005) or ns (not significant). FACS, fluorescence-activated cell sorting.
Figure 4
Figure 4
Analysis of CD8+ T cell memory-differentiation phenotypes in vivo and in vitro. (a) Analyses of LCMV-specific Gp33+ splenic CD8+ T cells on day 30 post-LCMV infection of ATM+/+ (white-filled bar, n = 10), ATM+/+ mCAT+ (white filled with black stripes, n = 7), ATM−/− (gray-filled bar, n = 10), and ATM−/− mCAT+ (gray filled with black stripes, n = 9) mice. (b) Percent CD62Lhi, KLRG1+ (effector-memory TEM) and CD127+ (central memory, TCM) GP33+ CD8+ T cells from the mice analyzed in a. (c) Phospho-S6 MFI of splenic CD8+ T cells 72 hours post-TCR activation in vitro and (d) number of TCR-activated CD8+ T cells after additional 72 hours of IL-15 treatment from ATM+/+ (white-filled bar, n = 5), ATM+/+ mCAT+ (white filled with black stripes, n = 4), ATM−/− (gray-filled bar, n = 5), and ATM−/− mCAT+ (gray filled with black stripes, n = 5) mice. Statistical significance is denoted by *(<0.05), **(<0.005), ***(<0.0005) or ns (not significant). IL, interleukin; LCMV, lymphochoriomeningitis virus; MFI, median fluorescence intensity; TCR, T cell receptor.
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