Fatal breathing dysfunction in a mouse model of Leigh syndrome
Albert Quintana, … , Jan M. Ramirez, Richard D. Palmiter
Albert Quintana, … , Jan M. Ramirez, Richard D. Palmiter
Published June 1, 2012
Citation Information: J Clin Invest. 2012;122(7):2359-2368. https://doi.org/10.1172/JCI62923.
View: Text | PDF
Research Article Neuroscience

Fatal breathing dysfunction in a mouse model of Leigh syndrome

Abstract

Leigh syndrome (LS) is a subacute necrotizing encephalomyelopathy with gliosis in several brain regions that usually results in infantile death. Loss of murine Ndufs4, which encodes NADH dehydrogenase (ubiquinone) iron-sulfur protein 4, results in compromised activity of mitochondrial complex I as well as progressive neurodegenerative and behavioral changes that resemble LS. Here, we report the development of breathing abnormalities in a murine model of LS. Magnetic resonance imaging revealed hyperintense bilateral lesions in the dorsal brain stem vestibular nucleus (VN) and cerebellum of severely affected mice. The mutant mice manifested a progressive increase in apnea and had aberrant responses to hypoxia. Electrophysiological recordings within the ventral brain stem pre-Bötzinger respiratory complex were also abnormal. Selective inactivation of Ndufs4 in the VN, one of the principle sites of gliosis, also led to breathing abnormalities and premature death. Conversely, Ndufs4 restoration in the VN corrected breathing deficits and prolonged the life span of knockout mice. These data demonstrate that mitochondrial dysfunction within the VN results in aberrant regulation of respiration and contributes to the lethality of Ndufs4-knockout mice.

Authors

Albert Quintana, Sebastien Zanella, Henner Koch, Shane E. Kruse, Donghoon Lee, Jan M. Ramirez, Richard D. Palmiter

×

Figure 6

Ndufs4 reexpression in the VN of KO mice improves breathing and ameliorates disease progression.

Options: View larger image (or click on image) Download as PowerPoint
Ndufs4 reexpression in the VN of KO mice improves breathing and ameliora...
(A) Representative image of the degree of transduction (GFP-positive cells) after vector delivery in the VN of KO mice (AAV-VN-VR mice). (B–E) Iba1 staining (red) in the VN (B and C) or striatum (D and E) of KO or AAV-VN-VR mice. Asterisk denotes presence of lesions. Cb, cerebellum. Scale bars: 500 μm (A); 250 μm (B–E). (F) Clinical score of the disease progression in KO (n = 9) and AAV-VN-VR (n = 7) mice as described (24). *P < 0.05 genotype, 2-way ANOVA. F(1,121) = 4.18. (G) Survival curve in KO (n = 16) and AAV-VN-VR (n = 7) mice. **P < 0.01, Gehan-Breslow-Wilcoxon test versus KO mice. (H) Changes in breathing of AAV-VN–CT (n = 14), AAV-VN-VR (n = 3), and KO (n = 10) mice exposed to 5-minute hypoxia (10% O2; gray area). *P < 0.05 versus control mice, 2-way ANOVA, Bonferroni’s post-hoc test. (I) Changes in breathing of AAV-VN–CT (n = 14), AAV-VN-VR (n = 3), and nonresponding KO (n = 5) mice exposed to 5-minute hypercapnia (5% CO2; gray area). *P < 0.05 versus control mice, 2-way ANOVA, Bonferroni’s post-hoc test. Data are shown as the mean ± SEM.