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 Article has an altmetric score of 10

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 3

Reduced breathing, heart rate, and oxygen saturation in KO mice.

Options: View larger image (or click on image) Download as PowerPoint
Reduced breathing, heart rate, and oxygen saturation in KO mice. Measure...
Measurements were made using a pulse oximeter attached to the bare necks of control (n = 7) and KO mice at various stages of disease progression (total n = 11; n = 2, 3, and 6 mice, early, mid-stage, and late-stage respectively) as described in Methods. For KO mice, there were often significant fluctuations of the values over time; average rates during the measurement period are plotted. (A) Breathing rate was lower in mid- and late-stage KO mice. *P < 0.05, 1-way ANOVA, Tukey’s post-test. (B) Representative traces of control and early- and late-stage KO mice (C) Heart rate at all stages of disease progression was significantly less than that of controls. *P < 0.05, 1-way ANOVA, Tukey’s post-test. (D) Representative traces of control and early- and late-stage KO mice. (E) Arterial blood oxygen saturation became variable and significantly lower in late-stage KO mice. (F) Representative traces of control and early- and late-stage KO mice. Data points represent individual mice. Data are shown as mean ± SEM.