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.
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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

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Figure 1

Alterations in MRI and histopathology in KO mice.

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Alterations in MRI and histopathology in KO mice. (A) T2-weighted in viv...
(A) T2-weighted in vivo MRI of control and late-stage KO mouse. Sagittal MRIs (top panels) of control (CT) mouse and late-stage KO mouse show hyperintense regions (white areas) in lateral ventricles of control mouse, whereas KO mouse shows distinct lesions in exterior plexus of OB and dorsal surface of brain stem with extensive lesions of cerebellum (white arrows) together with a hypointense alteration in the midbrain (asterisk). Coronal imaging of control and KO mice shows only moderate T2-weighted MRI intensity in fourth ventricular region of control mouse whereas a mid-stage KO mouse (bottom, right) had significant lesions of the dorsal medulla (VN, white arrow) and tenth cerebellar lobe (black arrow). (B) Diagram of the VN according to Franklin and Paxinos (60). VN is circled. 4v, fourth ventricle. (C) Staining for Iba1 (microglial cell marker) and GFAP (astrocyte marker) in the VN of control (top left) and KO (top right) mice shows presence of symmetrical lesions filled with abundant microglial cells and surrounded by GFAP-positive reactive astrocytes in KO compared with control mice. Scale bar: 1,000 μm. (Bottom row) Close-up images of the VN (indicated by asterisks in C) show increased GFAP and Iba1 intensity and morphological changes in glial cells in KO mice. Scale bar: 250 μm. (D) Survival curve of KO mice (n = 101).