Fatal breathing dysfunction in a mouse model of Leighsyndrome

摘要

Leigh syndrome (LS) is a subacute necrotizing encephalomyelopathy with gliosis inseveral brain regions that usually results in infantile death. Loss of murine Ndufs4 , which encodes NADH dehydrogenase (ubiquinone) iron-sulfurprotein 4, results in compromised activity of mitochondrial complex I as well asprogressive neurodegenerative and behavioral changes that resemble LS. Here, wereport the development of breathing abnormalities in a murine model of LS. Magneticresonance imaging revealed hyperintense bilateral lesions in the dorsal brain stemvestibular nucleus (VN) and cerebellum of severely affected mice. The mutant micemanifested a progressive increase in apnea and had aberrant responses to hypoxia.Electrophysiological recordings within the ventral brain stempre-B?tzinger respiratory complex were also abnormal. Selectiveinactivation of Ndufs4 in the VN, one of the principle sites ofgliosis, also led to breathing abnormalities and premature death. Conversely, Ndufs4 restoration in the VN corrected breathing deficits andprolonged the life span of knockout mice. These data demonstrate that mitochondrialdysfunction within the VN results in aberrant regulation of respiration andcontributes to the lethality of Ndufs4 -knockout mice.