Abstract
Mitochondrial deficits in energy production cause untreatable and fatal pathologies known as mitochondrial disease (MD). Central nervous system affectation is critical in Leigh Syndrome (LS), a common MD presentation, leading to motor and respiratory deficits, seizures and premature death. However, only specific neuronal populations are affected. Furthermore, their molecular identity and their contribution to the disease remains unknown. Here, using a mouse model of LS lacking the mitochondrial complex I subunit Ndufs4, we dissect the critical role of genetically-defined neuronal populations in LS progression. Ndufs4 inactivation in Vglut2-expressing glutamatergic neurons leads to decreased neuronal firing, brainstem inflammation, motor and respiratory deficits, and early death. In contrast, Ndufs4 deletion in GABAergic neurons causes basal ganglia inflammation without motor or respiratory involvement, but accompanied by hypothermia and severe epileptic seizures preceding death. These results provide novel insight in the cell type-specific contribution to the pathology, dissecting the underlying cellular mechanisms of MD.
Highlights
Leigh syndrome (LS) is the most frequent pediatric mitochondrial disorder, leading to defective mitochondrial energy metabolism
Ndusf4 gene inactivation in glutamatergic or GABAergic neurons of both male and female mice resulted in failure to thrive and premature death (Figure 1B–F); there was no effect on survival, body weight, or motor function when Ndufs4 expression was abolished in cholinergic neurons (Figure 1—figure supplement 1)
Male and female Gad2: Ndufs4cKO mice body weight reached a plateau 2–3 weeks before manifesting a sudden unexpected death (Figure 1E,F). Both Vglut2:Ndufs4cKO and Gad2:Ndufs4cKO mice were significantly smaller than their littermate controls (Figure 1G–H). This lack of weight gain and reduced size appeared to be due to decreased food intake in both genotypes (Figure 1I,J); this was not significantly different when food consumption was normalized to body weight (Figure 1—figure supplement 2)
Summary
Leigh syndrome (LS) is the most frequent pediatric mitochondrial disorder, leading to defective mitochondrial energy metabolism. LS affects 1 in 40,000 births (Rahman et al, 1996), adult onset has been described (McKelvie et al, 2012). Mutations in more than 75 genes have been described to cause LS (Lake et al, 2016). Albeit highly variable, LS symptoms usually include failure to thrive, hypotonia, rigidity, seizures, ataxia, lactic acidosis, encephalopathy and premature death (Rahman et al, 1996; Lake et al, 2016; Sofou et al, 2014). LS is characterized by restricted anatomical and cellular
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