| First Author | Terburgh K | Year | 2021 |
| Journal | Biochim Biophys Acta Mol Basis Dis | Volume | 1867 |
| Issue | 5 | Pages | 166082 |
| PubMed ID | 33486097 | Mgi Jnum | J:304102 |
| Mgi Id | MGI:6515373 | Doi | 10.1016/j.bbadis.2021.166082 |
| Citation | Terburgh K, et al. (2021) Aberrant BCAA and glutamate metabolism linked to regional neurodegeneration in a mouse model of Leigh syndrome. Biochim Biophys Acta Mol Basis Dis 1867(5):166082 |
| abstractText | The dysfunction of respiratory chain complex I (CI) is the most common form of mitochondrial disease that most often presents as Leigh syndrome (LS) in children - a severe neurometabolic disorder defined by progressive focal lesions in specific brain regions. The mechanisms underlying this region-specific vulnerability to CI deficiency, however, remain elusive. Here, we examined brain regional respiratory chain enzyme activities and metabolic profiles in a mouse model of LS with global CI deficiency to gain insight into regional vulnerability to neurodegeneration. One lesion-resistant and three lesion-prone brain regions were investigated in Ndufs4 knockout (KO) mice at the late stage of LS. Enzyme assays confirmed significantly decreased (60-80%) CI activity in all investigated KO brain regions, with the lesion-resistant region displaying the highest residual CI activity (38% of wild type). A higher residual CI activity, and a less perturbed NADH/NAD(+) ratio, correlate with less severe metabolic perturbations in KO brain regions. Moreover, less perturbed BCAA oxidation and increased glutamate oxidation seem to distinguish lesion-resistant from -prone KO brain regions, thereby identifying key areas of metabolism to target in future therapeutic intervention studies. |
