Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, United States.
Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Elife. 2019 Aug 12;8:e47163. doi: 10.7554/eLife.47163.
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 , we dissect the critical role of genetically-defined neuronal populations in LS progression. inactivation in Vglut2-expressing glutamatergic neurons leads to decreased neuronal firing, brainstem inflammation, motor and respiratory deficits, and early death. In contrast, 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.
线粒体在能量产生方面的缺陷会导致无法治疗和致命的疾病，这些疾病被称为线粒体疾病（MD）。中枢神经系统的影响在 Leigh 综合征（LS）中至关重要，LS 是一种常见的 MD 表现形式，导致运动和呼吸功能缺陷、癫痫发作和过早死亡。然而，只有特定的神经元群体受到影响。此外，它们的分子特征及其对疾病的贡献仍然未知。在这里，我们使用一种缺乏线粒体复合物 I 亚基的 LS 小鼠模型，剖析了遗传定义的神经元群体在 LS 进展中的关键作用。在 Vglut2 表达的谷氨酸能神经元中失活 会导致神经元放电减少、脑干炎症、运动和呼吸功能缺陷以及早期死亡。相比之下，在 GABA 能神经元中缺失 会导致基底神经节炎症而不涉及运动或呼吸，但伴随着体温过低和严重的癫痫发作，导致死亡。这些结果为特定于细胞类型的病理学贡献提供了新的见解，剖析了 MD 的潜在细胞机制。
