Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs.

原发性线粒体疾病 (PMD) 与儿科神经系统疾病有关，传统上与​​神经元氧化磷酸化系统 (OXPHOS) 缺陷有关。有趣的是，PMD 小鼠模型和 PMD 患者均表现出神经胶质增生，而小胶质细胞（大脑的先天免疫细胞）的药理学消耗可改善小鼠模型中的多种症状。鉴于小胶质细胞的激活与 OXPHOS 基因的表达相关，我们研究了小胶质细胞中 OXPHOS 的缺陷是否可能导致 PMD。我们首先观察到，与体外小胶质细胞刺激（通过 IL-33 或 TAU 治疗）相关的代谢重新布线因复合物 I (CI) 抑制（通过鱼藤酮治疗）而部分改变。在体内，我们建立了小胶质细胞 CI 活性缺陷的小鼠模型 (MGcCI)。 MGcCI 小胶质细胞表现出代谢重连和逐渐转录激活，分别导致幼年（1 个月大）和成年（3 个月大）阶段的肥大和功能障碍。 MGcCI 小鼠表现出广泛的反应性星形胶质细胞、突触标记物的减少伴随着小清蛋白神经元数量的增加，这是一种以长时间不动、体重减轻和过早死亡为特征的行为缺陷，但通过小胶质细胞的药理学耗竭部分缓解。我们的数据表明，小胶质细胞的发育取决于线粒体 CI，并表明小胶质细胞对 PMD 有直接贡献。