Mitochondrial diseases (MDs) are genetic disorders characterized by dysfunctions in mitochondria. Clinical data suggest that additional factors, beyond genetics, contribute to the onset and progression of this group of diseases, but these influencing factors remain largely unknown. Mounting evidence indicates that immune dysregulation or distress could play a role. Clinical observations have described the co-incidence of infection and the onset of the disease as well as the worsening of symptoms following infection. These findings highlight the complex interactions between MDs and immunity and underscore the need to better understand their underlying relationships. We used Ndufs4 KO mice, a well-established mouse model of Leigh syndrome (one of the most relevant MDs), to test whether chronic induction of a neuroinflammatory state in the central nervous system before the development of neurological symptoms would affect both the onset and progression of the disease in Ndufs4 KO mice. To this aim, we took advantage of the GFAP-IL6 mouse, which overexpresses interleukin-6 (IL-6) in astrocytes and produces chronic glial reactivity, by generating a mouse line with IL-6 overexpression and NDUFS4 deficiency. IL-6 overexpression aggravated the mortality of female Ndufs4 KO mice but did not alter the main motor and respiratory phenotypes measured in any sex. Interestingly, an abnormal region-dependent microglial response to IL-6 overexpression was observed in Ndufs4 KO mice compared to controls. Overall, our data indicate that chronic neuroinflammation may worsen the disease in Ndufs4 KO female mice, but not in males, and uncovers an abnormal microglial response due to OXPHOS dysfunction, which may have implications for our understanding of the effect of OXPHOS dysfunction in microglia.

中文翻译：

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Interleukin-6 引发的慢性神经炎症可能会降低 Leigh 综合征小鼠模型的生存率，但不足以驱动疾病进展

线粒体疾病（MD）是一种以线粒体功能障碍为特征的遗传性疾病。临床数据表明，除了遗传学之外，还有其他因素导致这组疾病的发生和进展，但这些影响因素仍然很大程度上未知。越来越多的证据表明，免疫失调或应激可能发挥了一定作用。临床观察描述了感染与疾病同时发生以及感染后症状恶化的情况。这些发现强调了MD与免疫之间复杂的相互作用，并强调需要更好地了解它们的潜在关系。我们使用 Ndufs4 KO 小鼠（一种成熟的 Leigh 综合征小鼠模型（最相关的 MD 之一））来测试在神经症状出现之前在中枢神经系统中慢性诱导神经炎症状态是否会影响发病和症状。 Ndufs4 KO 小鼠疾病的进展。为此，我们利用 GFAP-IL6 小鼠，通过产生 IL-6 过度表达和 NDUFS4 缺陷的小鼠系，该小鼠在星形胶质细胞中过度表达白细胞介素 6 (IL-6) 并产生慢性神经胶质反应性。IL-6过表达加剧了雌性Ndufs4 KO小鼠的死亡率，但没有改变任何性别的主要运动和呼吸表型。有趣的是，与对照组相比，在 Ndufs4 KO 小鼠中观察到异常的区域依赖性小胶质细胞对 IL-6 过表达的反应。总体而言，我们的数据表明，慢性神经炎症可能会使 Ndufs4 KO 雌性小鼠的疾病恶化，但不会使雄性小鼠病情恶化，并且发现由于 OXPHOS 功能障碍导致的异常小胶质细胞反应，这可能对我们理解 OXPHOS 功能障碍对小胶质细胞的影响具有影响。