Hypothalamic inflammation has been linked to various aspects of central metabolic dysfunction and diseases in humans, including hyperphagia, altered energy expenditure, and obesity. We previously reported that loss of β-carotene oxygenase 2 (BCO2), a mitochondrial inner membrane protein, causes the alteration of the hypothalamic metabolome, low-grade inflammation, and an increase in food intake in mice at an early age, e.g., 3–6 weeks. Here, we determined the extent to which the deficiency of BCO2 induces hypothalamic inflammation in BCO2 knockout mice. Mitochondrial proteomics, electron microscopy, and immunoblotting were used to assess the changes in hypothalamic mitochondrial dynamics and mitochondrial DNA sensing and signaling. The results showed that deficiency of BCO2 altered hypothalamic mitochondrial proteome and respiratory supercomplex assembly by enhancing the expression of NADH:ubiquinone oxidoreductase subunit A11 protein and improved cardiolipin synthesis. BCO2 deficiency potentiated mitochondrial fission but suppressed mitophagy and mitochondrial biogenesis. Furthermore, deficiency of BCO2 resulted in inactivation of mitochondrial MnSOD enzyme, excessive production of reactive oxygen species, and elevation of protein levels of stimulator of interferon genes (STING) and interferon regulatory factor 3 (IRF3) in the hypothalamus. The data suggest that BCO2 is essential for hypothalamic mitochondrial dynamics. BCO2 deficiency induces mitochondrial fragmentation and mitochondrial oxidative stress, which may lead to mitochondrial DNA release into the cytosol and subsequently sensing by activation of the STING-IRF3 signaling pathway in the mouse hypothalamus.

下丘脑炎症与人类中枢代谢功能障碍和疾病的各个方面有关，包括摄食过多、能量消耗改变和肥胖。我们之前曾报道，β-胡萝卜素加氧酶 2 (BCO2)（一种线粒体内膜蛋白）的缺失会导致小鼠下丘脑代谢组的改变、低度炎症和小鼠早期食物摄入量的增加，例如, 3-6 周。在这里，我们确定了 BCO2 缺乏在 BCO2 敲除小鼠中诱导下丘脑炎症的程度。线粒体蛋白质组学、电子显微镜和免疫印迹被用来评估下丘脑线粒体动力学和线粒体 DNA 传感和信号传导的变化。结果表明，BCO2 缺乏通过增强 NADH：泛醌氧化还原酶亚基 A11 蛋白的表达和改善心磷脂合成来改变下丘脑线粒体蛋白质组和呼吸超复合体的组装。BCO2 缺乏增强了线粒体裂变，但抑制了线粒体自噬和线粒体生物发生。此外，BCO2 缺乏导致线粒体 MnSOD 酶失活，活性氧产生过多，下丘脑中干扰素基因刺激物 (STING) 和干扰素调节因子 3 (IRF3) 的蛋白质水平升高。数据表明 BCO2 对下丘脑线粒体动力学至关重要。BCO2 缺乏诱导线粒体断裂和线粒体氧化应激，这可能导致线粒体 DNA 释放到细胞质中，随后通过激活小鼠下丘脑中的 STING-IRF3 信号通路进行感知。