The mitochondrial negative regulator MCJ modulates the interplay between microbiota and the host during ulcerative colitis
The mitochondrial negative regulator MCJ modulates the interplay between microbiota and the host during ulcerative colitis
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DOI：
10.1038/s41598-019-57348-0
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发表时间：
2020-01-17
影响因子：
4.6
通讯作者：
Abecia, Leticia
中科院分区：
文献类型：
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作者：
Angel Pascual-Itoiz, Miguel;Pena-Cearra, Ainize;Abecia, Leticia
最近的证据表明，活动性溃疡性结肠炎（UC）患者的线粒体基因和功能下降，特别是电子传递链复合体I的活性严重受损。MCJ是一种线粒体内膜蛋白，被鉴定为呼吸链复合物i的天然抑制剂。MCJ缺陷小鼠实验性结肠炎的诱导导致Timp3表达上调，从而抑制TACE活性，可能抑制Tnf和Tnfr1从结肠细胞膜脱落。mcj缺陷小鼠也表现出Myd88和Tlr9、促炎基因和疾病严重程度的更高表达。有趣的是，MCJ的缺失导致了不同的微生物群代谢和组成，包括UC患者肠道菌群的成员，瘤球菌。这些变化引起了对IgA水平的影响。UC患者的基因表达分析显示MCJ水平降低，TIMP3表达升高，提示线粒体基因和功能在活动性UC中发挥了相关作用。MCJ缺乏扰乱宿主线粒体和影响疾病严重程度的微生物群之间的调节关系。我们的研究结果表明，线粒体功能可能是发病机制中的一个重要因素。所有这些都支持UC期间MCJ调节的重要性。
Recent evidences indicate that mitochondrial genes and function are decreased in active ulcerative colitis (UC) patients, in particular, the activity of Complex I of the electron transport chain is heavily compromised. MCJ is a mitochondrial inner membrane protein identified as a natural inhibitor of respiratory chain Complex I. The induction of experimental colitis in MCJ-deficient mice leads to the upregulation of Timp3 expression resulting in the inhibition of TACE activity that likely inhibits Tnf and Tnfr1 shedding from the cell membrane in the colon. MCJ-deficient mice also show higher expression of Myd88 and Tlr9, proinflammatory genes and disease severity. Interestingly, the absence of MCJ resulted in distinct microbiota metabolism and composition, including a member of the gut community in UC patients, Ruminococcus gnavus. These changes provoked an effect on IgA levels. Gene expression analyses in UC patients showed decreased levels of MCJ and higher expression of TIMP3, suggesting a relevant role of mitochondrial genes and function among active UC. The MCJ deficiency disturbs the regulatory relationship between the host mitochondria and microbiota affecting disease severity. Our results indicate that mitochondria function may be an important factor in the pathogenesis. All together support the importance of MCJ regulation during UC.