Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48.
Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48.
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DOI：
10.1126/sciadv.abl5182
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发表时间：
2021-12-10
期刊：
影响因子：
13.6
通讯作者：
Clark AR
中科院分区：
文献类型：
--
作者：
Clayton SA;Daley KK;MacDonald L;Fernandez-Vizarra E;Bottegoni G;O'Neil JD;Major T;Griffin D;Zhuang Q;Adewoye AB;Woolcock K;Jones SW;Goodyear C;Elmesmari A;Filer A;Tennant DA;Alivernini S;Buckley CD;Pitceathly RDS;Kurowska-Stolarska M;Clark AR
线粒体亚基C15 ORF 48和NDUFA 4的交换发生在体外巨噬细胞活化期间和炎性疾病中。线粒体功能失调是免疫介导的炎性疾病的标志。细胞色素c氧化酶（CcO）介导线粒体呼吸中的限速步骤，在发育过程中以及响应氧可用性的变化而重塑，但对炎症期间CcO重塑的研究很少。在这里，我们描述了一个优雅的分子开关介导的双功能转录C15 orf 48，它协调的替代CcO亚基NDUFA 4由其parparamount C15 ORF 48在原代巨噬细胞。C15 orf 48的表达是对炎症信号的保守反应，并且发生在许多免疫相关的病理中。在类风湿性关节炎中，C15 orf 48 mRNA在外周单核细胞和促炎性滑膜组织巨噬细胞中升高，其表达与疾病严重程度呈正相关，并在缓解期下降。C15 orf 48也由2019年严重冠状病毒病（COVID-19）中的致病性巨噬细胞表达。对一种罕见代谢疾病综合征的研究提供了证据，表明NDUFA 4亚基的缺失支持促炎性巨噬细胞功能。
Exchange of mitochondrial subunits C15ORF48 and NDUFA4 occurs during macrophage activation in vitro and in inflammatory disease. Dysregulated mitochondrial function is a hallmark of immune-mediated inflammatory diseases. Cytochrome c oxidase (CcO), which mediates the rate-limiting step in mitochondrial respiration, is remodeled during development and in response to changes of oxygen availability, but there has been little study of CcO remodeling during inflammation. Here, we describe an elegant molecular switch mediated by the bifunctional transcript C15orf48, which orchestrates the substitution of the CcO subunit NDUFA4 by its paralog C15ORF48 in primary macrophages. Expression of C15orf48 is a conserved response to inflammatory signals and occurs in many immune-related pathologies. In rheumatoid arthritis, C15orf48 mRNA is elevated in peripheral monocytes and proinflammatory synovial tissue macrophages, and its expression positively correlates with disease severity and declines in remission. C15orf48 is also expressed by pathogenic macrophages in severe coronavirus disease 2019 (COVID-19). Study of a rare metabolic disease syndrome provides evidence that loss of the NDUFA4 subunit supports proinflammatory macrophage functions.
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