Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver

Mitochondrial oxidative phosphorylation (OXPHOS) fuels cellular ATP demands. OXPHOS defects lead to severe human disorders with unexplained tissue specific pathologies. Mitochondrial gene expression is essential for OXPHOS biogenesis since core subunits of the complexes are mitochondrial-encoded. COX14 is required for translation of COX1, the central mitochondrial-encoded subunit of complex IV. Here we describe a COX14 mutant mouse corresponding to a patient with complex IV deficiency. COX14M19I mice display broad tissue-specific pathologies. A hallmark phenotype is severe liver inflammation linked to release of mitochondrial RNA into the cytosol sensed by RIG-1 pathway. We find that mitochondrial RNA release is triggered by increased reactive oxygen species production in the deficiency of complex IV. Additionally, we describe a COA3Y72C mouse, affected in an assembly factor that cooperates with COX14 in early COX1 biogenesis, which displays a similar yet milder inflammatory phenotype. Our study provides insight into a link between defective mitochondrial gene expression and tissue-specific inflammation. Overall design: To compare differences in gene expression between WT and COX14M19I mouse liver RNA samples

线粒体氧化磷酸化（oxidative phosphorylation, OXPHOS）为细胞ATP需求供能。氧化磷酸化缺陷可引发严重人类疾病，但其组织特异性病理机制尚未阐明。由于复合物的核心亚基由线粒体基因组编码，线粒体基因表达对于氧化磷酸化复合体的生物发生至关重要。COX14是复合物IV核心线粒体编码亚基COX1的翻译所必需的因子。本研究报道了一种与复合物IV缺陷患者对应的COX14突变小鼠模型。COX14M19I小鼠呈现广泛的组织特异性病理表型，其标志性特征为严重肝脏炎症，该炎症与线粒体RNA释放至细胞质并被RIG-1通路识别密切相关。研究发现，复合物IV缺陷时活性氧生成增多会触发线粒体RNA释放。此外，本研究还报道了一种COA3Y72C突变小鼠，该小鼠的组装因子存在缺陷，该组装因子可在COX1早期生物发生过程中与COX14协同作用，小鼠表现出相似但程度更轻的炎症表型。本研究揭示了线粒体基因表达缺陷与组织特异性炎症之间的潜在关联。
实验整体设计：比较野生型（wild type, WT）与COX14M19I小鼠的肝脏RNA样本之间的基因表达差异