Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in 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 generated 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 generated a COA3Y72C mouse, affected in an assembly factor in early COX1 biogenesis, which displayed a similar yet milder inflammatory phenotype. Our study provides mechanistic insight into how defective mitochondrial gene expression causes tissue-specific inflammation.