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.

Bioanalytical Mass Spectrometry Group Max Planck Institute for Multidisciplinary Sciences Göttingen Germany

Clinic of Neurology University Medical Center Göttingen 37075 Göttingen Germany

Cluster of Excellence Cellular Stress Responses in Aging associated Diseases Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Cluster of Excellence Multiscale Bioimaging from Molecular Machines to Networks of Excitable Cells University of Göttingen Göttingen Germany

Czech Centre for Phenogenomics Institute of Molecular Genetics of the CAS v v i 252 50 Vestec Czech Republic

Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases German Center for Neurodegenerative Diseases Göttingen Germany

Department of Cellular Biochemistry University Medical Center Göttingen 37073 Göttingen Germany

Department of Molecular Biochemistry University Medical Center Göttingen 37073 Göttingen Germany

Department of NanoBiophotonics Max Planck Institute for Multidisciplinary Sciences 37077 Göttingen Germany

Department of Psychiatry and Psychotherapy University Medical Center Göttingen Göttingen Germany

Fraunhofer Institute for Translational Medicine and Pharmacology ITMP Translational Neuroinflammation and Automated Microscopy Goettingen Germany

German Center for Cardiovascular Research partner site Göttingen Göttingen Germany

Heidelberg University Biochemistry Center 69120 Heidelberg Germany

Institute for Clinical Chemistry University Medical Center Göttingen Göttingen Germany

Institute of Pathology University Medical Center Göttingen Göttingen Germany

Laboratory for Electron Microscopy Max Planck Institute for Multidisciplinary Sciences Göttingen 37077 Germany

Max Planck Institute for Biology of Ageing 50931 Köln Germany

Max Planck Institute for Multidisciplinary Science Department of Neurogenetics 37077 Göttingen Germany

Max Planck Institute for Multidisciplinary Sciences D 37077 Goettingen Germany

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