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. COX14<sup>M19I</sup> 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 COA3<sup>Y72C</sup> 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.
Authors
- Angela Boshnakovska (ORCID: https://orcid.org/0009-0008-3572-0223)
- Stefan Jakobs (ORCID: https://orcid.org/0000-0002-8028-3121)
- Patrick Giavalisco (ORCID: https://orcid.org/0000-0002-4636-1827)
- Susann Michanski (ORCID: https://orcid.org/0000-0001-5893-1981)
- Aditi Methi (ORCID: https://orcid.org/0009-0000-7585-4615)
- Philipp Ströbel (ORCID: https://orcid.org/0000-0002-8528-8060)
- Jan Procházka (ORCID: https://orcid.org/0000-0003-4675-8995)
- Miles Joseph Raishbrook
- Simon E. Tröder (ORCID: https://orcid.org/0000-0003-1156-2976)
- Peter Rehling (ORCID: https://orcid.org/0000-0001-5661-5272)
- Arpita Chowdhury (ORCID: https://orcid.org/0000-0001-5025-0268)
- André Fischer (ORCID: https://orcid.org/0000-0001-8546-1161)
- Britta Brügger (ORCID: https://orcid.org/0000-0002-3477-8270)
- Gizela Koubkova (ORCID: https://orcid.org/0000-0001-6497-6094)
- Zuzana Nichtová (ORCID: https://orcid.org/0000-0001-7358-3268)
- Abhishek Aich (ORCID: https://orcid.org/0000-0001-8331-9874)
- Radislav Sedláček (ORCID: https://orcid.org/0000-0002-3352-392X)
- Marcela Pálková
- Branko Zevnik (ORCID: https://orcid.org/0000-0001-7845-9522)
- Christian Lüchtenborg (ORCID: https://orcid.org/0000-0002-6770-6046)
- Dietmar Riedel (ORCID: https://orcid.org/0000-0003-2970-6894)
- Roya Yousefi
- Ivan Silbern (ORCID: https://orcid.org/0000-0001-8284-954X)
- Henning Urlaub (ORCID: https://orcid.org/0000-0003-1837-5233)
- Drishan Dahal (ORCID: https://orcid.org/0009-0009-7280-2102)
- Steffen Witte
- Wiebke Möbius (ORCID: https://orcid.org/0000-0002-2902-7165)
- Tanja Gall
- K Unthan-Fechner
- Svenja V. Kaufmann
Institutions
- University of Cologne (DE)
- Heidelberg University (DE)
- German Center for Neurodegenerative Diseases (DE)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- Universitätsmedizin Göttingen (DE)
- German Centre for Cardiovascular Research (DE)
- Nanoscale Microscopy and Molecular Physiology of the Brain Cluster of Excellence 171 — DFG Research Center 103 (DE)
- Max Planck Institute for Biophysical Chemistry (DE)
- Czech Academy of Sciences, Institute of Molecular Genetics (CZ)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- University Hospital Cologne (DE)
- Max Planck Institute for Biology of Ageing (DE)
- Max Planck Institute for Multidisciplinary Sciences (DE)
- University of Göttingen (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-12
- DOI
- https://doi.org/10.1038/s41467-024-51109-y
- Citations
- 17
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.97
Funders
- Deutsche Forschungsgemeinschaft
- Ministerstvo Školství, Mládeže a Tělovýchovy
- Max-Planck-Gesellschaft
- Akademie Věd České Republiky