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

Abhishek Aich, Angela Boshnakovska, Steffen Witte, Tanja Gall, Kerstin Unthan-Fechner, Roya Yousefi, Arpita Chowdhury, Drishan Dahal, Aditi Methi, Svenja Kaufmann, Ivan Silbern, Jan Prochazka, Zuzana Nichtova, Marcela Palkova, Miles Raishbrook, Gizela Koubkova, Radislav Sedlacek, Simon E. Tröder, Branko Zevnik, Dietmar Riedel, Susann Michanski, Wiebke Möbius, Philipp Ströbel, Christian Lüchtenborg, Patrick Giavalisco, Henning Urlaub, Andre Fischer, Britta Brügger, Stefan Jakobs and Peter Rehling ()
Additional contact information
Abhishek Aich: University Medical Center Göttingen
Angela Boshnakovska: University Medical Center Göttingen
Steffen Witte: University Medical Center Göttingen
Tanja Gall: University Medical Center Göttingen
Kerstin Unthan-Fechner: University Medical Center Göttingen
Roya Yousefi: University Medical Center Göttingen
Arpita Chowdhury: University Medical Center Göttingen
Drishan Dahal: University Medical Center Göttingen
Aditi Methi: University Medical Center Göttingen
Svenja Kaufmann: Max Planck Institute for Multidisciplinary Sciences
Ivan Silbern: Max Planck Institute for Multidisciplinary Sciences
Jan Prochazka: 252 50
Zuzana Nichtova: 252 50
Marcela Palkova: 252 50
Miles Raishbrook: 252 50
Gizela Koubkova: 252 50
Radislav Sedlacek: 252 50
Simon E. Tröder: University of Cologne
Branko Zevnik: University of Cologne
Dietmar Riedel: Max Planck Institute for Multidisciplinary Sciences
Susann Michanski: University of Göttingen
Wiebke Möbius: Department of Neurogenetics
Philipp Ströbel: University Medical Center Göttingen
Christian Lüchtenborg: Heidelberg University Biochemistry Center (BZH)
Patrick Giavalisco: Max Planck Institute for Biology of Ageing
Henning Urlaub: University of Göttingen
Andre Fischer: University of Göttingen
Britta Brügger: Heidelberg University Biochemistry Center (BZH)
Stefan Jakobs: University of Göttingen
Peter Rehling: University Medical Center Göttingen

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-51109-y

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