bims-cytox1 2024-08-18 papers

Issue of 2024‒08‒18
three papers selected by
Gavin McStay, Liverpool John Moores University

Nat Commun. 2024 Aug 12. 15(1): 6914

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.

DOI: https://doi.org/10.1038/s41467-024-51109-y

J Cancer. 2024 ;15(15): 5072-5084

COA6 promotes the oncogenesis and progression of breast cancer by oxidative phosphorylation pathway.

Xiaoxia Jin, Xinyan Chen, Haiyan Yu, Yushan Liu, Xiaoyun Lu, Haibing Yin, Wencheng Dai.

Mitochondrial oxidative phosphorylation (OXPHOS) has long been considered the primary energy source in breast cancer cells. Cytochrome c oxidase assembly factor 6 (COA6), which functions as a metal chaperone to transport copper to complex Ⅳ during the OXPHOS process, plays a crucial role in the carcinogenesis of lung adenocarcinoma. Nevertheless, its specific function in breast cancer is undefined. The present investigation aimed to clarify COA6's expression profile and regulatory functions in breast cancer, as well as to unveil its underlying mechanisms. Initially, our findings revealed a significant upregulation of COA6 in breast cancer, as evidenced by an analysis of the TCGA database and tissue microarrays. This upregulation correlated with tumor size and histological grade. Additionally, survival analysis revealed that elevated COA6 amounts were correlated with decreased overall survival (OS) in breast cancer. To delve deeper into the functions of COA6, both COA6-overexpressing and COA6-knockdown breast cancer cell models were established. These experiments demonstrated COA6 is pivotal in regulating cell proliferation, apoptosis, migration, and invasion, thereby promoting cancer progression in vitro. Notably, functional enrichment analysis indicated COA6 might be involved in breast cancer progression by modulating oxidative phosphorylation (OXPHOS). Collectively, this study reveals an overt tumorigenic role for COA6 in breast cancer and sheds light on its potential mechanisms, offering valuable therapeutic targets for breast cancer therapy.

Keywords: Breast cancer; COA6; OXPHOS; The Cancer Genome Atlas (TCGA)

DOI: https://doi.org/10.7150/jca.98570

Nat Struct Mol Biol. 2024 Aug 12.

Structural basis of LRPPRC-SLIRP-dependent translation by the mitoribosome.

Vivek Singh, J Conor Moran, Yuzuru Itoh, Iliana C Soto, Flavia Fontanesi, Mary Couvillion, Martijn A Huynen, L Stirling Churchman, Antoni Barrientos, Alexey Amunts.

In mammalian mitochondria, mRNAs are cotranscriptionally stabilized by the protein factor LRPPRC (leucine-rich pentatricopeptide repeat-containing protein). Here, we characterize LRPPRC as an mRNA delivery factor and report its cryo-electron microscopy structure in complex with SLIRP (SRA stem-loop-interacting RNA-binding protein), mRNA and the mitoribosome. The structure shows that LRPPRC associates with the mitoribosomal proteins mS39 and the N terminus of mS31 through recognition of the LRPPRC helical repeats. Together, the proteins form a corridor for handoff of the mRNA. The mRNA is directly bound to SLIRP, which also has a stabilizing function for LRPPRC. To delineate the effect of LRPPRC on individual mitochondrial transcripts, we used RNA sequencing, metabolic labeling and mitoribosome profiling, which showed a transcript-specific influence on mRNA translation efficiency, with cyclooxygenase 1 and 2 translation being the most affected. Our data suggest that LRPPRC-SLIRP acts in recruitment of mitochondrial mRNAs to modulate their translation. Collectively, the data define LRPPRC-SLIRP as a regulator of the mitochondrial gene expression system.

DOI: https://doi.org/10.1038/s41594-024-01365-9