bims-tricox 2024-08-18 papers

Issue of 2024‒08‒18
four papers selected by
Yash Verma, University of Zurich

J Cell Biol. 2024 Nov 04. pii: e202307036. [Epub ahead of print]223(11):

Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane.

Zachary N Wilson, Sai Sangeetha Balasubramaniam, Sara Wong, Max-Hinderk Schuler, Mitchell J Wopat, Adam L Hughes.

The outer mitochondrial membrane (OMM) creates a boundary that imports most of the mitochondrial proteome while removing extraneous or damaged proteins. How the OMM senses aberrant proteins and remodels to maintain OMM integrity remains unresolved. Previously, we identified a mitochondrial remodeling mechanism called the mitochondrial-derived compartment (MDC) that removes a subset of the mitochondrial proteome. Here, we show that MDCs specifically sequester proteins localized only at the OMM, providing an explanation for how select mitochondrial proteins are incorporated into MDCs. Remarkably, selective sorting into MDCs also occurs within the OMM, as subunits of the translocase of the outer membrane (TOM) complex are excluded from MDCs unless assembly of the TOM complex is impaired. Considering that overloading the OMM with mitochondrial membrane proteins or mistargeted tail-anchored membrane proteins induces MDCs to form and sequester these proteins, we propose that one functional role of MDCs is to create an OMM-enriched trap that segregates and sequesters excess proteins from the mitochondrial surface.

DOI: https://doi.org/10.1083/jcb.202307036

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

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

Front Microbiol. 2024 ;15 1436579

Hibernating ribosomes as drug targets?

Chinenye L Ekemezie, Sergey V Melnikov.

When ribosome-targeting antibiotics attack actively growing bacteria, they occupy ribosomal active centers, causing the ribosomes to stall or make errors that either halt cellular growth or cause bacterial death. However, emerging research indicates that bacterial ribosomes spend a considerable amount of time in an inactive state known as ribosome hibernation, in which they dissociate from their substrates and bind to specialized proteins called ribosome hibernation factors. Since 60% of microbial biomass exists in a dormant state at any given time, these hibernation factors are likely the most common partners of ribosomes in bacterial cells. Furthermore, some hibernation factors occupy ribosomal drug-binding sites - leading to the question of how ribosome hibernation influences antibiotic efficacy, and vice versa. In this review, we summarize the current state of knowledge on physical and functional interactions between hibernation factors and ribosome-targeting antibiotics and explore the possibility of using antibiotics to target not only active but also hibernating ribosomes. Because ribosome hibernation empowers bacteria to withstand harsh conditions such as starvation, stress, and host immunity, this line of research holds promise for medicine, agriculture, and biotechnology: by learning to regulate ribosome hibernation, we could enhance our capacity to manage the survival of microorganisms in dormancy.

Keywords: antimicrobial resistance; dormancy; hibernation; ribosome; ribosome-targeting drugs

DOI: https://doi.org/10.3389/fmicb.2024.1436579