bims-tricox 2023-04-16 papers

Nat Struct Mol Biol. 2023 Apr 10.

A co-transcriptional ribosome assembly checkpoint controls nascent large ribosomal subunit maturation.

Zahra A Sanghai, Rafal Piwowarczyk, Arnaud Vanden Broeck, Sebastian Klinge.

During transcription of eukaryotic ribosomal DNA in the nucleolus, assembly checkpoints exist that guarantee the formation of stable precursors of small and large ribosomal subunits. While the formation of an early large subunit assembly checkpoint precedes the separation of small and large subunit maturation, its mechanism of action and function remain unknown. Here, we report the cryo-electron microscopy structure of the yeast co-transcriptional large ribosomal subunit assembly intermediate that serves as a checkpoint. The structure provides the mechanistic basis for how quality-control pathways are established through co-transcriptional ribosome assembly factors, that structurally interrogate, remodel and, together with ribosomal proteins, cooperatively stabilize correctly folded pre-ribosomal RNA. Our findings thus provide a molecular explanation for quality control during eukaryotic ribosome assembly in the nucleolus.

DOI: https://doi.org/10.1038/s41594-023-00947-3

Int J Mol Sci. 2023 Mar 28. pii: 6334. [Epub ahead of print]24(7):

Specialized Ribosomes in Health and Disease.

Sarah C Miller, Clinton C MacDonald, Morgana K Kellogg, Zemfira N Karamysheva, Andrey L Karamyshev.

Ribosomal heterogeneity exists within cells and between different cell types, at specific developmental stages, and occurs in response to environmental stimuli. Mounting evidence supports the existence of specialized ribosomes, or specific changes to the ribosome that regulate the translation of a specific group of transcripts. These alterations have been shown to affect the affinity of ribosomes for certain mRNAs or change the cotranslational folding of nascent polypeptides at the exit tunnel. The identification of specialized ribosomes requires evidence of the incorporation of different ribosomal proteins or of modifications to rRNA and/or protein that lead(s) to physiologically relevant changes in translation. In this review, we summarize ribosomal heterogeneity and specialization in mammals and discuss their relevance to several human diseases.

Keywords: human disease; protein synthesis; ribosomal RNA; ribosomal protein; ribosome heterogeneity; ribosome specialization; translation; translational control

DOI: https://doi.org/10.3390/ijms24076334

bioRxiv. 2023 Mar 31. pii: 2023.03.31.535139. [Epub ahead of print]

An intermembrane space protein facilitates completion of mitochondrial division in yeast.

Olivia M Connor, Srujan K Matta, Jonathan R Friedman.

Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by the dynamin-related protein Dnm1 (Drp1 in humans), a large GTPase that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity alone is sufficient to complete fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1. Loss of Mdi1 leads to hyper-fused mitochondria networks due to defects in mitochondrial fission, but not lack of Dnm1 recruitment to mitochondria. Mdi1 plays a conserved role in fungal species and its homologs contain a putative amphipathic α-helix, mutations in which disrupt mitochondrial morphology. One model to explain these findings is that Mdi1 associates with and distorts the mitochondrial inner membrane to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of a protein that resides inside mitochondria.

DOI: https://doi.org/10.1101/2023.03.31.535139

iScience. 2023 Apr 21. 26(4): 106386

Tom40 in cholesterol transport.

Himangshu S Bose, Mahuya Bose, Randy M Whittal.

Cholesterol initiates steroid metabolism in adrenal and gonadal mitochondria, which is essential for all mammalian survival. During stress an increased cholesterol transport rapidly increases steroidogenesis; however, the mechanism of mitochondrial cholesterol transport is unknown. Using rat testicular tissue and mouse Leydig (MA-10) cells, we report for the first time that mitochondrial translocase of outer mitochondrial membrane (OMM), Tom40, is central in cholesterol transport. Cytoplasmic cholesterol-lipids complex containing StAR protein move from the mitochondria-associated ER membrane (MAM) to the OMM, increasing cholesterol load. Tom40 interacts with StAR at the OMM increasing cholesterol transport into mitochondria. An absence of Tom40 disassembles complex formation and inhibits mitochondrial cholesterol transport and steroidogenesis. Therefore, Tom40 is essential for rapid mitochondrial cholesterol transport to initiate, maintain, and regulate activity.

Keywords: Biomolecules; Cell biology; Protein folding

DOI: https://doi.org/10.1016/j.isci.2023.106386

bioRxiv. 2023 Mar 29. pii: 2023.03.29.534670. [Epub ahead of print]

Metabolic regulation of misfolded protein import into mitochondria.

Yuhao Wang, Linhao Ruan, Jin Zhu, Xi Zhang, Alexander Chih-Chieh Chang, Alexis Tomaszewski, Rong Li.

Mitochondria are the cellular energy hub and central target of metabolic regulation. Mitochondria also facilitate proteostasis through pathways such as the 'mitochondria as guardian in cytosol' (MAGIC) whereby cytosolic misfolded proteins are imported into and degraded inside mitochondria. In this study, a genome-wide screen in yeast uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of misfolded proteins into mitochondria while promoting mitochondrial biogenesis under glucose starvation. We show that this inhibition requires a downstream transcription factor regulating mitochondrial gene expression and is likely to be conferred through substrate competition and mitochondrial import channel selectivity. We further show that Snf1/AMPK activation protects mitochondrial fitness in yeast and human cells under stress induced by misfolded proteins such as those associated with neurodegenerative diseases.

DOI: https://doi.org/10.1101/2023.03.29.534670