bims-tricox 2024-06-23 papers

Issue of 2024–06–23
four papers selected by
Yash Verma, University of Zurich

Nat Commun. 2024 Jun 20. 15(1): 5265

DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring.

Adinarayana Marada, Corvin Walter, Tamara Suhm, Sahana Shankar, Arpita Nandy, Tilman Brummer, Ines Dhaouadi, F-Nora Vögtle, Chris Meisinger.

Mitochondria require an extensive proteome to maintain a variety of metabolic reactions, and changes in cellular demand depend on rapid adaptation of the mitochondrial protein composition. The TOM complex, the organellar entry gate for mitochondrial precursors in the outer membrane, is a target for cytosolic kinases to modulate protein influx. DYRK1A phosphorylation of the carrier import receptor TOM70 at Ser91 enables its efficient docking and thus transfer of precursor proteins to the TOM complex. Here, we probe TOM70 phosphorylation in molecular detail and find that TOM70 is not a CK2 target nor import receptor for MIC19 as previously suggested. Instead, we identify TOM20 as a MIC19 import receptor and show off-target inhibition of the DYRK1A-TOM70 axis with the clinically used CK2 inhibitor CX4945 which activates TOM20-dependent import pathways. Taken together, modulation of DYRK1A signalling adapts the central mitochondrial protein entry gate via synchronization of TOM70- and TOM20-dependent import pathways for metabolic rewiring. Thus, DYRK1A emerges as a cytosolic surveillance kinase to regulate and fine-tune mitochondrial protein biogenesis.

DOI: https://doi.org/10.1038/s41467-024-49611-4

FEBS Open Bio. 2024 Jun 12.

Oxidative protein folding in the intermembrane space of human mitochondria.

Christine Zarges, Jan Riemer.

The mitochondrial intermembrane space hosts a machinery for oxidative protein folding, the mitochondrial disulfide relay. This machinery imports a large number of soluble proteins into the compartment, where they are retained through oxidative folding. Additionally, the disulfide relay enhances the stability of many proteins by forming disulfide bonds. In this review, we describe the mitochondrial disulfide relay in human cells, its components, and their coordinated collaboration in mechanistic detail. We also discuss the human pathologies associated with defects in this machinery and its protein substrates, providing a comprehensive overview of its biological importance and implications for health.

Keywords: ALR; IMS; MIA40; mitochondria; oxidative protein folding; protein import

DOI: https://doi.org/10.1002/2211-5463.13839

Elife. 2024 Jun 20. pii: RP87518. [Epub ahead of print]12

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 (MPs) are imported into and degraded inside mitochondria. In this study, a genome-wide screen in Saccharomyces cerevisiae uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of MPs 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 MPs such as those associated with neurodegenerative diseases.

Keywords: AMPK; MAGIC; S. cerevisiae; cell biology; human; metabolism; misfolded protein; mitochondria; protein import; proteostasis

DOI: https://doi.org/10.7554/eLife.87518

STAR Protoc. 2024 Jun 14. pii: S2666-1667(24)00302-2. [Epub ahead of print]5(3): 103137

Protocol for comparing ribosomal levels in single bacterial cells at different growth stages using rRNA-FISH.

Camilla Ciolli Mattioli, Roi Avraham.

Ribosome quantification in single cells is typically achieved through fluorescence tagging of ribosomal proteins. Here, we present a protocol for comparing ribosomal levels in bacteria at different growth stages using fluorescence in situ hybridization of rRNA (rRNA-FISH), eliminating the need for genetic engineering of the strain of interest. We detail the steps for preparing bacterial samples, staining with fluorescent probes, and acquiring data using flow cytometry and microscopy. Furthermore, we provide guidelines on controlling for proper labeling through signal localization analysis. For complete details on the use and execution of this protocol, please refer to Ciolli Mattioli et al.1.

Keywords: cell biology; flow cytometry; in situ hybridization; microbiology; single cell

DOI: https://doi.org/10.1016/j.xpro.2024.103137