bims-tricox 2026-05-31 papers

Issue of 2026–05–31
four papers selected by
Yash Verma, Universität Zürich

Protein Sci. 2026 Jun;35(6): e70631

Orchestrating mitochondrial protein import: The emerging role of DYRK1A in health and disease.

The translocase of the outer mitochondrial membrane (TOM complex) serves as the central entry gate for more than 1000 nuclear-encoded precursor proteins imported into the organelle. Recently, the human import receptor TOM70 has been identified as a substrate of the serine/threonine kinase DYRK1A. DYRK1A activates the metabolite carrier import pathway, and its impairment triggers a transcriptional adaptive response that induces remodeling of the TOM complex. This compensatory mechanism activates additional import pathways to mitigate reduced DYRK1A signaling. Patients with dysfunctional DYRK1A signaling exhibit clinical manifestations that resemble classical features of mitochondriopathies. The emerging DYRK1A-TOM70 axis therefore represents a central signaling platform coordinating mitochondrial protein import pathways in health and disease.

Keywords: DYRK1A; DYRK1A‐related syndrome; Down syndrome; TOM complex; mitochondrial protein import; organellar signaling

DOI: https://doi.org/10.1002/pro.70631

Protein Sci. 2026 Jun;35(6): e70653

MICOS and MIMAS, multifunctional assemblies linking mitochondrial biogenesis, architecture, and function.

Patrick Horten, Kuo Song, Nikolaus Pfanner, Heike Rampelt.

Mitochondrial cristae architecture is central for optimal oxidative phosphorylation and a healthy mitochondrial physiology. The intricate architecture of the inner mitochondrial membrane relies on protein complexes that compartmentalize the membrane by imposing membrane curvature, forming membrane contact sites or membrane subdomains, regulating the partitioning of mitochondrial proteins between the different subcompartments and thereby enabling functional asymmetry, and by governing membrane dynamics. Studies in recent years have expanded our understanding of the machineries and mechanisms underlying the manifold functions of the inner membrane. This review focuses on the mitochondrial contact site and cristae organizing system (MICOS), a protein complex that stabilizes the narrow entry gates of cristae, and on a novel inner membrane megacomplex, the mitochondrial multifunctional assembly (MIMAS), as well as on their roles in organizing the inner membrane.

Keywords: cristae; membrane organization; metabolism; mitochondria; respiratory chain

DOI: https://doi.org/10.1002/pro.70653

Mol Cell. 2026 May 26. pii: S1097-2765(26)00308-4. [Epub ahead of print]

Uncovering the initial response: Intra-mitochondrial surveillance activates the UPRmt.

Asli Aras Taskin, Sahana Shankar, Carlotta Peselj, Annette Flotho, Maria Gomez-Fabra Gala, Daniel Poveda-Huertes, Lisa Myketin, Duygu Mutlu, Adinayarana Marada, Sebastian Schuck, Mandy Jeske, Sabrina Büttner, Marcin Luzarowski, Chris Meisinger, F-Nora Vögtle.

The mitochondrial unfolded protein response (UPRmt) protects mitochondria from proteotoxic stress. Current models induce acute and severe mitochondrial disruption and propose cytosolic detection following the release of mitochondrial damage signals into the cytosol. However, this mode of toxicity contrasts sharply with physiological stress, such as the gradual accumulation of reactive oxygen species (ROS) during aging or chronic respiratory chain defects. Here, we employ a chemogenetic strategy in yeast to induce low levels of hydrogen peroxide (H2O2) in the mitochondrial matrix and show that mild oxidative stress activates the UPRmt independently of cytosolic damage. We identify the presequence proteases MPP and Oct1 as early ROS targets, thereby linking redox imbalance to UPRmt activation: oxidative stress induces glutathionylation of critical cysteines, impairing protease activity and causing the accumulation of unprocessed precursors in proteotoxic matrix aggregates. These aggregates are detected by intra-mitochondrial surveillance, activating UPRmt signaling. Thus, mitochondrial self-surveillance initiates rapid protective signaling as a primary response to mitochondrial dysfunction.

Keywords: mitochondria-nucleus communication; mitochondrial protein biogenesis; mitochondrial unfolded protein response; oxidative stress; presequence processing; reactive oxygen species

DOI: https://doi.org/10.1016/j.molcel.2026.05.002

Mol Biol Cell. 2026 May 27. mbcE25100479

Yeast Ribosomal Protein Rpl32 Modulates Ribosome Biogenesis, Ribosome Stability and the Cell Cycle.

Stephen M Doris, Elizabeth S Noblin, Raphyel Rosby, Susan A Gerbi.

How does the cell coordinate its two major activities of cell growth and cell division? To explore this, we have genetically depleted yeast ribosomal protein Rpl32 of the 60S ribosomal subunit, which is an essential protein for cell proliferation. 3-4 hours after Rpl32 depletion, the cell cycle arrests at G1. We have undertaken a kinetic analysis of the early cellular events to deduce the pathway from Rpl32 depletion to G1 arrest. Rpl32 depletion blocks pre-rRNA processing of the initial 35S pre-rRNA, thus preventing ribosomal biogenesis and nuclear export of 60S ribosomal subunits. Interestingly, the L25-GFP reporter transiently accumulates in a focal spot that resembles the nucleolar body/Cajal body. Amazingly, the inhibition of ribosome biogenesis in the nucleus is signalled to the cytoplasm where mature 18S and 25S rRNAs are degraded in a ribophagy-independent manner; Rpl32 protease-degradation uses de-ubiquitination. Nonetheless, the ribosomes that remain after degradation are sufficient for translation whose efficiency is unchanged through 6 hours after Rpl32 depletion, and the cell size and vacuole increase in size. The level of cyclin 1 mRNA is rapidly diminished after Rpl32 depletion and is a likely factor for the arrest of the cell cycle at G1.

DOI: https://doi.org/10.1091/mbc.E25-10-0479