bims-tricox 2026-05-03 papers

Issue of 2026–05–03
three papers selected by
Yash Verma, Universität Zürich

Protein Sci. 2026 May;35(5): e70585

Quality control of protein import into mammalian mitochondria.

Madeleine Goldstein, Laurie Lee-Glover, Hilla Weidberg.

Mitochondrial function depends on the continuous import of hundreds of nuclear-encoded proteins. Targeting and translocation of mitochondrial proteins is a multistep process that is inherently vulnerable to defects in cytosolic quality control systems as well as perturbations in mitochondrial protein import machinery and organelle function. Failure of mitochondrial protein import has dual consequences: it compromises mitochondrial biogenesis and activity, and it poses a cytosolic proteotoxic threat due to the accumulation of unimported precursor proteins. Accordingly, mitochondrial protein import defects are detrimental to cellular homeostasis and are associated with a wide range of disorders, including metabolic and neurodegenerative diseases. Cells therefore rely on layered quality control systems that monitor mitochondrial protein biogenesis and mitigate stress arising from mislocalized mitochondrial proteins. In this review, we summarize recent progress in understanding pathways that modulate mitochondrial protein import and the fate of unimported proteins in mammals. We highlight cytosolic and mitochondrial protein quality control mechanisms and discuss how import defects are translated into cellular stress responses and mitochondrial protective programs to restore cellular and mitochondrial homeostasis.

Keywords: Proteostasis; mitochondrial dysfunction; mitochondrial protein import; quality control mechanisms; stress responses

DOI: https://doi.org/10.1002/pro.70585

Sci Adv. 2026 May;12(18): eaeb2995

A dynamic gateway: Uncovering the expanded human TOM complex interactome and its regulatory complexity.

Mayra A Borrero-Landazabal, Vanessa Linke, Tereza Kadavá, Zeshi Li, Piotr Draczkowski, Kacper Kaszuba, Lea Bertgen, Remigiusz A Serwa, Albert J R Heck, Agnieszka Chacinska.

The translocase of the outer mitochondrial membrane (TOM) is the conserved entry gate for nuclear-encoded proteins. While structurally similar from yeast to humans, the human TOM complex operates in a cellular environment of vastly greater complexity. Here, we present a high-confidence map of the human TOM interactome using a membrane-permeable cross-linker to capture both stable and transient interactors. Alongside extensive overlap with known yeast partners, we uncover a set of human-specific interactors including regulatory factors and TOM-associated proteins. Mapping unique interprotein cross-links reveals conformational flexibility of the receptor TOM20 and enhanced recovery of peripheral components such as TOM70 and several associated quality control factors. Notably, we identify FKBP8 (FK506 binding protein 8) as a human-specific interactor that binds multiple TOM subunits and promotes organization of the complex. Our work redefines the human TOM complex as a dynamic, multifaceted hub coordinating biogenesis, quality control, and signaling. This expanded TOM landscape offers a rich resource for exploring mitochondrial regulation in health and disease.

DOI: https://doi.org/10.1126/sciadv.aeb2995

Mol Biol Cell. 2026 Apr 29. mbcE25100504

Stage- and stress-specific phosphorylation of ribosomal protein Rps5 (uS7) by Smk1 and Kns1 kinases in Saccharomyces cerevisiae.

Gwendolyn Resch, Thomas Swayne, Erica Johnson, Abhimannyu Rimal, Dimitri G Pestov, Natalia Shcherbik, Edward Winter.

In the yeast Saccharomyces cerevisiae, nutrient deprivation triggers cell-type-specific responses: haploid cells exit the mitotic cycle and enter stationary phase, while diploid cells undergo meiosis and form spores. The meiosis-specific mitogen-activated protein kinase (MAPK) Smk1 regulates spore formation. The ubiquitously expressed Cdc2-like kinase (CLK) Kns1 downregulates ribosomal RNA and tRNA synthesis in mitotically dividing cells under nutrient-deprived conditions. Here, we show that Smk1 phosphorylates ribosomal protein Rps5 (uS7) on threonine residues 21 and 27 during the early stages of spore formation. As spore formation progresses, Kns1 is required to further increase the phosphorylation of these residues. Kns1-dependent phosphorylation of Rps5 is also observed in nutrient-deprived or rapamycin-treated haploid cells. Upon exposure to nutrient-rich media and spore germination, ribosomal subunits containing unphosphorylated Rps5 are incorporated into translationally active polysomes, while phosphorylated Rps5 is retained in inactive 80S ribosomes. Taken together, our data support a model in which Smk1 and Kns1 cooperate across the yeast life cycle to promote Rps5 phosphorylation and thereby bias a subset of ribosomes toward translational quiescence.

DOI: https://doi.org/10.1091/mbc.E25-10-0504