bims-mitpro 2026-05-24 papers

Issue of 2026–05–24
three papers selected by
Andreas Kohler, Umeå University

Protein Sci. 2026 Jun;35(6): e70622

The role of the nucleus in the control of mitochondrial precursor proteins in yeast.

Kira Ritzenhofen, Stefano Rossi, Axel Mogk, Fabian den Brave.

Mitochondria are essential organelles of eukaryotic cells, with vital roles in energy production, biosynthesis of macromolecules, and intracellular signaling. Their function depends on a complex proteome with proteins targeted to different mitochondrial sub-compartments. Synthesis of precursors of mitochondrial proteins (mitoPREs) mostly occurs in the cytosol followed by post-translational import. Delay or block of mitochondrial import leads to mitoPRE accumulation in the cytosol, where they interact with cytosolic protein quality control (PQC) factors and might get re-routed to other cellular organelles, including the nucleus. Recent research implies the nucleus as a central hub in cellular PQC. Here, not only nuclear but also proteins from other organelles, including mitochondria or the cytosol, are handled by intra-nuclear PQC factors. In addition, the nucleus controls the expression of mitochondrial proteins and PQC components involved in handling mitoPREs and surveilling the integrity of mitochondrial import channels. In this review, we discuss recent insights from yeast on the dual function of the nucleus in controlling the biogenesis of mitoPREs and as a compartment for quality control of non-imported mitoPREs. We additionally describe how mitochondrial dysfunction and defects in mitochondrial import trigger compensatory stress responses inside the nucleus. Here, nuclear targeting of non-imported mitoPREs may serve as a direct signal to adjust stress response pathways to the status of mitochondrial import.

Keywords: chaperones; mitochondria; nucleus; protein quality control; protein sorting; stress response; ubiquitin‐proteasome system

DOI: https://doi.org/10.1002/pro.70622

Protein Sci. 2026 Jun;35(6): e70630

Dynamic disorder is crucial for mitochondrial protein import.

Jakob Schneider, Undina Guillerm, Caroline Simões Pereira, Paul Schanda.

The import of proteins into mitochondria poses fundamental mechanistic challenges: aggregation-prone precursor proteins must be maintained in aqueous compartments and threaded through narrow pores without becoming stuck or mislocalized. Recent evidence from mitochondrial protein import studies and other chaperone systems underscores the critical role of dynamics in balancing sufficiently tight binding, promiscuity, specificity, and release. Dynamic binding of client precursor proteins to import machinery components arises naturally from the avidity of their interactions. Conformational entropy enhances their stability, while the multivalent nature of these interactions ensures that client transfer to downstream insertases occurs without a substantial energy barrier. Here, we discuss this emerging paradigm of dynamic protein handling, using examples where dynamic structures have been resolved and highlight outstanding questions.

Keywords: avidity; chaperones; import machinery; intrinsic disorder; mitochondria

DOI: https://doi.org/10.1002/pro.70630

Proc Natl Acad Sci U S A. 2026 May 26. 123(21): e2536912123

A mechanism for substrate quality control in outer membrane protein assembly.

Ashton N Combs, Anna Konovalova, Thomas J Silhavy.

The assembly of β-barrel proteins into the outer membrane (OM) of Gram-negative bacteria is catalyzed by the β-barrel assembly machine (Bam) complex, which consists of two essential proteins, the BamA β-barrel and the lipoprotein BamD, and three nonessential lipoproteins BamBCE. While it is well established that BamD serves an essential role in regulating the activity of BamA, the physiological reasons underpinning the need for BamD-mediated regulation of β-barrel assembly are unclear. Here, we demonstrate that BamD-mediated regulation of BamA functions as a mechanism of substrate quality control that ensures the efficient assembly of β-barrel proteins into the OM. Through the use of substrate C-terminal fragments and multiple alleles of bamA and bamD that prevent effective regulation of BamA by BamD, we show that BamD activity is necessary to prevent the accumulation of defective β-barrel substrates on BamA. Notably, these bamAD alleles all confer resistance to the Bam complex inhibitor MRL-494 in a manner that correlates with the degree to which BamD activity is bypassed, suggesting that MRL-494 inhibits β-barrel assembly by disrupting BamD-mediated conformational changes in BamA. We further show that BamD activity functions to prevent the uptake of toxic small molecules across the OM through a mechanism that functionally overlaps with that of the substrate quality control protein Skp. Collectively, these results not only establish that BamD, like Skp, functions to ensure proper quality control of β-barrel substrates but also demonstrate the importance of substrate quality control functions in maintaining the integrity of the OM permeability barrier.

Keywords: Bam complex; gram-negative bacteria; outer membrane proteins; protein folding; protein quality control

DOI: https://doi.org/10.1073/pnas.2536912123