bims-mitpro Biomed News
on Mitochondrial proteostasis
Issue of 2025–06–22
four papers selected by
Andreas Kohler, Umeå University



  1. EMBO J. 2025 Jun 16.
      The accumulation of mitochondrial precursor proteins in the cytosol due to mitochondrial dysfunction compromises cellular proteostasis and is a hallmark of diseases. Why non-imported precursors are toxic and how eukaryotic cells prevent their accumulation in the cytosol is still poorly understood. Using a proximity labeling-based assay to globally monitor the intramitochondrial location of proteins, we show that, upon mitochondrial dysfunction, many mitochondrial matrix proteins are sequestered in the intermembrane space (IMS); something we refer to as "mitochondrial triage of precursor proteins" (MitoTraP). MitoTraP is not simply the result of a general translocation block at the level of the inner membrane, but specifically directs a subgroup of matrix proteins into the IMS, many of which are constituents of the mitochondrial ribosome. Using the mitoribosomal protein Mrp17 (bS6m) as a model, we found that IMS sequestration prevents its mistargeting to the nucleus, potentially averting interference with assembly of cytosolic ribosomes. Thus, MitoTraP represents a novel, so far unknown mechanism of the eukaryotic quality control system that protects the cellular proteome against the toxic effects of non-imported mitochondrial precursor proteins.
    Keywords:  Intermembrane Space; Mitochondria; Nucleolus; Protein Targeting; Ribosome
    DOI:  https://doi.org/10.1038/s44318-025-00486-1
  2. Nat Commun. 2025 Jun 17. 16(1): 5328
      Aneuploidy, or aberrant chromosomal content, disrupts cellular proteostasis through altered expression of numerous proteins. Aneuploid cells accumulate SQSTM1/p62-positive cytosolic bodies, exhibit impaired protein folding, and show altered proteasomal and lysosomal activity. Here, we employ p62 proximity- and affinity-based proteomics to elucidate p62 interactors in aneuploid cells and observe an enrichment of mitochondrial proteins. Increased protein aggregation and colocalization of p62 with both novel interactors and mitochondrial proteins is further confirmed by microscopy. Compared to parental diploids, aneuploid cells suffer from mitochondrial defects, including perinuclearly-clustered mitochondrial networks, elevated reactive oxygen species levels, reduced mitochondrial DNA abundance, and impaired protein import, leading to cytosolic accumulation of mitochondrial precursor proteins. Overexpression of heat shock proteins in aneuploid cells mitigates protein aggregation and decreases the colocalization of p62 with the mitochondrial protein TOMM20. Thus, proteotoxic stress caused by chromosome gains results in the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies, thereby compromising mitochondrial function.
    DOI:  https://doi.org/10.1038/s41467-025-60857-4
  3. Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00471-X. [Epub ahead of print]85(12): 2261-2263
      In this issue of Molecular Cell, Ham et al.1 demonstrate that the metabolite fumarate, when accumulated in cells, can influence mitochondrial quality control by inhibiting Parkin translocation to mitochondria and blocking its E3 ligase activity via the fumarate-dependent post-translational modification called succination.
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.032
  4. Nat Cell Biol. 2025 Jun;27(6): 890-901
      Mitochondria are critical double-membraned organelles that act as biosynthetic and bioenergetic cellular factories, with the outer membrane providing an interface with the rest of the cell. Mitochondrial outer membrane proteins regulate a variety of processes, including metabolism, innate immunity and apoptosis. Although the biophysical and functional diversity of these proteins is highly documented, the mechanisms of their biogenesis and the integration of that into cellular homeostasis are just starting to take shape. Here, focusing on α-helical outer membrane proteins, we review recent insights into the mechanisms of synthesis and cytosolic chaperoning, insertion and assembly in the lipid bilayer, and quality control of unassembled or mislocalized transmembrane domains. We further discuss the role convergent evolution played in this process, comparing key biogenesis players from lower eukaryotes, including yeast and trypanosomes, with multicellular metazoan systems, and draw comparisons with the endoplasmic reticulum biogenesis system, in which membrane proteins face similar challenges.
    DOI:  https://doi.org/10.1038/s41556-025-01683-0