bims-mitpro 2026-06-28 papers

Issue of 2026–06–28
four papers selected by
Andreas Kohler, Umeå University

Adv Exp Med Biol. 2026 ;1514 85-111

The TOM Complex in the Outer Membrane of Mitochondria: A Supramolecular Assembly for Protein Import.

Stephan Nussberger, Robin Ghosh, Shuo Wang.

Currently, there is no comprehensive physical model explaining how unfolded polypeptide chains with diverse characteristics are transported into the mitochondria. On a molecular scale, the kinetics of how transit polypeptides approach, are captured by the protein translocation machinery at the outer mitochondrial membrane, and cross the protein translocation pore to enter the intermembrane space remain unclear. This knowledge gap is primarily due to the lack of dynamic single-molecule data on the "protein-conducting channels" involved in mitochondrial protein translocation. In this chapter, we explore the recently resolved sub-nanometer cryo-EM structures, which are a prerequisite for a fundamental understanding of the translocation mechanism, and our existing knowledge of the mitochondrial two-pore outer membrane protein translocation machinery (TOM complex). Particularly intriguing are recent findings from single-molecule TIRF microscopy indicating that the TOM core complex can function as a mechanosensor, with the pores closing upon interaction with nearby membrane structures. We emphasize novel and unexpected correlations between the structural components of the TOM complexes and their dynamic behavior within the membrane environment.

Keywords: Droplet interface bilayer membranes; Electron cryo-microscopy; Mechanosensitivity; Mitochondria; Native mass spectrometry; Protein import; Single-molecule fluorescence microscopy; TOM complex

DOI: https://doi.org/10.1007/978-3-032-26629-3_5

bioRxiv. 2026 Jun 10. pii: 2026.06.09.731211. [Epub ahead of print]

Mitochondrial-derived compartments buffer outer membrane protein load during acute mitochondrial adaptation.

Bo J Price, Sai Sangeetha Balasubramaniam, Adam L Hughes.

Cells undergoing metabolic transitions rapidly remodel mitochondria through coordinated expansion and reorganization of the mitochondrial proteome. How the outer mitochondrial membrane (OMM) accommodates acute increases in newly synthesized proteins before organelle adaptation is complete remains poorly understood. Here we show that mitochondrial-derived compartments (MDCs), multilamellar domains that form from the OMM and selectively sequester OMM-associated cargo, arise during metabolic perturbations associated with acute mitochondrial biogenesis, including glucose restriction, carbon-source switching, and salt stress. In these situations, MDC formation requires the energy-sensing kinase Snf1 and derepression of the transcriptional repressor Mig1, linking MDC induction to transcriptional programs that increase mitochondrial protein expression. Activation of mitochondrial biogenesis in the absence of metabolic changes is sufficient to trigger MDCs, whereas disruption of mitochondrial protein targeting and import prevents MDC formation and causes mislocalization of outer membrane cargos. Together, these findings, combined with previous observations that MDCs are induced by hydrophobic protein overexpression, mistargeting, and metabolic perturbations, support an emerging model in which MDCs function as adaptive outer-membrane remodeling domains that buffer outer membrane protein load during mitochondrial adaptation.

DOI: https://doi.org/10.64898/2026.06.09.731211

Sci Adv. 2026 Jun 26. 12(26): eaec8143

FUBL-3/FUBP1 mediates mitochondrial stress-induced chromatin remodeling and longevity.

Qian Zhang, Hangyu Dong, Yayun Jiang, Zihao Wang, Jiasheng Li, Ye Tian.

Mitochondrial stress activates nuclear transcriptional programs to restore homeostasis and promote longevity; yet, the nuclear effector that directly reshapes chromatin during stress remains unclear. Through a forward genetic screen in Caenorhabditis elegans, we identify FUBL-3, the homolog of human far-upstream elements binding protein 1 (FUBP1), as a conserved regulator that couples mitochondrial stress to chromatin remodeling. FUBL-3 translocates to intestinal nuclei upon stress, where it drives nucleosome remodeling and deacetylase-dependent chromatin condensation and activates mitochondrial unfolded protein response (UPRmt). Loss of fubl-3 disrupts chromatin compaction and abolishes stress-induced lifespan extension, while its overexpression is sufficient to restructure chromatin, trigger UPRmt, and extend lifespan. Notably, human FUBP1 rescues fubl-3 mutants in worms and mediates chromatin remodeling in mammalian cells under mitochondrial stress. FUBP1 binds promoters of proteostasis and mitochondrial quality control genes, supporting its role in nuclear adaptation. Our study identifies FUBL-3/FUBP1 as a conserved mitochondrial-to-nuclear communicator that reprograms chromatin architecture to promote stress resilience and healthy aging.

DOI: https://doi.org/10.1126/sciadv.aec8143

Nat Neurosci. 2026 Jun 26.

The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.

Maria Jose Perez J, Alicia Lam, Christin Weissleder, Federico Bertoli, Hariam Raji, Mariella Bosch, Ivan Nemazanyy, Stefanie Kalb, Mohammed Kehili, Insa Hirschberg, Dario Brunetti, Indra Heckenbach, Morten Scheibye-Knudsen, Michela Deleidi.

Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPRmt activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal-glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress-driven neurodegenerative processes. UPRmt activation disrupts microglial communication with neighboring cells, triggering inflammatory signaling and impairing proteostasis. Together, these findings reveal how impaired mitochondrial proteostasis alters intercellular networks and identify a critical role for the UPRmt in neurodegenerative disease pathogenesis.

DOI: https://doi.org/10.1038/s41593-026-02320-1