bims-mitpro 2026-05-03 papers

Issue of 2026–05–03
three papers selected by
Andreas Kohler, Umeå University

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

EMBO Rep. 2026 Apr 27.

Mitochondrial protein import stress causes lysosomal damage and progressive tissue atrophy.

Nicholas A Brennan, Xiaowen Wang, Arnav Rana, Sanaea Z Bhagwagar, Jason Horton, Patricia M Kane, Xin Jie Chen.

Mitochondrial and lysosomal abnormalities co-occur in aging-related diseases with progressive tissue atrophy. It remains unclear whether these two pathogenic pathways affect tissue homeostasis independently, convergently or epistatically. We show that mitochondrial protein import stress causes vacuolar damage in yeast, manifested by V-ATPase disassembly, and vacuolar deacidification and fragmentation. In a mouse model of mitochondrial protein import stress induced by overloading of the nuclear-encoded ANT1 protein, we observe progressive muscle atrophy independent of bioenergetic defects. Like in yeast mutants with severe vacuolar damage, genes involved in amino acid uptake/biosynthesis, one-carbon metabolism, lysosomal biogenesis and iron homeostasis are activated in the skeletal muscle of Ant1-transgenic mice. The affected muscles accumulate glycogen, lipofuscin and poorly processed multivesicular bodies. Despite activation of lysosomal repair and lysophagic pathways, autophagic flux is severely stalled. During aging, various proteolytic cathepsins are increasingly released from the lysosomal lumen into the cytosol. Together with proteasomal activation, this may contribute to unbalanced proteostasis, reduced myofiber size and skeletal muscle atrophy. Our study therefore discovered an evolutionarily conserved mitochondria-to-lysosome proteotoxic axis that affects tissue mass homeostasis during aging.

DOI: https://doi.org/10.1038/s44319-026-00774-9