bims-mitpro 2026-05-31 papers

bims-mitpro

Biomed News

on Mitochondrial proteostasis

Issue of 2026–05–31
nine papers selected by
Andreas Kohler, Umeå University

Orchestrating mitochondrial protein import: The emerging role of DYRK1A in health and disease.
Uncovering the initial response: Intra-mitochondrial surveillance activates the UPRmt.
MICOS and MIMAS, multifunctional assemblies linking mitochondrial biogenesis, architecture, and function.
A Stress-Responsive Nuclear Factor, GLDI-8, Mediates Mitochondrial Stress Responses to ETC Dysfunction.
A multilayered stress-response circuit: The mammalian mitochondrial UPR.
Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.
Transmembrane domain switching controls PINK1 import and fate in mitochondria.
Prohibitin 2 links damaged mitochondria to intracellular bacteria to trigger xenophagy independent of mitophagy.
Ubiquitin-dependent mitochondrial protein degradation ensures seedling emergence by regulating ER-mitochondrial interaction and mitophagy.

Protein Sci. 2026 Jun;35(6): e70631

Orchestrating mitochondrial protein import: The emerging role of DYRK1A in health and disease.

Sahana Shankar, Chris Meisinger.

  The translocase of the outer mitochondrial membrane (TOM complex) serves as the central entry gate for more than 1000 nuclear-encoded precursor proteins imported into the organelle. Recently, the human import receptor TOM70 has been identified as a substrate of the serine/threonine kinase DYRK1A. DYRK1A activates the metabolite carrier import pathway, and its impairment triggers a transcriptional adaptive response that induces remodeling of the TOM complex. This compensatory mechanism activates additional import pathways to mitigate reduced DYRK1A signaling. Patients with dysfunctional DYRK1A signaling exhibit clinical manifestations that resemble classical features of mitochondriopathies. The emerging DYRK1A-TOM70 axis therefore represents a central signaling platform coordinating mitochondrial protein import pathways in health and disease.

Keywords:  DYRK1A; DYRK1A‐related syndrome; Down syndrome; TOM complex; mitochondrial protein import; organellar signaling

DOI:  https://doi.org/10.1002/pro.70631
Mol Cell. 2026 May 26. pii: S1097-2765(26)00308-4. [Epub ahead of print]

Uncovering the initial response: Intra-mitochondrial surveillance activates the UPRmt.

Asli Aras Taskin, Sahana Shankar, Carlotta Peselj, Annette Flotho, Maria Gomez-Fabra Gala, Daniel Poveda-Huertes, Lisa Myketin, Duygu Mutlu, Adinayarana Marada, Sebastian Schuck, Mandy Jeske, Sabrina Büttner, Marcin Luzarowski, Chris Meisinger, F-Nora Vögtle.

  The mitochondrial unfolded protein response (UPRmt) protects mitochondria from proteotoxic stress. Current models induce acute and severe mitochondrial disruption and propose cytosolic detection following the release of mitochondrial damage signals into the cytosol. However, this mode of toxicity contrasts sharply with physiological stress, such as the gradual accumulation of reactive oxygen species (ROS) during aging or chronic respiratory chain defects. Here, we employ a chemogenetic strategy in yeast to induce low levels of hydrogen peroxide (H2O2) in the mitochondrial matrix and show that mild oxidative stress activates the UPRmt independently of cytosolic damage. We identify the presequence proteases MPP and Oct1 as early ROS targets, thereby linking redox imbalance to UPRmt activation: oxidative stress induces glutathionylation of critical cysteines, impairing protease activity and causing the accumulation of unprocessed precursors in proteotoxic matrix aggregates. These aggregates are detected by intra-mitochondrial surveillance, activating UPRmt signaling. Thus, mitochondrial self-surveillance initiates rapid protective signaling as a primary response to mitochondrial dysfunction.

Keywords:  mitochondria-nucleus communication; mitochondrial protein biogenesis; mitochondrial unfolded protein response; oxidative stress; presequence processing; reactive oxygen species

DOI:  https://doi.org/10.1016/j.molcel.2026.05.002
Protein Sci. 2026 Jun;35(6): e70653

MICOS and MIMAS, multifunctional assemblies linking mitochondrial biogenesis, architecture, and function.

Patrick Horten, Kuo Song, Nikolaus Pfanner, Heike Rampelt.

  Mitochondrial cristae architecture is central for optimal oxidative phosphorylation and a healthy mitochondrial physiology. The intricate architecture of the inner mitochondrial membrane relies on protein complexes that compartmentalize the membrane by imposing membrane curvature, forming membrane contact sites or membrane subdomains, regulating the partitioning of mitochondrial proteins between the different subcompartments and thereby enabling functional asymmetry, and by governing membrane dynamics. Studies in recent years have expanded our understanding of the machineries and mechanisms underlying the manifold functions of the inner membrane. This review focuses on the mitochondrial contact site and cristae organizing system (MICOS), a protein complex that stabilizes the narrow entry gates of cristae, and on a novel inner membrane megacomplex, the mitochondrial multifunctional assembly (MIMAS), as well as on their roles in organizing the inner membrane.

Keywords:  cristae; membrane organization; metabolism; mitochondria; respiratory chain

DOI:  https://doi.org/10.1002/pro.70653
Int J Mol Sci. 2026 May 14. pii: 4387. [Epub ahead of print]27(10):

A Stress-Responsive Nuclear Factor, GLDI-8, Mediates Mitochondrial Stress Responses to ETC Dysfunction.

Yung Wu, Hongyun Tang.

  Mitochondrial electron transport chain (ETC) impairment triggers mitochondrial unfolded protein response (UPRmt) that promotes mitochondrial homeostasis, yet the nuclear factors that mediate these responses remain incompletely defined. Here, we identify GLDI-8 as a nuclear factor required for robust activation of the hsp-6p::gfp UPRmt reporter induced by ETC dysfunction in Caenorhabditis elegans. Depletion of gldi-8 markedly compromises mitochondrial stress-induced hsp-6p::gfp reporter activation, and transgenic rescue restores the response, supporting a specific requirement for GLDI-8 in this pathway. Mitochondrial stress promotes nuclear accumulation of GLDI-8; however, a GLDI-8 transcriptional (promoter) reporter shows no detectable induction under the same conditions, suggesting that regulation occurs at the post-transcriptional level. Genetic analysis further shows that stress-induced nuclear translocation of GLDI-8 is not abolished by atfs-1 knockdown, and GLDI-8 is dispensable for DVE-1 nuclear translocation under mitochondrial stress. Together, these findings establish GLDI-8 as a mitochondrial stress-responsive nuclear factor that contributes to ETC impairment-induced transcriptional responses and adds to the complex regulatory network underlying the UPRmt.

Keywords:  Caenorhabditis elegans; GLDI-8; electron transport chain dysfunction; mitochondrial unfolded protein response

DOI:  https://doi.org/10.3390/ijms27104387
FEBS J. 2026 May 29.

A multilayered stress-response circuit: The mammalian mitochondrial UPR.

Paulina Czechowicz, Anna Więch-Walów, Sylwia Kozioł, Jakub Dudzik, James F Collawn, Rafal Bartoszewski.

  Mitochondrial proteotoxic stress activates the mammalian UPRmt through a multilayered mechanistic architecture rather than a linear pathway. At its core lies an import-gated sensing logic: reduced preprotein import and mito-nuclear stoichiometric imbalance activates the integrated stress response (ISR) toward the translation of ATF4, CHOP, and the mitochondria-targeted transcription factor ATF5. These factors cooperatively reprogram transcription to expand the chaperone-protease capacity while transiently reducing the nuclear-encoded OXPHOS load. Parallel translational mechanisms that include eIF2α-dependent repression, stress-granule triage, and miRNA-driven selective silencing reduce the mitochondrial precursor import and maintain proteostatic symmetry between the cytosol and mitochondria. Within the organelle, LONP1- and CLPP-dependent proteolysis, mitoribosome pausing, and tRNA-processing checkpoints further dampen nascent chain pressure. Epigenetic licensing by demethylases and acetyltransferases links metabolic and bioenergetic status to promoter accessibility at UPRmt loci. Together, these import-gated, translational, and epigenetic control layers form a coherent mechanistic circuit ensuring that mitochondrial recovery is matched to folding, assembly, and metabolic capacity. We propose a unified framework explaining how these layers cooperate to determine adaptive versus maladaptive outcomes.

Keywords:  Integrated stress response (ISR); Mitochondrial protein import stress; Mitochondrial proteostasis; Mitochondrial stress signaling; Mitochondrial unfolded protein response (UPRmt)

DOI:  https://doi.org/10.1111/febs.70607
Muscles. 2026 May 22. pii: 39. [Epub ahead of print]5(2):

Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.

Victoria C Sanfrancesco, Daniella Della Mea, David A Hood.

  To maintain homeostatic conditions and optimal function during stressors, mitochondria initiate retrograde signaling. The mitochondrial integrated stress response (ISR) and unfolded protein response (UPRmt) are critical quality control mechanisms activated during instances of mitochondrial perturbations. Restoration of mitochondrial homeostasis is orchestrated by three transcription factors, ATF4, CHOP, and ATF5, which upregulate protective genes to counteract stress. As the health and function of skeletal muscle are heavily dependent on a highly adaptive mitochondrial network, defining how mitochondrial health is maintained across various conditions is essential. Although several studies demonstrate the importance of these responses following instances of stress, the signaling mechanisms required to initiate such pathways remain poorly characterized in skeletal muscle. This review examines how the mitochondrial ISR/UPRmt and related transcription factors respond to organellar stress by emphasizing the molecular events that occur during exercise, aging and muscle disuse. By consolidating the literature, this work aims to highlight the current understanding of mitochondrial stress response signaling within skeletal muscle and thus emphasize areas for future research and potential therapeutic strategies during divergent metabolic conditions.

Keywords:  ATF4; ATF5; CHOP; adaptation; aging; exercise; integrated stress response; mitochondria; muscle inactivity; skeletal muscle; stress response; unfolded protein response

DOI:  https://doi.org/10.3390/muscles5020039
EMBO J. 2026 May 26.

Transmembrane domain switching controls PINK1 import and fate in mitochondria.

James S Lorriman, Rhiannon J Hughes, Adam G Grieve, Robin A Corey, Ian Collinson.

Mitochondrial targeting of the PINK1 kinase results, under normal conditions, in membrane-potential-driven inner membrane penetration and cleavage by the resident protease PARL before retro-translocation and proteasomal degradation. In compromised mitochondria, with reduced membrane potential, inner membrane incorporation is not achieved, which leads to surface activation of the full-length protein, Parkin recruitment and mitophagy. Here, we identify a third pathway in which PINK1 is imported into the mitochondrial matrix. Structural modelling predicts that PINK1's transmembrane domain (TMD) is conformationally plastic, forming either an α-helix or α/β-hybrid at the interface between Tim17 of the TIM23-complex for engagement of either ROMO1 or PARL. These mutually exclusive assemblies define distinct protein-import channels with differing biological roles. PINK1's α-helical TMD adopts a pose suggestive of translocation through the ROMO1/Tim17-channel, while the α/β-hybrid engages PARL and is cleaved. We propose that TMD structural plasticity determines whether PINK1 is imported into the matrix or cleaved and retro-translocated. The results expand the role of PINK1 beyond that of a damage sensor and imply a role in healthy mitochondrial function with potential relevance to Parkinson's disease.

DOI: https://doi.org/10.1038/s44318-026-00789-x
Cell Rep. 2026 May 28. pii: S2211-1247(26)00541-3. [Epub ahead of print]45(6): 117463

Prohibitin 2 links damaged mitochondria to intracellular bacteria to trigger xenophagy independent of mitophagy.

Jing Yang, Yitian Ying, Huiwen Ye, Meiyi Chen, Xia Liu, Ganlu Wei, Jiayue She, Xinyu Lin, Muyang Wan, Xun Tan.

  Mitophagy and xenophagy, two selective autophagy pathways sharing common E3 ligases, have been proposed to intersect in host defense against invading pathogens. Here, we show that mitochondrial damage, but not mitophagy, is essential for triggering xenophagy via the inner mitochondrial membrane protein prohibitin 2 (PHB2). Upon bacteria-induced disruption of the outer mitochondrial membrane, PHB2 bridges mitochondria to bacteria by binding bacterial surface proteins, while concurrently interacting with either auto-ubiquitinated E3 ligase ARIH1 or Parkin, two well-characterized mitophagy-associated E3 ligases. This interaction positions polyubiquitin chains near PHB2-targeted bacteria to recruit selective autophagy receptors for initiating xenophagy, leading to the co-autophagic degradation of bacteria and mitochondria, a process unaffected by mitophagy inhibition. Our findings establish an uncovered mechanism of mitochondria-dependent antibacterial autophagy, positioning mitochondrial PHB2 as both a bacterial sensor and an E3 ligase scaffold, and unveiling a previously unidentified process governing the recruitment of mitophagy-associated E3 ligases to intracellular bacteria.

Keywords:  ARIH1; CP: cell biology; CP: molecular biology; Listeria; PHB2; Salmonella; Staphylococcus aureus; mitochondria; mitophagy; parkin; ubiquitin; xenophagy

DOI:  https://doi.org/10.1016/j.celrep.2026.117463
Nat Plants. 2026 May 28.

Ubiquitin-dependent mitochondrial protein degradation ensures seedling emergence by regulating ER-mitochondrial interaction and mitophagy.

Zhen Tian, Yawen Huo, Chengyang Li, Qiwei Zheng, Fan Hu, Jing Li, Juncai Ma, Xiaolu Qu, Yunjiang Cheng, Byung-Ho Kang, Patrick Duckney, Pengwei Wang.

Seedling emergence is a pivotal step of plant survival, requiring rapid hypocotyl elongation for soil penetration1,2. This energy-demanding process necessitates active mitochondrial respiration, which inevitably induces oxidative damage3-6. Plants have therefore evolved a quality-control mechanism that selectively removes dysfunctional mitochondria through the mitophagy pathway. Here we identified SPL2, a mitochondrial E3 ligase that is essential for hypocotyl elongation and seedling emergence through degrading mitochondrial outer membrane proteins, such as TRB1 and FIS1A. Intriguingly, these proteins also interact with an endoplasmic reticulum (ER) protein, VAP27-1, forming a complex at the ER-mitochondria contact sites, which is essential for mitophagy initiation. The spl2 mutant exhibits enhanced ER-mitochondrial tethering and mitophagy activation, whereas the overexpression of SPL2 has the opposite effects. The expression of SPL2 increases after light perception, in agreement with the reduced mitophagy. Collectively, our findings reveal mechanistic insights into seedling emergence, which is coordinated through protein ubiquitination, ER-mitochondrial interaction and mitophagy.

DOI: https://doi.org/10.1038/s41477-026-02306-8