bims-cemest Biomed News
on Cell metabolism and stress
Issue of 2025–09–14
nine papers selected by
Jessica Rosarda, Uniformed Services University
  1. Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
  2. The Role of Phospholipids in Mitochondrial Dynamics and Associated Diseases.
  3. Cycloheximide resistant ribosomes reveal adaptive translation dynamics in C. elegans.
  4. Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.
  5. Two-Color Timestamping of Gene Expression with a Chemigenetic Reporter System.
  6. In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
  7. Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.
  8. Environmental and genetic risk factors of depression converge on neuronal dysfunction driven by changes in cholesterol homeostasis.
  9. TurboID-based mapping of organelle membrane protein interactomes with digitonin-permeabilization.
  1. EMBO J. 2025 Sep 08.
    Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
    Amanda L Gunawan, Irene Liparulo, Andreas Stahl.
      A variety of stressors, including environmental insults, pathological conditions, and transition states, constantly challenge cells that, in turn, activate adaptive responses to maintain homeostasis. Mitochondria have pivotal roles in orchestrating these responses that influence not only cellular energy production but also broader physiological processes. Mitochondria contribute to stress adaptation through mechanisms including induction of the mitochondrial unfolded protein response (UPRmt) and the integrated stress response (ISR). These responses are essential for managing mitochondrial proteostasis and restoring cellular function, with each being tailored to specific stressors and cellular milieus. While excessive stress can lead to maladaptive responses, mitohormesis refers to the beneficial effects of low-level mitochondrial stress. Initially studied in invertebrates and cell cultures, recent research has expanded to mammalian models of mitohormesis. In this literature review, we describe the current landscape of mammalian mitohormesis research and identify mechanistic patterns that result in local, systemic, or interorgan mitohormesis. These investigations reveal the potential for targeting mitohormesis for therapeutic benefit and can transform the treatment of diseases commonly associated with mitochondrial stress in humans.
    Keywords:  Integrated Stress Response; Mammalian Models; Mitochondrial Retrograde Signaling; Mitochondrial Unfolded Protein Response (UPRmt); Mitohormesis
    DOI:  https://doi.org/10.1038/s44318-025-00549-3
  2. Front Biosci (Landmark Ed). 2025 Aug 27. 30(8): 27634
    The Role of Phospholipids in Mitochondrial Dynamics and Associated Diseases.
    Solenn Plouzennec, Juan Manuel Chao de la Barca, Arnaud Chevrollier.
      The bioenergetic machinery of the cell is protected and structured within two layers of mitochondrial membranes. The mitochondrial inner membrane is extremely rich in proteins, including respiratory chain complexes, substrate transport proteins, ion exchangers, and structural fusion proteins. These proteins participate directly or indirectly in shaping the membrane's curvature and facilitating its folding, as well as promoting the formation of nanotubes, and proton-rich pockets known as cristae. Recent fluorescent super-resolution images have demonstrated the strong dynamics of these events, with constant remodeling processes. The mitochondrial outer membrane itself is also highly dynamic, interacting with the endoplasmic reticulum and its environment to ensure a rapid diffusion of surface components throughout the mitochondrial networks. All these movements occur besides migration, fusion, and fission of the mitochondria themselves. These dynamic events at the level of mitochondrial membranes are primarily dependent on their unique lipid composition. In this review, we discuss the latest advances in phospholipid research, focusing on their metabolism and role in mitochondrial dynamics. This process emphasizes the importance of interactions with the endoplasmic reticulum and mitochondrial matrix enzymes, extending its relevance to lipid sources, in particular, cardiolipins and phosphatidylethanolamines at the cellular, tissue and even whole-organism level. Given the expanding array of characterized mitochondrial functions, ranging from calcium homeostasis to inflammation and cellular senescence, research in the field of mitochondrial lipids is particularly significant. As mitochondria play a central role in various pathological processes, including cancer and neurodegenerative disorders, lipid metabolism may offer promising therapeutic approaches.
    Keywords:  dynamic; lipids; membrane; mitochondria; mitochondrial diseases
    DOI:  https://doi.org/10.31083/FBL27634
  3. Genetics. 2025 Sep 10. pii: iyaf189. [Epub ahead of print]
    Cycloheximide resistant ribosomes reveal adaptive translation dynamics in C. elegans.
    Qiuxia Zhao, Blythe Bolton, Reed Rothe, Reiko Tachibana, Can Cenik, Elif Sarinay Cenik.
      Protein translation regulation is critical for cellular responses and development, yet how elongation stage disruptions shape these processes remains incompletely understood. Here, we identify a single amino acid substitution (P55Q) in the ribosomal protein RPL-36A of Caenorhabditis elegans that confers complete resistance to the elongation inhibitor cycloheximide (CHX). Heterozygous animals carrying both wild-type RPL-36A and RPL-36A(P55Q) develop normally but show intermediate CHX resistance, indicating a partial dominant effect. Leveraging RPL-36A(P55Q) as a single-copy positive selection marker for CRISPR-based genome editing, we introduced targeted modifications into multiple ribosomal protein genes, confirming its broad utility for altering essential loci. In L4-stage heterozygotes, where CHX-sensitive and CHX-resistant ribosomes coexist, ribosome profiling revealed increased start-codon occupancy, reduced disome formation, and no codon-specific pausing. Surprisingly, chronic CHX treatment did not activate canonical stress pathways (RQC, RSR, ISR), as indicated by the absence of RPS-10 ubiquitination, eIF2α or PMK-1 phosphorylation, or ATF-4 induction. Instead, RNA-normalized ribosome footprints revealed selective changes in translation efficiency, with reduced nucleolar/P-granule components and increased oocyte development genes. Consistently, premature oocyte development was observed in L4 animals. These findings suggest that partial inhibition of translation elongation disrupts developmental timing across tissues, likely by altering translation efficiency.
    Keywords:   C. elegans ; CRISPR selection; WormBase; cycloheximide; oogenesis; protein translation
    DOI:  https://doi.org/10.1093/genetics/iyaf189
  4. Nat Aging. 2025 Sep 10.
    Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.
    Yan Bai, Tengfei Ma, Shan Zhao, Shalan Li, Xin Wang, Jingyang Li, Wenhao Sun, Yang Yang, Fenglian Liu, Qian Shan, Zizhen Qin, Nan Liu, Jie Zhang, Fei Tian, Mei Duan, Shunkai Chen, Fan Lai, Qingfeng Chen, Xuna Wu, Chonglin Yang.
      Membraneless organelles assembled by liquid-liquid phase separation interact with diverse membranous organelles to regulate distinct cellular processes. It remains unknown how membraneless organelles are engaged in mitochondrial homeostasis. Here we demonstrate that mitochondria-associated translation organelles (MATOs) mediate local synthesis of proteins required for structural and functional maintenance of mitochondria. In Caenorhabditis elegans, the RNA-binding protein LARP-1 (La-related protein 1) orchestrates coalescence of translation machinery and multiple RNA-binding proteins via liquid-liquid phase separation into MATOs that associate with mitochondria in a translocase of the outer membrane complex-dependent manner. LARP-1 deficiency markedly reduces mitochondrial protein levels, impairing cristae organization and ATP production. Specifically, we show that the membrane-shaping MICOS subunit IMMT-1(MIC60) and the ATP synthase β subunit ATP-2, both being important for cristae organization, are synthesized in LARP-1 MATOs. During aging and starvation, LARP-1 MATOs dissociate from mitochondria; however, mitochondrion-persistent LARP-1 MATOs protect mitochondrial health and greatly extend lifespan. These findings suggest an important mitochondrion-regulating mechanism in aging and stress.
    DOI:  https://doi.org/10.1038/s43587-025-00942-x
  5. Chembiochem. 2025 Sep 12. e202500494
    Two-Color Timestamping of Gene Expression with a Chemigenetic Reporter System.
    Henriette Lämmermann, Jade Nguyen, Juan F Tamez-Fernández, Fabien Kuttler, Julien Bortoli Chapalay, Marc Chambon, Gerardo Turcatti, Pablo Rivera-Fuentes.
      Stress response pathways rely on coordinated gene expression regulation. In the endoplasmic reticulum, the unfolded protein response plays an important role in maintaining the homeostasis of protein folding and processing. A chemigenetic reporter assay is developed that allows monitoring of BiP/GRP78 expression, a key regulator of the unfolded protein response. The system is based on the coexpression of the self-labeling protein HaloTag via an internal ribosome entry site. HaloTag allows for flexibility in labeling color as well as labeling timepoint. A two-color timestamping strategy is designed that provides improved readout sensitivity. The reporter system can be used in live-cell imaging as well as flow cytometry. It is applied in a high-content screening experiment in which a new promising activator of BiP/GRP78 expression was identified.
    Keywords:  BiP/GRP78; HaloTag; high‐content screening; reporter gene assays
    DOI:  https://doi.org/10.1002/cbic.202500494
  6. Nat Metab. 2025 Sep 10.
    In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
    Hanna F Willenbockel, Alexander T Williams, Alfredo Lucas, Mack B Reynolds, Emeline Joulia, Maureen L Ruchhoeft, Birte Dowerg, Pedro Cabrales, Christian M Metallo, Thekla Cordes.
      Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized by tricarboxylic acid (TCA) metabolism downstream of TLR signalling. Itaconate-based treatment strategies are under investigation to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13C itaconate tracing in male mice, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine and fuels TCA cycle metabolism specifically in the liver and kidneys. Our results further reveal that itaconate is converted into acetyl-CoA, mesaconate and citramalate. Itaconate administration also influences branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase and methylmalonyl-CoA mutase activity in male rats and mice. Our findings uncover a previously unknown aspect of itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.
    DOI:  https://doi.org/10.1038/s42255-025-01363-1
  7. Nat Metab. 2025 Sep 09.
    Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.
    Ran Liu, Zihan Zhang, Aye K Kyaw, Kariona A Grabińska, Hardik Shah, Hongying Shen.
      The essential cofactor coenzyme A (CoASH) and its thioester derivatives (acyl-CoAs) have pivotal roles in cellular metabolism. However, the mechanism by which different acyl-CoAs are accurately partitioned into different subcellular compartments to support site-specific reactions, and the physiological impact of such compartmentalization, remain poorly understood. Here, we report an optimized liquid chromatography-mass spectrometry-based pan-chain acyl-CoA extraction and profiling method that enables a robust detection of 33 cellular and 23 mitochondrial acyl-CoAs from cultured human cells. We reveal that SLC25A16 and SLC25A42 are critical for mitochondrial import of free CoASH. This CoASH import process supports an enriched mitochondrial CoA pool and CoA-dependent pathways in the matrix, including the high-flux TCA cycle and fatty acid oxidation. Despite a small fraction of the mitochondria-localized CoA synthase COASY, de novo CoA biosynthesis is primarily cytosolic and supports cytosolic lipid anabolism. This mitochondrial acyl-CoA compartmentalization enables a spatial regulation of anabolic and energy-related catabolic processes, which promises to shed light on pathophysiology in the inborn errors of CoA metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01358-y
  8. Dev Cell. 2025 Sep 10. pii: S1534-5807(25)00531-3. [Epub ahead of print]
    Environmental and genetic risk factors of depression converge on neuronal dysfunction driven by changes in cholesterol homeostasis.
    Polina Oberst, Nan Xu, Hermany Munguba, Chao Zhang, Aaron Zhong, Ting Zhou, Conor Liston, Joshua Levitz, Lorenz Studer.
      Major depressive disorder (MDD) is a complex, multifactorial neuropsychiatric disorder influenced by both genetic and environmental factors, but how these factors impact human neuronal function remains unclear. Using a highly defined human pluripotent stem cell (hPSC)-based prefrontal cortex (PFC) platform, we examined three high-confidence environmental and genetic factors associated with depression: chronic exposure to high levels of cortisol or interferon alpha (IFN-a), and a mutation in SIRTUIN 1 (SIRT1). All three conditions induced overlapping phenotypes of neuronal dysfunction, characterized by dendritic atrophy, synaptic loss, and neuronal hypoactivity across multiple cell lines. RNA sequencing uncovered converging alterations in neuronal cholesterol homeostasis. Depleting cholesterol in control neurons reproduced core depression-associated neuronal phenotypes, while cholesterol supplementation was sufficient to rescue these phenotypes in depression-associated conditions. These findings point to cholesterol imbalance as a common driver of neuronal dysfunction in MDD, linking diverse genetic and environmental risk factors through a shared cellular pathway.
    Keywords:  cholesterol; glutamate; human disease modeling; human pluripotent stem cells; major depression; synapse
    DOI:  https://doi.org/10.1016/j.devcel.2025.08.011
  9. Biophys Rep. 2025 Aug 31. 11(4): 219-231
    TurboID-based mapping of organelle membrane protein interactomes with digitonin-permeabilization.
    Yang Sun, Lan Yang, Jingzi Zhang, Pu Tian, Shue Chen, Lei Fang, Zhi Hong.
      Protein-protein interactions at organelle membranes bridge organelles in close proximity, facilitating regulated metabolite exchange and maintaining cellular homeostasis. Enzyme-catalyzed proximity labeling (PL) has been widely used to uncover the molecular composition of these interactions, but excessive labeling of irrelevant cytosolic proteins complicates data analysis. To address this, we developed a streamlined protocol that combines the TurboID system with digitonin-permeabilization to efficiently map protein interactions at organelle membranes in live mammalian cells. Digitonin selectively permeabilizes the plasma membrane, removing cytosolic proteins while preserving the integrity of inner membranes like the ER and mitochondria. This approach enhances spatial resolution in proteo-mic analysis, enabling a more precise map for protein interactome. Using this method, we successfully achieved proximal labeling of ER-localized proteins REEP1 and REEP6 to decipher their interaction networks, demonstrating its applicability for studying membrane-associated interactions with greater clarity and reduced contamination.
    Keywords:  Digitonin-permeabilization; Organelle interactomes; Protein–protein interactions; Proximity labeling; REEP1/REEP6
    DOI:  https://doi.org/10.52601/bpr.2025.240051
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