bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–03–01
eighteen papers selected by
Marc Segarra Mondejar, AINA
  1. Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.
  2. Modeling lipid homeostasis using stable isotope tracing and flux analysis.
  3. mtDNA leakage promotes neuron-glia crosstalk to induce epilepsy by cGAS-STING-driven neuroinflammation and serine metabolic reprogramming.
  4. Phenotypic CRISPR screens identify NLRX1 as an essential activator of the human mitochondrial permeability transition.
  5. Reversible dissociation of mitochondrial Complex V balances anabolic and energy-generating needs in cancer.
  6. Aspartate availability drives differential engagement of the malate-aspartate shuttle.
  7. Opposing roles of DGAT-mediated lipid droplet biogenesis in the regulation of ferroptosis sensitivity.
  8. Clinically distinct metabotypes of pediatric MASLD identified through unsupervised clustering of NASH CRN data.
  9. Single-Atom Nanozyme Driven Lactate Reversal Fuels Oxidative Metabolism and Represses Lactylation to Heal Diabetic Wounds.
  10. The research advances of crosstalk between cancer-associated fibroblasts and tumor cells using co-culture organoids.
  11. Isogenic cortical organoids enable precision targeting of APP variant-specific pathways in Alzheimer's disease.
  12. COX7A1-mediated mitochondrial dysfunction can induce ferroptosis in endometrial cancer cells.
  13. Proteoliposomes containing ATPase as microreactors to mimic microbial metabolism for bioenergy synthesis.
  14. UIP4 governs nuclear shape by modulating Saccharomyces cerevisiae lipidome.
  15. Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.
  16. Specific SLC25 carriers regulate mitochondrial protein synthesis.
  17. Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis.
  18. Targeting one-carbon metabolic vulnerabilities of metastasis with therapeutic potential.
  1. Nat Struct Mol Biol. 2026 Feb 27.
    Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.
    Lara Kroczek, Hendrik Nolte, Yvonne Lasarzewski, Ishita Agrawal, Thibaut Molinié, Daniel Curbelo Piñero, Kathrin Lemke, Elena Rugarli, Thomas Langer.
      Mitochondria dynamically adapt to cellular stress to ensure cell survival. The stress-regulated mitochondrial peptidase OMA1 orchestrates these adaptive responses, which limit mitochondrial fusion and promote mitochondrial stress signaling and metabolic rewiring. Here, we show that cellular stress adaptation involves OMA1-mediated regulation of mitochondrial protein import and OXPHOS biogenesis. OMA1 cleaves the mitochondrial chaperone DNAJC15 and promotes its degradation by the m-AAA protease AFG3L2. Loss of DNAJC15 impairs mitochondrial protein import and restricts OXPHOS biogenesis under conditions of mitochondrial dysfunction. Non-imported mitochondrial preproteins accumulate at the endoplasmic reticulum, inducing an unfolded protein response. Our results demonstrate stress-dependent changes in mitochondrial protein import as part of the OMA1-mediated mitochondrial stress response and highlight the interdependence of proteostasis regulation between different organelles.
    DOI:  https://doi.org/10.1038/s41594-026-01756-0
  2. Cell Metab. 2026 Feb 20. pii: S1550-4131(26)00020-3. [Epub ahead of print]
    Modeling lipid homeostasis using stable isotope tracing and flux analysis.
    Karl Wessendorf-Rodriguez, Maureen L Ruchhoeft, Christopher W Murray, Yale Huang, Ethan L Ashley, Hector M Galvez, Grace H McGregor, Shrikaar Kambhampati, Reuben J Shaw, Christian M Metallo.
      Lipids enable compartmentation and coordinate membrane-localized signaling events in cells, and dysregulation of lipid metabolism is linked to many disease states. However, limited tools are available for quantifying metabolic fluxes across the lipidome. To measure fluxes encompassing lipid homeostasis in cells and tissue slices, we apply stable isotope tracing, liquid chromatography-high-resolution mass spectrometry, and network-based isotopologue modeling to non-small cell lung cancer (NSCLC) models. Lipid metabolic flux analysis (Lipid-MFA) enables quantitation of fatty acid synthesis, elongation, headgroup assembly, and salvage reactions within virtually any biological system. Using Lipid-MFA, we observed decreased fatty acid synthase and very long-chain fatty acid (VLCFA) elongation fluxes, along with increased sphingolipid recycling, in p53-deficient versus liver kinase B1 (LKB1)-deficient NSCLC tumors using precision-cut lung slice culture. We also apply Lipid-MFA to demonstrate the unique trafficking of ceramides with distinct n-acyl chain lengths, highlighting the utility of this approach in elucidating molecular mechanisms in lipid homeostasis.
    Keywords:  ELOVL1; LKB1; TP53; ceramide; lipid homeostasis; metabolic flux analysis; non-small cell lung cancer; precision-cut lung slice culture; sphingolipids; very long-chain fatty acids
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.020
  3. Proc Natl Acad Sci U S A. 2026 Mar 03. 123(9): e2522313123
    mtDNA leakage promotes neuron-glia crosstalk to induce epilepsy by cGAS-STING-driven neuroinflammation and serine metabolic reprogramming.
    Jie Jiang, Meiling Zuo, Kehan Zhao, Zhihao Ling, Zhida Wu, Dongfang Xue, Shouyong Mo, Yuanhui Liu, Yongjun Chen, Jie Wang, Bin Lu, Chuanzhou Li, Yaqi Duan, He He, Zhiyin Song.
      Epilepsy is increasingly recognized as a disorder involving metabolic dysregulation beyond neural hyperexcitability, yet the underlying metabolic mechanisms remain poorly defined. Here, we identify a mitochondrion-immunity-metabolism axis that drives spontaneous chronic epilepsy. Brain-specific deletion of Mic19 impairs mitochondrial cristae structure and mitochondrial integrity in neurons, leading to activation of the Z-mitochondrial DNA (mtDNA)-ZBP1-RIPK3-mixed lineage kinase domain-like protein (MLKL) axis and p-MLKL-mediated pore formation on the mitochondrial membrane. This process results in cytosolic and extracellular leakage of mtDNA, which is subsequently taken up by microglia and triggers cyclic GMP-AMP synthase (cGAS)-STING-dependent inflammatory signaling. The resulting neuroinflammation promotes sustained activation of astrocytes. Critically, reactive astrocytes undergo profound metabolic reprogramming, marked by upregulated glycolysis and enhanced L-serine biosynthesis. Astrocyte-derived L-serine is subsequently transferred to neurons and converted into D-serine, a key NMDA receptor coagonist that enhances neuronal excitability. This metabolic shift in astrocytes exacerbates excitotoxicity and sustains epileptic activity. Importantly, pharmacologic inhibition of STING with H-151 treatment markedly suppresses seizures, reinforcing the therapeutic potential of targeting immunometabolic crosstalk in epilepsy. Our findings reveal that mtDNA-mediated cGAS-STING activation and D-serine act as important drivers of epilepsy initiation, offering mechanistic insights into neuron-microglia-astrocyte crosstalk and highlighting immunometabolic modulation as a promising therapeutic strategy for epilepsy.
    Keywords:  cGAS–STING; epilepsy; mitochondrial DNA; neuroinflammation; serine
    DOI:  https://doi.org/10.1073/pnas.2522313123
  4. Proc Natl Acad Sci U S A. 2026 Mar 03. 123(9): e2535298123
    Phenotypic CRISPR screens identify NLRX1 as an essential activator of the human mitochondrial permeability transition.
    William C Valinsky, Robert P Ray, Kathy S Schaefer, Jonathan B Grimm, Carla Nicolini, Luke D Lavis, David E Clapham.
      The mitochondrial permeability transition (mPT) is an evolutionarily conserved destructive process that permeabilizes the inner mitochondrial membrane in response to calcium overload. The molecular mechanism underlying the mPT is not established. To unambiguously identify essential proteins, we designed two phenotypic assays for mitochondrial calcium overload and applied them to FACS-based CRISPR screening in human cells, ultimately evaluating 19,113 genes. The first screen studied mitochondrial membrane potential (MMP) collapse in response to calcium overload. Top-ranked genes were the essential proteins of the mitochondrial calcium uniporter complex, MCU and EMRE, reflecting that the calcium-induced MMP collapse results from mitochondrial calcium entry and not the mPT. The second screen measured the permeability of the inner mitochondrial membrane. Here, the fluorescent interaction of a membrane impermeant ~600 Da dye and a mitochondrial-targeted HaloTag protein was studied under mPT activating conditions; calcium overload and the thiol-reactive molecule phenylarsine oxide. With secondary validation, we identified four protein-encoding genes that delayed or prevented the mPT under knockout: NF2, REST, BPTF, and NRLX1. Knockout of the nonmitochondrial proteins BPTF, NF2, or REST increased mitochondrial calcium retention capacity (CRC). However, calcium release or sensitivity to cyclosporin A (CsA) persisted, indicative of mPT sensitizers. Only knockout of the mitochondrial matrix protein, NLRX1, increased CRC, abolished calcium release, and was CsA-insensitive. This top-ranked hit of the mitochondrial permeability screen meets the definition of an essential mPT activator. Integral membrane proteins, including all previously proposed mPT candidates, were not essential activators.
    Keywords:  MCU; NLRX1; calcium; mitochondria; permeability transition
    DOI:  https://doi.org/10.1073/pnas.2535298123
  5. iScience. 2026 Mar 20. 29(3): 114889
    Reversible dissociation of mitochondrial Complex V balances anabolic and energy-generating needs in cancer.
    Huabo Wang, Jie Lu, Colin Henchy, Steven J Mullett, Adam C Richert, Eric S Goetzman, Ahmet Toksoz, Leonardo Hale, Brandon B Wang, Nelli Mnatsakanyan, Edward V Prochownik.
      Cancer cell metabolic re-programming provides the additional energy and anabolic precursors necessary to sustain unregulated proliferation. This is partially mediated by the Warburg effect, which generates ATP while oxidizing glucose to a subset of these anabolites. Concurrently, mitochondrial mass and ATP generation via oxidative phosphorylation decline in most tumors. This raises the question of how increased glycolysis-derived anabolites can be balanced with those supplied by the TCA cycle. Using primary murine liver cancers and their derivative cell lines, we show that this can be explained by the dissociation of mitochondrial Complex V (CV or ATP synthase) into its component and functionally independent Fo and F1 domains. This occurs as a result of marked declines in MT-ATP6, a CV subunit that stabilizes Fo-F1 assembly. Serving as a proton pore, free Fo maintains a normal mitochondrial membrane potential without generating ATP, thus allowing the TCA cycle, electron transport chain, and anaplerotic reactions to function at high levels. Concurrently, free F1 functions in reverse as an ATPase to limit excess ATP accumulation. The uncoupling of TCA-cycle-derived anabolic substrate production from membrane hyperpolarization and ATP overproduction by a smaller population of highly efficient mitochondria allows TCA-cycle-generated anabolic precursors to match those generated via glycolysis.
    Keywords:  Biochemistry; Cancer; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.114889
  6. Mol Cell. 2026 Feb 26. pii: S1097-2765(26)00099-7. [Epub ahead of print]
    Aspartate availability drives differential engagement of the malate-aspartate shuttle.
    Julia S Brunner, Anna E Bridgeman, Benjamin T Jackson, Sangita Chakraborty, Maider Fagoaga-Eugui, Katrina I Paras, Abigail Xie, Paige K Arnold, Julia Losner, Lydia W S Finley.
      The malate-aspartate shuttle is a major electron shuttle that transfers reducing equivalents from the cytosol to the mitochondria, where they can be safely deposited onto the electron transport chain. Nevertheless, many proliferating cells discard reducing equivalents in the form of lactate, raising the question of what factors limit electron shuttle use. Here, we show that aspartate availability determines engagement of the malate-aspartate shuttle. In proliferating cells, increasing aspartate availability enhances use of the malate-aspartate shuttle and increases metabolism of glucose-derived pyruvate in mitochondria, a process that requires regeneration of oxidized electron carriers in the cytosol. During differentiation, elevated flux through the malate-aspartate shuttle cells enables cells to fuel mitochondrial networks from glucose-derived carbon. Engineering aspartate demand reverses this metabolic signature of differentiated cells. Together, these results demonstrate that cell-state-specific demand for aspartate is sufficient to determine use of the malate-aspartate shuttle and drives changing mitochondrial substrate preferences during differentiation.
    Keywords:  GOT1; GOT2; TCA cycle; Warburg effect; aspartate; differentiation; electron shuttles; malate-aspartate shuttle; metabolism; proliferation
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.004
  7. FEBS J. 2026 Feb 23.
    Opposing roles of DGAT-mediated lipid droplet biogenesis in the regulation of ferroptosis sensitivity.
    Ana Kump, Leja Perne, Špela Koren, Eva Jarc Jovičić, Nastja Feguš, Carina Pinto Kozmus, Michele Wölk, Kristyna Brejchova, Maria Fedorova, Ondrej Kuda, Toni Petan.
      Lipid droplets (LDs) are dynamic fat storage organelles involved in fatty acid metabolism, signaling, and trafficking. By storing polyunsaturated fatty acids (PUFAs) in the form of neutral lipids, LDs can either mitigate or exacerbate lipotoxic damage. However, their role in regulating cellular fatty acid distribution, membrane unsaturation, and ferroptosis susceptibility remains poorly understood. Here, we show that inhibition of diacylglycerol acyltransferase (DGAT)-mediated LD biogenesis in PUFA-supplemented triple-negative breast cancer cells triggers widespread lipidome reorganization and membrane phospholipid acyl-chain remodeling, promoting lipid peroxidation and ferroptosis sensitivity. Lipidomic analyses reveal that LDs efficiently sequester exogenous PUFAs within triacylglycerols and cholesteryl esters, significantly altering neutral lipid unsaturation profiles. When LD formation is impaired by DGAT inhibition, PUFAs are redistributed into membrane ester and ether glycerophospholipids, enhancing overall membrane unsaturation, lipid peroxidation, and increasing ferroptosis susceptibility, even in the absence of additional ferroptosis inducers. In contrast, in human lung adenocarcinoma cells, LDs exhibit a dual, context-dependent role in ferroptosis regulation, whereby exogenous PUFA levels and the extent of ferroptosis protection determine whether DGAT inhibition promotes or protects against cell death. The pro-ferroptotic function of LDs predominates in these cells and is strongly enhanced by ferroptosis suppressor protein 1 (FSP1) deficiency, which amplifies lipid peroxidation within LDs and promotes its propagation to other cellular compartments. This study highlights LDs as multifaceted regulators of ferroptosis, interlinking metabolic and redox quality control mechanisms.
    Keywords:  diacylglycerol acyltransferase; fatty acids; ferroptosis; lipid droplets; lipid peroxidation; lipidomics
    DOI:  https://doi.org/10.1111/febs.70467
  8. Nat Commun. 2026 Feb 24.
    Clinically distinct metabotypes of pediatric MASLD identified through unsupervised clustering of NASH CRN data.
    Helaina E Huneault, Pradeep Tiwari, Zachery R Jarrell, Matthew Ryan Smith, Chih-Yu Chen, Ana Ramirez Tovar, Cristian Sanchez-Torres, Scott Gillespie, Shasha Bai, Rodrigo M Carrillo-Larco, Ajay K Jain, Katherine P Yates, Brent A Neuschwander-Tetri, Jeffrey B Schwimmer, Stavra A Xanthakos, Jean P Molleston, Cynthia A Behling, Mark H Fishbein, Terryl J Hartman, Francisco J Pasquel, Rishikesan Kamaleswaran, Dean P Jones, Jean A Welsh, Miriam B Vos.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease worldwide, yet treatment remains "one size fits all," despite phenotypic heterogeneity. We analyzed clinical and metabolomics data from 514 children (ages 5-18, 73% male) with biopsy-proven MASLD across three NASH Clinical Research Network studies. Unsupervised clustering of clinical data identified three distinct metabotypes: early-mild (49.4%, youngest, lowest lipids, liver enzymes, insulin resistance), cardiometabolic (36.8%, highest waist circumference, lipids, uric acid, SBP), and inflammatory-fibrotic (13.8%, highest liver enzymes, steatohepatitis, advanced fibrosis). Integrative network and pathway enrichment analyses revealed alterations in tryptophan metabolism within the inflammatory-fibrotic group, including elevated kynurenine pathway metabolites, which were significantly correlated with fibrosis stage. Branched-chain amino acid degradation, butanoate, and purine metabolism demonstrated greater enrichment in the cardiometabolic group. Here, we show that pediatric MASLD subtypes differ in clinical and metabolic features, providing a framework for targeted interventions, with validation needed in independent cohorts.
    DOI:  https://doi.org/10.1038/s41467-026-69735-z
  9. ACS Nano. 2026 Feb 27.
    Single-Atom Nanozyme Driven Lactate Reversal Fuels Oxidative Metabolism and Represses Lactylation to Heal Diabetic Wounds.
    Wei Wu, Houqi Zhou, Muxin Zhang, Xiao Zhang, Mengjiao Huang, Siyu Tao, Wei Du, Shuang Wang, Jiayi Zhao, Xiang Zhou, Nanxin Liu, Tao Chen.
      In this study, single-cell RNA sequencing (scRNA-seq) analysis revealed that both reactive oxygen species (ROS) and excessive lactate accumulation play critical roles in sustaining the local chronic inflammatory microenvironment. Guided by these insights, we developed a phosphorus-doped single-atom iron nanozyme (Fe@CN-P) designed to overcome the long-standing challenge of achieving lactate oxidation with metal-based nanozymes. Phosphorus, acting as a stronger electron donor, effectively increases the electron density at the iron active center, thereby enhancing its proton-capture capacity. In Fe@CN-P, the downward shift of the Fe d-band center, coupled with the increased density of electronic states near the Fermi level, lowers the energy barrier for proton transfer in the rate-determining step, ultimately enabling the efficient conversion of lactate into pyruvate. Notably, the dual functions of lactate oxidation and ROS scavenging restore mitochondrial activity and establish a "reversal-reutilization" metabolic pathway. Our findings demonstrate that phosphorus-induced electronic redistribution at the iron center enables efficient catalytic lactate "reversal-reutilization," thereby driving metabolic reprogramming and epigenetic remodeling to regulate inflammation. This work illustrates how atomic-level electronic structure engineering can be integrated with biological metabolic processes, providing insights and theoretical foundations for the design of single-atom nanozymes with both precise electronic modulation and therapeutic functionality.
    Keywords:  diabetic chronic wounds; epigenetic regulation; lactate; metabolic reprogramming; nanozyme
    DOI:  https://doi.org/10.1021/acsnano.5c20192
  10. Cell Death Dis. 2026 Feb 26.
    The research advances of crosstalk between cancer-associated fibroblasts and tumor cells using co-culture organoids.
    Minghui Wang, Xiaodi Ding, Lin Chen, Zhichao Cui, Yiyi Ding, Yongmin Song, Wentong Li, Xumei Zhang.
      Cancer-associated fibroblasts (CAFs) fundamentally impact on characteristics of tumor cells and are concerned with therapy resistance via extensive interplay with cancer cells and other stromal components. In addition, inherent plasticity and multifunctionality of CAFs enable cancer cells to cultivate them, leading to dynamic changes in the population of CAFs in a context-dependent manner. Despite CAFs have long been regarded as a key participant in cancer development and therefore an appealing therapeutic target, most clinical trials targeting CAFs end in failure, and even accelerate progression of cancers, indicating that dynamic complicated identity and function of CAFs far exceed the current view. Accordingly, analyzing the heterogeneous subgroups and different functions of CAFs in a context dependent mode is of great significance. To ascertain the functional interactions between CAFs and cancer cells, various three-dimensional co-culture models of organoid with CAFs and cancer cells from murine or human have been successfully established. In the review, we recapitulate the proposed methods for cultivating organoids consisted of tumor cells and CAFs as well as molecular mechanisms involving in regulating variety of CAF subgroups. Current strategies targeting tumor-promoting CAFs selectively are also discussed, offering perception and perspectives for scientific investigation and clinical trials concerning various methods targeting CAFs.
    DOI:  https://doi.org/10.1038/s41419-026-08512-8
  11. bioRxiv. 2026 Feb 19. pii: 2026.02.19.706886. [Epub ahead of print]
    Isogenic cortical organoids enable precision targeting of APP variant-specific pathways in Alzheimer's disease.
    T Grass, I M Cosacak, A Ordureau, F D Price, S Kavali, A Caldarelli, M N Qiao, B Vardarajan, Joao A Paulo, Michele Marass, L L Rubin, C Kizil, N Rodriguez-Muela.
      Alzheimer's disease (AD) lacks disease-modifying therapies, in part due to the limitations of existing disease models, which have struggled to capture the early pathogenic events leading to neuronal degeneration. Unfortunately, recent therapies targeting hallmarks of AD have proven inefficient in humans, and it is thus necessary to identify alternative targets. Here, by generating an isogenic panel of hiPSC-derived cortical organoids carrying familial AD-associated APP variants or the protective A673T variant, we identified distinct, actionable pathogenic pathways specific to each variant. Proteomic analyses revealed variant-specific molecular disruptions: A673V organoids show impairments in proteostasis and cholesterol metabolism, whereas KM670/671NL organoids exhibit mitochondrial bioenergetic defects. These signatures overlapped with dysregulated proteins in post-mortem AD brains, demonstrating the reliability of our in vitro model. Importantly, targeted interventions restored neuronal survival in a variant-specific manner: overexpression of the master regulator of lysosomal biogenesis, TFEB, rescued A673V neurons, while ferroptosis inhibition selectively protected KM670/671NL neurons. Overall, our results indicate that differential treatments can be tailored based on distinct genetic backgrounds, supporting the development of precision medicine approaches in AD.
    DOI:  https://doi.org/10.64898/2026.02.19.706886
  12. PLoS One. 2026 ;21(2): e0342333
    COX7A1-mediated mitochondrial dysfunction can induce ferroptosis in endometrial cancer cells.
    Qi Wu, Suning Bai, Liyun Song, Lina Han, Pei Wang.
      In endometrial cancer, research on ferroptosis is still in its nascent stages, yet its potential therapeutic value is becoming increasingly evident. We explore the impact of COX7A1 on mitochondrial dysfunction and ferroptosis in endometrial cancer. In this study, through comprehensive bioinformatics analysis, differentially expressed genes related to ferroptosis in endometrial cancer were identified. In vitro experiments were conducted using cytochrome c oxidase subunit 7A1 (COX7A1) overexpression and knockdown cell lines, followed by ferroptosis-related phenotypic assays to validate the effect of COX7A1 on the inhibition of endometrial cancer cell growth. Mechanistically, mitochondrial function-related parameters were assessed to explore the potential mechanisms by which COX7A1 induces ferroptosis. Online data analysis revealed that COX7A1 acts as a ferroptosis driver and is significantly downregulated in endometrial cancer tissues. In vitro experiments have demonstrated that overexpression of COX7A1 inhibits the proliferation of endometrial cancer cells and induces ferroptosis by regulating intracellular iron metabolism and mitochondrial function. The specific mechanisms include increasing intracellular Fe2+ and malondialdehyde (MDA) levels, decreasing the GSH/GSSG ratio, and disrupting mitochondrial membrane potential, thereby leading to mitochondrial dysfunction. Furthermore, COX7A1 overexpression significantly reduces the expression of glutathione peroxidase 4 (GPX4) and SLC7A11, while upregulating acyl-coenzyme A synthetase long-chain family member 4 (ACSL4). In contrast, knockdown of COX7A1 promotes the proliferation of endometrial cancer cells and inhibits ferroptosis, exhibiting the opposite effects. These findings provide new insights into the molecular mechanisms of endometrial cancer.
    DOI:  https://doi.org/10.1371/journal.pone.0342333
  13. J Colloid Interface Sci. 2026 Feb 16. pii: S0021-9797(26)00301-2. [Epub ahead of print]712 140124
    Proteoliposomes containing ATPase as microreactors to mimic microbial metabolism for bioenergy synthesis.
    Xuanze Meng, Yang Xu, Yi Jia, Rong Shu, Zibo Li, Junbai Li.
      Learning and imitating the inherent metabolic pathways of organisms in nature has emerged as a crucial approach to achieve artificial biomimetic synthesis of Adenosine triphosphate (ATP). We have constructed a biomimetic microreactor inspired by the ethanol metabolism pathway in microorganisms. The alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) loaded in the microreactor can catalyze the cascade reaction of ethanol to acetic acid. This proton-producing reaction is spatially coupled with the ATP synthase embedded in proteoliposomes, establishing a transmembrane proton gradient that drives ATP synthase to synthesize ATP. The generated ATP concentration can reach up to 6.3 μM within 30 min, which is rather high. The microreactors effectively reconstruct the core step of acetic fermentation process to convert chemical energy into bioenergy. This work demonstrates a novel and efficient route to transform low-value, readily available basic chemical products into universal biological energy carrier ATP, bypassing the need for intricate metabolic networks. Such a design provides a foundational model for understanding and engineering cellular metabolism.
    Keywords:  ATP synthase; Cascade reaction; Energy conversion; Nanoarchitecture; Supramolecular assembly
    DOI:  https://doi.org/10.1016/j.jcis.2026.140124
  14. J Cell Sci. 2026 Feb 27. pii: jcs.264392. [Epub ahead of print]
    UIP4 governs nuclear shape by modulating Saccharomyces cerevisiae lipidome.
    Pallavi Deolal, Bhaskar Das, Kathirvel Ramalingam, Amarthya Siddhartha, Reema Sahu, Krishnaveni Mishra.
      Cell survival under nutrient stress requires coordinated changes in metabolism and organelle function, yet the molecular mechanisms governing these adaptations remain poorly understood. In budding yeast, the protein Uip4 regulates nuclear morphology during the stationary phase, but its regulation and broader cellular roles are unknown. Here, we investigated how Uip4 expression is controlled and its effects on cellular homeostasis. We found that Uip4 expression is regulated by the transcription factor Msn2, downstream of Sch9 signalling, and responds to nutrient availability and energy state. Cells lacking Uip4 show poor stationary phase survival, dysregulated lipid profiles, and aberrant organelle morphology. These defects are rescued by overexpressing the lipin Pah1, indicating Uip4 functions in lipid homeostasis. Our findings reveal that such mechanisms linking nutrient signalling to lipid metabolism and organelle architecture are conserved, with implications for understanding cellular stress responses from yeast to humans.
    Keywords:  Lipid droplets; Mitochondria; Organelle contact; Stationary phase; Yeast
    DOI:  https://doi.org/10.1242/jcs.264392
  15. Nat Cell Biol. 2026 Feb 26.
    Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.
    Sandra Heinen, Vitasta Tiku, Alexander Grevel, Marie Hugenroth, Lars Ellenrieder, Isabelle Steymans, Mariya Licheva, Sara Bonini, Silke Oeljeklaus, Nicole Okon, Jessica Lambertz, Sylvia Poppe, Jiyao Song, Lars Fester, Chris Meisinger, Bettina Warscheid, Matthias Eckhardt, Nils Wiedemann, Dominic Winter, Claudine Kraft, Fabian den Brave, Maria Bohnert, Nikolaus Pfanner, Thomas Becker.
      Mitochondria play central roles in the energetics and metabolism of eukaryotic cells. Their outer membrane is essential for protein transport, membrane dynamics, signalling and metabolic exchange with other cellular compartments. The mitochondrial import (MIM) complex functions as main translocase for importing the precursors of more than 90% of integral outer-membrane proteins. Here we report that the MIM complex performs a second major function in lipid-droplet homeostasis. Lipid droplets are crucial in cellular lipid metabolism and as storage organelles for neutral lipids. The lipid metabolism enzyme Ayr1 captures the MIM complex, promoting the formation of mitochondria-lipid droplet contact sites. MIM and Ayr1 enhance the lipid droplet number in cells. Ayr1 binds to MIM via its single hydrophobic segment in a substrate-mimicry mechanism but remains bound and is not released into the outer membrane. The functional diversity is mediated by different MIM complexes: MIM-Ayr1 for recruiting lipid droplets and MIM-preprotein for protein insertion into the outer membrane. Our work uncovers translocase capture as a mechanism for functional conversion of a membrane protein complex from protein insertion to lipid metabolism.
    DOI:  https://doi.org/10.1038/s41556-026-01890-3
  16. Sci Adv. 2026 Feb 27. 12(9): eaeb0049
    Specific SLC25 carriers regulate mitochondrial protein synthesis.
    Danielle L Rudler, Laetitia A Hughes, Martin S King, Jessica Baker, Richard G Lee, Andrianto P Gandadireja, Anisha Sunil, Samuel V Fagan, Blake Payne, Nicola Gray, Tim McCubbin, Edmund R S Kunji, Oliver Rackham, Aleksandra Filipovska.
      A genome-wide knockout screen identified members of the SLC25 family of mitochondrial carrier proteins as important regulators of the rate of de novo mitochondrial protein synthesis. To elucidate this relationship, we generated human cell knockouts for SLC25A25, SLC25A44, SLC25A45, and SLC25A48, which have been shown to exchange adenosine triphosphate-magnesium (ATP-Mg) and phosphate, branched-chain amino acids, methylated basic amino acids, and choline, respectively. Multiomic and functional analyses identified that these four carriers are crucial for mitochondrial translation, biogenesis and function of the oxidative phosphorylation system, as well as mitochondrial morphology. Thermostability screens showed that SLC25A48 is specifically stabilized by choline, and changes in the mitochondrial metabolome and lipidome indicated defects in choline biosynthetic pathways and remodeling of mitochondrial membranes, both consistent with SLC25A48 being a choline transporter. These results highlight the essential roles of specific SLC25 transporters in maintaining mitochondrial structure and function and show that impaired transport of branched-chain amino acids, methylated basic amino acids, ATP-Mg, and choline affects mitochondrial translation.
    DOI:  https://doi.org/10.1126/sciadv.aeb0049
  17. Nat Commun. 2026 Feb 24.
    Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis.
    Chien Huang, Joo-Hyun Park, Ali Altıntaş, Natasa Stanic, Kristine Kyle de Leon, Signe Isacson, Panagiotis Kalogeropoulos, Hande Topel, Tobias Madsen, Sebastian Zanner, Phillip Mm Ruppert, Rocio Valdebenito, Jesper Havelund, Bjørk Ditlev Marcher Larsen, Yen-Ting Chien, Wen-Chi Huang, Yovita Permata Budi, Yi-Fan Jiang, Andréa Livia Rocha, Niedson Correia Lima-Junior, Karolina Szczepanowska, Jan-Wilm Lackmann, Aleksandra Trifunovic, Eva Kildall Hejbøl, Sönke Detlefsen, Ida Engberg Jepsen, Stefanie Hansborg Kolstrup, Ricardo Laguna-Barraza, Javier Martin-Gonzalez, Konstantin Khodosevich, Nils J Færgeman, Marcelo A Mori, Marc R Friedländer, Anita Öst, Romain Barrès, Jan-Wilhelm Kornfeld.
      Male obesity negative affects gametic function and offspring metabolism. We here describe that (F0) obesity and weight loss in male mice reversibly alter metabolism and impair adipose mitochondrial function. These metabolic aberrations are transmitted to male offsprings (F1), which display reduced mitochondrial gene expression. Mechanistically, we identify microRNAs let-7d/e as epigenetic mediators induced in obese F0 sperm and in F0/F1 adipose tissue, where they silence the miRNA processor DICER1 and impair mitochondrial activity. Microinjecting let-7d/e into lean zygotes phenocopies the paternal obesity phenotype, inducing glucose intolerance and mitochondrial gene suppression in sired offspring. Single-cell RNA sequencing of blastomeres reveals that let-7d/e impair oxidative metabolism in early embryos. Furthermore, lifestyle-induced weight loss in males with obesity downregulates human HSA-LET-7D/E in semen, indicating a conserved role for let-7 in transmission of metabolic health. These findings demonstrate that microRNA let-7 in sperm reprograms offspring metabolism by modulating mitochondrial function during early development.
    DOI:  https://doi.org/10.1038/s41467-026-69686-5
  18. bioRxiv. 2026 Feb 10. pii: 2026.02.07.704548. [Epub ahead of print]
    Targeting one-carbon metabolic vulnerabilities of metastasis with therapeutic potential.
    Yanlin Yu, Weiping Chen, Glenn Merlino.
      Evidence has shown that tumor progression is associated with the acquisition of growing autonomy and the creation of a complex signaling network through various signal pathways. Which particular signaling pathway is involved in the metastasis of a specific cancer is unclear. Here, we applied metastatic functional screening and identified that one-carbon and SSP metabolism pathways, as well as related genes, are associated with tumor metastasis inhibition. We engineered the cancer cells with poorly or highly metastatic potential to confirm the metabolism pathways regulating the ability to colonize different tissue sites. We also asked whether the restriction of the metabolism pathways by known inhibitors. We then identified three new compounds that can inhibit the expression of these genes and block tumor metastasis. Our findings uncovered a mechanism by which tumor cells reprogram their metabolism to promote migration, invasion, and survival at distant sites in tumor metastasis, offering a rational strategy to guide clinical treatment. The identified novel molecular proteins and pathways represent a promising therapeutic target for metastatic disease.
    DOI:  https://doi.org/10.64898/2026.02.07.704548
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