bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–03–08
fourteen papers selected by
Marc Segarra Mondejar, AINA
  1. Mitochondrial dynamics in neurodevelopment and neurodevelopmental disorders.
  2. Imaging and quantifying organelle contact sites using a reversible splitFAST complementation system.
  3. Lipid droplets meet mitochondria at the MIM protein insertase.
  4. Imaging intracellular lipid heterogeneity with fluorogen-activating coincidence encounter sensing.
  5. Glucose metabolism sustains aberrant STAT3 signaling in colorectal cancer through glycosylated local signaling factors.
  6. Unconventional model organisms bend our view on mitochondrial cristae.
  7. SLC4A1 mutations that cause distal renal tubular acidosis alter cytoplasmic pH and cellular autophagy.
  8. Function and regulation of the mitochondrial stress response.
  9. TIGAR regulates intestinal mucus barrier integrity by inhibiting lactylation of G6PD/6PGD in ulcerative colitis.
  10. Targeting tRNA-dependent tyrosine usage unveils a metabolic vulnerability in hepatocellular carcinoma.
  11. The lncRNA DAMER selectively guides m6A-dependent regulation of ATF4 and asparagine metabolism under nutrient stress in cancer.
  12. Dynein upsizes under load.
  13. Native chromatome profiling reveals hundreds of metabolic enzymes in the nucleus across tissues.
  14. Early-activated extracellular matrix proteins shape the metabolic and spatial dynamics of the kidney fibrotic microenvironment.
  1. Nat Rev Neurosci. 2026 Mar 04.
    Mitochondrial dynamics in neurodevelopment and neurodevelopmental disorders.
    Carissa L Sirois, Jiyoun Lee, Audrey L Chambers, Xinyu Zhao.
      Mitochondrial deficits have been found in individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). However, how mitochondria are regulated during brain development and how their dysregulation contributes to NDDs remains unclear. Mitochondria are continuously generated and degraded, dynamically remodelled through fusion and fission and actively transported to specific cellular compartments. Altered mitochondrial dynamics have been linked to several human diseases, and there is rising interest in their roles in neurodevelopment. However, most studies of mitochondrial contributions to NDDs have focused on the metabolic consequences of their dysfunction. This Review focuses on the mitochondrion itself, with particular emphasis on mitochondrial dynamics. We summarize recent advances in understanding the mechanisms that regulate mitochondrial dynamics during brain development and discuss how genetic and epigenetic alterations that affect mitochondrial dynamics contribute to NDDs. Finally, we consider mitochondrial dynamics as a potential therapeutic target for treatment of NDDs.
    DOI:  https://doi.org/10.1038/s41583-026-01031-7
  2. Methods Enzymol. 2026 ;pii: S0076-6879(25)00527-0. [Epub ahead of print]727 75-91
    Imaging and quantifying organelle contact sites using a reversible splitFAST complementation system.
    Jason A Weesner, Chi-Lun Chang.
      Organelle contact sites are crucial hubs for inter-organelle logistics; yet, visualizing these dynamic foci of sub-micro scale in living cells is challenging. In this chapter, we describe how to use the FABCON (Fluorogen-Activated Bimolecular complementation at CONtact sites) toolkit to detect and quantify contact sites. FABCON labels contact sites via a reversible, fluorogen-dependent complementation of the splitFAST system. This protocol first describes the engineering principle of FABCON, allowing customization to model systems of interest. Next, we provide detailed instructions for using FABCON to monitor mitochondria-lipid droplet interactions in mammalian cells and how to quantify levels of contact sites via intensity-based measurement and line scanning. FABCON can be broadly applied to visualize and quantify other contact sites. With proper validation and optimization, FABCON provides a robust platform to study the dynamic regulation of organelle contact sites.
    Keywords:  Bimolecular fluorescence complementation; Lipid droplets; Mitochondria; Organelle contact sites; SplitFAST
    DOI:  https://doi.org/10.1016/bs.mie.2025.11.023
  3. Nat Cell Biol. 2026 Mar 05.
    Lipid droplets meet mitochondria at the MIM protein insertase.
      
    DOI:  https://doi.org/10.1038/s41556-026-01901-3
  4. Methods Enzymol. 2026 ;pii: S0076-6879(25)00517-8. [Epub ahead of print]727 145-160
    Imaging intracellular lipid heterogeneity with fluorogen-activating coincidence encounter sensing.
    William M Moore, Itay Budin.
      Here we describe techniques for the implementation of fluorogen-activated coincidence sensing (FACES), a new chemical genetic tool for quantitatively imaging lipids in organelle membranes and reporting their transbilayer orientation in living cells. FACES combines bioorthogonal chemistry with genetically encoded fluorogen-activating proteins (FAPs) for reversible proximity sensing of fluorogen-conjugated azido-phospholipids in target membranes. Here, we provide and discuss method details and experimental considerations for the approach. We focus on the investigation of phosphatidylcholine in azido-choline fed HeLa cells, but the techniques described are broadly applicable to other biomolecules labeled with azido-metabolites in live cells.
    Keywords:  Bioorthogonal chemistry; Biosensing; Click chemistry; Fluorogen-activating protein; Lipid imaging
    DOI:  https://doi.org/10.1016/bs.mie.2025.11.015
  5. Sci Signal. 2026 Mar 03. 19(927): eadz6443
    Glucose metabolism sustains aberrant STAT3 signaling in colorectal cancer through glycosylated local signaling factors.
    Kathryn Buscher, Kelsey Temprine, Christopher Mays, Noora Aabed, Samuel A Kerk, Hannah N Bell, Joseph A Nieto Carrion, Harrison S Greenbaum, Zheng Hong Lee, Varun Ponnusamy, Sadeesh K Ramakrishnan, Costas A Lyssiotis, Xiang Xue, Yatrik M Shah.
      The JAK-STAT3 signaling pathway is a key driver of colorectal cancer (CRC) progression. STAT3 is a transcription factor that is canonically activated by cytokines, such as IL-6, in a transient manner because of negative feedback mechanisms. However, STAT3 is aberrantly and persistently activated in CRC, promoting tumor cell proliferation and survival. Here, we demonstrated that glucose sustained STAT3 activation independently of cytokine availability. We manipulated glucose metabolism, which showed that both glucose and its downstream metabolite GlcNAc were essential to maintain STAT3 activation. Moreover, cells with high basal STAT3 activity produced proteins that were glycosylated in a glucose-dependent manner and that activated STAT3 in neighboring cells through paracrine signaling. Proteomic analysis identified multiple candidate proteins involved in this process; however, no single protein was sufficient to fully activate STAT3, suggesting that this activation process requires several glycosylated proteins. In a syngeneic mouse model of CRC, inhibition of glycolysis reduced STAT3 activation in tumors, and genetic deletion of STAT3 substantially decreased tumor growth. Together, these findings show how glucose metabolism supports sustained STAT3 activation in CRC, highlighting a potential metabolic vulnerability for therapeutic targeting.
    DOI:  https://doi.org/10.1126/scisignal.adz6443
  6. J Cell Sci. 2026 Mar 01. pii: jcs264310. [Epub ahead of print]139(5):
    Unconventional model organisms bend our view on mitochondrial cristae.
    Silvia Tassan-Lugrezin, Silje A C A Debets, Laura van Niftrik, Taco W A Kooij, Irina Bregy.
      Cristae, convolutions of the inner mitochondrial membrane, provide an extended surface area for respiratory chain complexes and ATP synthases. Crista structure has been extensively researched in opisthokont model organisms, such as yeast and various animals; however, the vast majority of eukaryotic cristae diversity has been largely unexplored. Here, we provide a comprehensive overview of crista formation and maintenance in Euglenozoa and Alveolata, two highly divergent eukaryotic clades that include parasites of clinical and veterinary importance. Within these clades, cristae have been studied primarily in the kinetoplastid Trypanosoma brucei and the apicomplexan Toxoplasma gondii. We also discuss the apicomplexan Plasmodium falciparum, the deadliest human parasite and etiological agent of malaria, in which de novo formation of cristae occurs naturally following an apparently acristate life cycle stage. We compare findings from these divergent and disease-relevant organisms with those from more traditional model organisms, highlighting conserved and unique traits across the eukaryotic kingdom. In this Review, we focus on the roles of three key players in crista curvature - ATP synthase, the mitochondrial contact site and cristae organizing system (MICOS) and cardiolipin, a lipid specific to the inner mitochondrial membrane. By comparing distantly related organisms, we synthesize a broadly applicable model of the general principles of crista formation.
    Keywords:   Plasmodium falciparum ; Toxoplasma gondii ; Trypanosoma brucei ; ATP synthase; Apicomplexa; Cardiolipin; Kinetoplastida; MICOS; Mitochondrial cristae
    DOI:  https://doi.org/10.1242/jcs.264310
  7. Elife. 2026 Mar 04. pii: RP108253. [Epub ahead of print]14
    SLC4A1 mutations that cause distal renal tubular acidosis alter cytoplasmic pH and cellular autophagy.
    Grace Essuman, Midhat Rizvi, Ensaf Almomani, Shahid A K M Ullah, Sarder M A Hasib, Forough Chelangarimiyandoab, Priyanka Mungara, Manfred J Schmitt, Marguerite Hureaux, Rosa Vargas-Poussou, Nicolas Touret, Emmanuelle Cordat.
      Distal renal tubular acidosis (dRTA) is a disorder characterized by the inability of the collecting duct system to secrete acids during metabolic acidosis. The pathophysiology of dominant or recessive SLC4A1 variant-related dRTA has been linked with the mis-trafficking defect of mutant kAE1 protein. However, in vivo studies in kAE1 R607H dRTA mice and humans have revealed a complex pathophysiology implicating a loss of kAE1-expressing intercalated cells and intracellular relocation of the H+-ATPase in the remaining type-A intercalated cells. These cells also displayed accumulation of ubiquitin and p62 autophagy markers. The highly active transport properties of collecting duct cells require the maintenance of cellular energy and homeostasis, a process dependent on intracellular pH. Therefore, we hypothesized that the expression of dRTA variants affects intracellular pH and autophagy pathways. In this study, we report the characterization of newly identified dRTA variants and provide evidence of abnormal autophagy and degradative pathways in mouse inner medullary collecting duct cells and kidneys from mice expressing kAE1 R607H dRTA mutant protein. We show that reduced transport activity of the kAE1 variants correlated with increased cytosolic pH, reduced ATP synthesis, attenuated downstream autophagic pathways pertaining to the fusion of autophagosomes and lysosomes and/or lysosomal degradative activity. Our study elucidated a close relationship between the expression of defective kAE1 proteins, reduced mitochondrial activity, and decreased autophagy and protein degradative flux.
    Keywords:  cell biology; kidney; mouse; transgenic animals
    DOI:  https://doi.org/10.7554/eLife.108253
  8. Nat Struct Mol Biol. 2026 Mar 05.
    Function and regulation of the mitochondrial stress response.
    Joshua B Sheetz, Srividya Chandrasekhar, Michael Rapé.
      As mitochondria have crucial roles in metabolism and signaling, their structure and function must be continuously monitored and rapidly adjusted to meet cellular demands. Critical to this regulation is a conserved stress response that detects and alleviates challenges to mitochondrial integrity. Recent work has shown that mitochondrial stress often elicits simultaneous protective reactions that act in a coordinated and tightly regulated fashion to preserve this essential organelle. Here we review components, coordination and control within this comprehensive stress response and discuss how increased understanding of mitochondrial stress signaling is beginning to inform therapeutic approaches directed against diseases of high unmet need.
    DOI:  https://doi.org/10.1038/s41594-026-01769-9
  9. Nat Commun. 2026 Mar 03.
    TIGAR regulates intestinal mucus barrier integrity by inhibiting lactylation of G6PD/6PGD in ulcerative colitis.
    Dan Wu, Sen Su, Panyang Zhang, Xule Zha, Yan Wei, Ting Zhang, Xiaoyan Liu, Qian Chen, Chunyan Li, Qianying Huang, Zhihao Zhou, Yan Yang, Lin Xia, Shijun Fan, Xi Peng.
      Oxidative stress and metabolic dysregulation in goblet cells are pivotal in ulcerative colitis (UC) pathogenesis. TIGAR promotes the synthesis of NADPH and contributes to mitigate oxidative stress, but how it regulates NADPH production and affects UC remains unclear. Here we demonstrate that TIGAR inhibits lactylation of the key NADPH-synthesizing enzymes G6PD (at K432) and 6PGD (at K38), thereby preserving their enzymatic activities by promoting G6PD homodimer formation and 6PGD binding to NADP+. In male UC mice, persistently low TIGAR expression elevates lactate levels, promoting the lactylation of G6PD and 6PGD and impairing their function. This process suppresses NADPH synthesis, exacerbating goblet cell oxidative stress. The resulting decline in Trx1 reductase activity induces S-nitrosylation of the mucin-processing enzyme AGR2, thereby inhibiting mature MUC2 production and compromising the intestinal mucus barrier. Our findings elucidate a mechanistic pathway through which TIGAR maintains cellular redox homeostasis, presenting it as a potential therapeutic target for UC.
    DOI:  https://doi.org/10.1038/s41467-026-70263-z
  10. Nat Commun. 2026 Mar 06. pii: 2244. [Epub ahead of print]17(1):
    Targeting tRNA-dependent tyrosine usage unveils a metabolic vulnerability in hepatocellular carcinoma.
    Hongli Zhang, Zixuan Wang, Yiqi Zhao, Xiya Deng, Jian Zhang, Fei Shang, Hongjie Zhang, Yan Liu, Hongbo Wang, Yating Yang, Huiyu Lin, Bo Zhang, Ce Liu, Fan Guo, Ruolin Zhang, Qipeng Yuan, Yue Feng, Shi-Zhong Luo, Wei-Dong Chen, Yan-Dong Wang.
      Cancer cells reprogramme translation and metabolism to fuel tumorigenesis. Here, we show that hepatocellular carcinoma (HCC) paradoxically maintains low tyrosine levels despite increased uptake and reduced metabolism, redirecting tyrosine to translation via MYC-driven upregulation of tyrosyl-tRNA synthetase 1 (YARS1) and tRNA-TyrGUA. Restricting tyrosine translation availability (RTTA) via dietary limitation, YARS1/tRNA-TyrGUA ablation, tyrosine degradation (TAL), or YARS1 inhibition (tyrosinol) disturbs this adaptation, leading to the mitigation of tumorigenesis and extension of survival. Mechanistically, RTTA reduces tyrosine codon-dependent translation of mitochondrial complex I subunit NDUFB8 and lipid regulator SCD1, causing complex I misassembly, oxidative phosphorylation failure, and lipid peroxidation-induced ferroptosis. Genome-wide CRISPR screening identifies that loss of GPX4 and BCL2 by genetic manipulation or pharmacological treatment enhances the ability of RTTA to inhibit hepatocellular carcinogenesis. Our findings establish RTTA as a therapeutic strategy targeting tyrosine dependency and highlight combinatorial targeting of translation-metabolism crosstalk and ferroptosis pathways in liver cancer.
    DOI:  https://doi.org/10.1038/s41467-026-70112-z
  11. Nat Cell Biol. 2026 Mar 06.
    The lncRNA DAMER selectively guides m6A-dependent regulation of ATF4 and asparagine metabolism under nutrient stress in cancer.
    Tianyu Tao, Xianming Feng, Yi Yang, Bangdong Liu, Jiaer Liang, Zishuo Chen, Shuqi Wang, Jiaqi Zhao, Xiuxiu Yang, Liyun Huo, Youhong Zhang, Zhen Gan, Weibin Wu, Jiayu Zeng, Yi Huang, Yaokai Ye, Xuemei Xu, Jianchen Yu, Ruohui Hong, Hongyu Guan, Jueheng Wu, Laixin Xia, Weiling He, Bo Li, Junchao Cai, Mengfeng Li.
      How cancer cells couple metabolic stress sensing to orchestrate specific survival programmes is a key question. Here we show a long non-coding RNA (lncRNA)-guided epitranscriptomic mechanism orchestrating metabolic adaptation by controlling the stability of master stress regulator ATF4. Glucose or glutamine deprivation induces endoplasmic reticulum stress via reactive oxygen species-NRF2-dependent transcription of the lncRNA DAMER. Following its demethylation and nuclear retention by the m6A-eraser ALKBH5, DAMER acts as a scaffold, guiding ALKBH5 to demethylate and stabilize ATF4 mRNA through specific base-pairing. This provides an alternative post-transcriptional pathway for ATF4 upregulation, rewiring asparagine metabolism to promote cancer cell survival under stress. Furthermore, we identified the US FDA-approved drug elbasvir as a potent inhibitor of the DAMER-ALKBH5 interaction. Elbasvir dismantles this adaptive programme, targeting tumour asparagine dependency and exhibiting potent antitumour effects in preclinical models. Our findings reveal a paradigm for lncRNA-guided RNA demethylation that solves a target specificity enigma and offers a strategy targeting metabolic adaptation in cancer.
    DOI:  https://doi.org/10.1038/s41556-026-01905-z
  12. Nat Cell Biol. 2026 Mar 02.
    Dynein upsizes under load.
    Andrew Hensley, Morgan E DeSantis.
      
    DOI:  https://doi.org/10.1038/s41556-026-01875-2
  13. Nat Commun. 2026 Mar 06. pii: 1655. [Epub ahead of print]17(1):
    Native chromatome profiling reveals hundreds of metabolic enzymes in the nucleus across tissues.
    S Kourtis, A Gañez Zapater, C R Elbæk, A Schmidt, R Ghose, A Coll Manzano, L Espinar Calvo, M Guirola, N Pardo-Lorente, M Garcia-Cao, M Pfeiffer, S Haynes, F Fontaine, A Müller, S Sdelci.
      Metabolic and epigenetic rewiring are hallmarks of cancer, with increasing evidence suggesting crosstalk between these processes. While previous studies have hinted at the role of metabolic enzymes in the nucleus, the extent and functional relevance of their nuclear localization remain unclear. In this study, we present a comprehensive chromatome proteomic analysis across cancer lineages and healthy samples, revealing that metabolic enzyme moonlighting on chromatin is widespread across various tissues and metabolic pathways. We show that the abundance of metabolic enzymes on chromatin is tissue-specific, with oxidative phosphorylation proteins notably depleted in lung cancer, suggesting a link between nuclear metabolism and cell identity. Further, we explore the dynamic chromatin association of one-carbon folate enzymes, demonstrating their involvement in DNA damage and repair processes. Finally, we asked whether restricting metabolic enzymes to specific subcellular compartments rewires the transcriptome, thereby decoupling the observed transcriptional changes from mere metabolite diffusion. Our findings propose and validate novel non-canonical nuclear roles for several metabolic enzymes, providing new insights into the functional relationship between metabolism and chromatin regulation. This study underscores the hypothesis that the nucleus is populated by metabolic enzymes, offering new avenues for understanding how nuclear metabolism impacts chromatin function and cancer progression.
    DOI:  https://doi.org/10.1038/s41467-026-69217-2
  14. Nat Metab. 2026 Mar 03.
    Early-activated extracellular matrix proteins shape the metabolic and spatial dynamics of the kidney fibrotic microenvironment.
    Yuan Gui, Wenxue Li, Jia-Jun Liu, Yuanyuan Wang, Cameron Jones, Riddhi Bansal, Samantha Mae Mallari, Henry Wells Shaffer, Yanbao Yu, Haiyan Fu, Tracy T Tang, Silvia Liu, Yansheng Liu, Dong Zhou.
      The fibrotic kidney microenvironment is shaped by cellular crosstalk, extracellular matrix (ECM) remodelling, metabolic reprogramming and spatial heterogeneity. While late-stage ECM changes dominate fibrosis, the role of early-activated matrix proteins remains unclear. Here we show that ECM1 is an early regulator of kidney remodelling. Global Ecm1 knockout mice develop spontaneous fibrosis and early death, whereas ECM1 levels markedly increase in biofluids during chronic kidney disease. Targeting Ecm1 through AAV9-mediated knockdown or fibroblast-specific deletion substantially reduces renal fibrosis. Mechanistically, Ecm1 deletion disrupts the integrin α2β1-RhoC axis, suppressing YAP activity. Reduced YAP nuclear translocation and diminished YAP-TEAD4 complex formation relieve TEAD4-mediated repression of Pgc1a, enhancing mitochondrial oxidative phosphorylation (OXPHOS) and promoting repair. Spatial transcriptomics and proteomics confirm this mechano-metabolic pathway, revealing mitochondrial reprogramming in tubules that counteracts fibrotic progression. Notably, YAP inactivation in fibroblasts limits aberrant activation without impairing their OXPHOS. This selective ECM-mitochondrial crosstalk uncovers a mechano-metabolic pathway in which mitochondrial shifts drive defence against kidney fibrosis.
    DOI:  https://doi.org/10.1038/s42255-026-01458-3
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