bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–09–06
seventeen papers selected by
Marc Segarra Mondejar, AINA
  1. NAD+ precursor treatment prevents cardiomyopathy but disrupts erythroid maturation in mitochondrial progeria.
  2. Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.
  3. Assessing cellular metabolic dynamics with two-photon NAD(P)H fluorescence polarization microscopy.
  4. Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.
  5. Lactate suppresses STING activation to promote tumor immune evasion.
  6. Western Blot Analysis of Microtubule-Associated Protein Light Chain 3 to Monitor Autophagosomal Dynamics in Mouse-Derived Pancreatic Cancer Cells.
  7. Fructose induces PERK-dependent ER stress and mitochondrial dysfunction via nucleotide depletion in clear cell renal cell carcinoma.
  8. Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis.
  9. "Trojan" Methionine Probe Reveals PKM2 as a Methionine-Sensing Protein in the mTORC1 Pathway.
  10. ATP13A4 gates extracellular polyamine levels to control excitatory synaptogenesis.
  11. Maternal metabolic stress regulates progeny intestinal stem cell niche signaling through heritable changes in redox metabolites.
  12. Design and structural basis of selective nonsteroidal inhibitors of aster cholesterol trafficking.
  13. H3K18 Lactylation Promotes Cell Proliferation in T-Cell Acute Lymphoblastic Leukemia.
  14. Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.
  15. Mitochondrial calcium, a potential sensor for homeostatic synaptic plasticity.
  16. Metabolite buffering of labile iron governs ferroptosis.
  17. A Fluorescent RNA-Based Genetically Encoded Mg2+ Sensor Allows Robust Detection of Mg2+ in Live Cells.
  1. Cell Rep. 2026 Aug 29. pii: S2211-1247(26)00927-7. [Epub ahead of print]45(9): 117849
    NAD+ precursor treatment prevents cardiomyopathy but disrupts erythroid maturation in mitochondrial progeria.
    Nahid A Khan, Kati Ahlqvist, Swagat Pradhan, Juan Landoni, Christopher Jackson, Aleksandra Zhaivoron, Riikka Kivelä, Liliya Euro, Anu Suomalainen.
      Nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, and its decline is linked to various degenerative diseases. While NAD+ restoration holds therapeutic promise, its long term, tissue-specific consequences remain poorly understood. We investigated effects of nicotinamide riboside (NR) supplementation for "mutator" mice manifesting mitochondrial progeria. Our results reveal strikingly divergent outcomes: in proliferative bone marrow, NR-treated mutators show reductive stress with accumulation of NADH/NADPH, altered amino acid, nucleotide, folate levels, and impaired heme biosynthesis. In blood, erythrocyte maturation defects are aggravated, exacerbating anemia. Conversely, in postmitotic cardiac tissue, NR enhanced contractility, reduces stress response markers and normalized metabolic profile. These findings indicate that while beneficial for heart, chronic NAD+ boosting can compromise erythrocyte maturation in the context of mitochondrial disease. The data emphasize importance of evaluating systemic effects of NAD+ boosting therapies beyond the primary affected tissues and development of tissue-specific metabolic interventions for degenerative diseases.
    Keywords:  CP: metabolism; NAD(+) metabolism; anemia; erythropoiesis; metabolism; mitochondria; post mitotic tissues; progeria
    DOI:  https://doi.org/10.1016/j.celrep.2026.117849
  2. J Clin Invest. 2026 Sep 01. pii: e199847. [Epub ahead of print]136(17):
    Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.
    Bishal Basak, Julia F Riley, Neha M Nataraj, Erika Lf Holzbaur.
      Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson's disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evolved to eliminate aged or damaged mitochondria. One such quality control process is autophagy, a process that involves turnover of mitochondria at presynaptic sites and the axon terminal under basal conditions. This highly conserved mechanism sequesters mitochondria from the cytosol within autophagosomes followed by degradation upon fusion with a lysosome. Acute mitochondrial damage activates a selective form of autophagy called mitophagy that involves receptor-mediated engulfment and degradation of the damaged organelle. Multiple mechanisms have been shown to drive efficient mitophagy in neurons and glia, including PTEN induced kinase 1 (PINK1)/Parkin-dependent mitophagy and receptor-mediated mitophagy. Genetic, pathological, and experimental evidence all implicate defects in the removal of damaged mitochondria in the onset or progression of neurodegenerative disease. Both the initiation of PINK1/Parkin-dependent mitophagy and deficits in the removal of damaged mitochondria are linked to activation of neuroinflammatory pathways, including NF-κB and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. In this Review, we discuss the molecular pathways governing mitophagy in neurons and glial cells and how deficits in these pathways may lead to neurodegeneration. We also highlight emerging therapeutic strategies aimed at restoring mitophagy to preserve neuronal homeostasis and function.
    DOI:  https://doi.org/10.1172/JCI199847
  3. Sci Adv. 2026 Sep 04. 12(36): eaed6844
    Assessing cellular metabolic dynamics with two-photon NAD(P)H fluorescence polarization microscopy.
    Lu Ling, Jack C Crowley, Matthew L Tan, Jennie A M R Kunitake, Adrian A Shimpi, Rebecca M Williams, Lara A Estroff, Claudia Fischbach, Warren R Zipfel.
      Altered metabolism enables adaptive advantages for cancer cells, driving the need for improved methods for noninvasive long-term monitoring of cellular metabolism. Here, we present a fast live-cell NADH imaging method that provides a real-time measurement of the fractional level of unbound NADH and show that it is a robust indicator of a cell's metabolic status. The method, two-photon fluorescence polarization ratiometric microscopy (FPRM), is easy and inexpensive to implement and more than an order of magnitude faster than fluorescence lifetime imaging microscopy (FLIM), a common means of assessing bound and unbound NADH levels. We show that FPRM returns instrument-independent ratiometric parameters that correlate with the expected metabolic changes arising from pharmaceutical and environmental perturbations. By correlating FPRM-returned parameters with cell morphology and migration in two- and three-dimensional collagen matrices, we demonstrate the technique's versatility in typical bioengineered platforms used in cancer metabolism research.
    DOI:  https://doi.org/10.1126/sciadv.aed6844
  4. Cell Rep Med. 2026 Aug 31. pii: S2666-3791(26)00432-5. [Epub ahead of print] 103015
    Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.
    Ozge Saatci, Burge Ulukan, Metin Cetin, Hellen Kuasne, Constanza Martinez, Elif Percin, Natalia Oleinik, Matthew T Savoca, Ali Nehme, Aldo Hernández-Corchado, Evelyn Zavacky, Kukkamudi Sreenivas, Abdol H Rezaeian, Jennifer R Bethard, Jean-Sebastien Anoma, Ozlem Sener Sahin, Adriana Aguilar-Mahecha, Marguerite Buchanan, Mertkaya Aras, Genevieve DeBlois, Mark Basik, Elizabeth G Hill, Lauren E Ball, Chintada Nageswara Rao, Campbell McInnes, Yasser Riazalhosseini, Hamed S Najafabadi, John J Lemasters, Besim Ogretmen, Morag Park, Ozgur Sahin.
      High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.
    Keywords:  DHODH; LOX; MERCS; TNBC; ferroptosis; glucose metabolism; lysyl oxidase; mitochondria-ER contacts; mitophagy
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103015
  5. Cell Metab. 2026 Sep 01. pii: S1550-4131(26)00333-5. [Epub ahead of print]38(9): 1744-1745
    Lactate suppresses STING activation to promote tumor immune evasion.
    Yuan Tian, Xin Cai.
      Lactate, known for its metabolic functions, has recently emerged as a signaling molecule. In a recent issue of Immunity, Guo and colleagues report that lactate is a competitive antagonist of STING and propose an epidermal growth factor receptor (EGFR)-mediated signaling cascade that enhances lactate dehydrogenase A (LDHA) activity, lactate production, and immunosuppression.1.
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.008
  6. J Vis Exp. 2026 Sep 03.
    Western Blot Analysis of Microtubule-Associated Protein Light Chain 3 to Monitor Autophagosomal Dynamics in Mouse-Derived Pancreatic Cancer Cells.
    Felipe J Renna, Raul Mostoslavsky, Maria I Vaccaro.
      Autophagy plays a complex role in pancreatic ductal adenocarcinoma (PDAC), contributing to tumor progression, stress adaptation, and therapy resistance. Accurate assessment of autophagosomal dynamics is therefore essential for studies of cancer biology. Among the available methods, immunoblotting of microtubule-associated protein light chain 3 (LC3) is widely used to monitor autophagosomal dynamics by distinguishing between the cytosolic (LC3-I) and lipidated, autophagosome-associated (LC3-II) forms. However, the low molecular weight of LC3 and the minimal difference in electrophoretic mobility between these isoforms present technical challenges that require careful optimization. Presented here is a reproducible protocol for the semi-quantitative analysis of LC3-II levels by Western blot in KPC-derived murine pancreatic cancer cells. The method incorporates optimized conditions for cell lysis, electrophoresis, protein transfer, and antibody-based detection to ensure reliable separation and detection of LC3 isoforms. In addition, a standardized workflow for densitometric analysis of LC3-II bands using Fiji (ImageJ) is provided. The sensitivity of the method is demonstrated through the detection of increased LC3-II levels under conditions of autophagy induction (gemcitabine treatment) and impaired autophagic flux (VMP1 knockdown). Critical technical parameters that influence data interpretation, including lysis buffer composition and antibody specificity, are also examined, together with common experimental pitfalls. Although LC3 immunoblotting alone is insufficient to fully define autophagic flux, when combined with complementary assays it provides a robust and accessible approach for monitoring autophagic activity. The protocol can be adapted to other experimental contexts, facilitating mechanistic studies of autophagy in cancer models.
    DOI:  https://doi.org/10.3791/71604
  7. Cell Death Dis. 2026 Aug 07. pii: 766. [Epub ahead of print]17(1):
    Fructose induces PERK-dependent ER stress and mitochondrial dysfunction via nucleotide depletion in clear cell renal cell carcinoma.
    Na Li, Yanhong Ding, Bowen Yu, Yongqiang Wang, Tongbin Gao, Huiyong Yin, Zhenhua Li, Shuzhen Liu, Guohua Yu, Ningning Wang.
      Clear cell renal cell carcinoma (ccRCC) exhibits a paradoxical fructose metabolism signature characterized by upregulation of the fructose transporter GLUT5 alongside downregulation of the catabolic enzymes (ketohexokinase, aldolase B, and triokinase), a pattern associated with poor prognosis. Functionally, unlike the pro-survival effect of fructose under glucose deprivation, in the presence of glucose, fructose co-treatment suppresses ccRCC cell proliferation, and induces profound mitochondrial dysfunction, including impaired oxidative phosphorylation, loss of membrane potential, excessive mitochondrial superoxide production, reduced mtDNA copy number, and downregulation of mitochondria-encoded electron transport chain subunits (notably ND2 and ND4 of complex I). Mechanistically, co-treatment with glucose and fructose creates a metabolic trap resulting in fructose-1-phosphate accumulation and ATP depletion. This energy crisis drives profound depletion of purine and pyrimidine nucleotide pools, which selectively triggers the PERK-eIF2S1-ATF4-CHOP axis of the integrated stress response, thereby mediating mitochondrial impairment and ultimately sensitizing ccRCC cells to intrinsic apoptosis via BID cleavage and caspase-3 activation under nutrient stress. Pharmacological treatment with the chemical chaperone 4-phenylbutyric acid (4-PBA) or nucleoside supplementation reverses mitochondrial dysfunction and fructose-induced cytotoxicity. The tumor-suppressive effect of fructose is validated in patient-derived organoids and xenograft mouse models, where fructose administration significantly attenuates tumor growth via ER stress. These findings reveal fructose-driven nucleotide depletion and PERK-dependent ER stress leading to mitochondrial dysfunction, which underlies the tumor-suppressive toxicity of fructose and exposes a targetable metabolic vulnerability in ccRCC.
    DOI:  https://doi.org/10.1038/s41419-026-09157-3
  8. Elife. 2026 Sep 02. pii: RP106976. [Epub ahead of print]14
    Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis.
    Marisa J Brothwell, Guoshen Cao, J Alan Maschek, Annelise M Poss, Alek D Peterlin, Liping Wang, Talia B Baker, Justin L Shahtout, Piyarat Siripoksup, Quentinn J Pearce, Jordan M Johnson, Fabian M Finger, Alexandre Prola, Sarah A Pellizzari, Gillian L Hale, Allison M Manuel, Shinya Watanabe, Edwin R Miranda, Kajsa E Affolter, Trevor S Tippetts, Linda S Nikolova, Ran Hee Choi, Stephen T Decker, Mallikarjun Patil, J Leon Catrow, William L Holland, Sara M Nowinski, Daniel S Lark, Kelsey H Fisher-Wellman, Patrice N Mimche, Kimberley Evason, James E Cox, Scott A Summers, Zach Gerhart-Hines, Katsuhiko Funai.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to metabolic dysfunction-associated steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, mitochondrial cardiolipin (CL) was downregulated with MASLD/MASH in humans and in mice. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous and robust MASH with extensive steatotic and fibrotic phenotype. Loss of CL paradoxically increased mitochondrial respiratory capacity but also promoted electron leak primarily at sites IIIQO and IIF of the electron transport chain (ETC), reduced the formation of I + III2 + IV respiratory supercomplex, and disrupted the propensity of coenzyme Q to become reduced. Thus, low mitochondrial CL disrupts the ETC to promote oxidative stress and contributes to the pathogenesis of MASH.
    Keywords:  cardiolipin; cell biology; human; liver; mitochondria; mouse
    DOI:  https://doi.org/10.7554/eLife.106976
  9. J Am Chem Soc. 2026 08 26. 148(33): 35538-35550
    "Trojan" Methionine Probe Reveals PKM2 as a Methionine-Sensing Protein in the mTORC1 Pathway.
    Zixin Sang, Yiqiang Zheng, Xia Wang, Cang Wu, Jiaqi Zhao, Jun Joelle Wang, Senfang Sui, Jie Wang.
      Methionine (Met) plays a pivotal role in numerous cellular functions. Methionine restriction has been demonstrated to provide metabolic benefits in aging, obesity, diabetes and as an adjunct to cancer therapy. However, the methionine-sensing proteins and how cells directly sense the methionine level have remained elusive. In this study, we developed a photoaffinity analogue of methionine to capture proteins that specifically recognize and sense methionine in living cells. Using chemoproteomic profiling and biochemical validation, we found that PKM2 is a specific methionine sensor that transduces methionine availability signals through the interaction with the GATOR2 complex, which, in turn, modulates the downstream response of the mTORC1 pathway through a novel methionine-recognition pocket on PKM2. As our findings indicate that the sensing of methionine by PKM2 is independent of its enzymatic activity, we envision that disrupting the binding of methionine to PKM2 or stabilizing the PKM2-GATOR2 interaction would create a methionine pseudostarvation state in living cells, which holds promise as a novel therapeutic avenue that could emulate the physiological benefits of a methionine-restricted diet and circumvent the drawbacks of dietary methionine restriction.
    DOI:  https://doi.org/10.1021/jacs.6c06772
  10. Nat Commun. 2026 08 04. pii: 9395. [Epub ahead of print]17(1):
    ATP13A4 gates extracellular polyamine levels to control excitatory synaptogenesis.
    Sarah van Veen, Emily Meeus, Dolores Irala, Kristina Sakers, Zhaolin Liu, Justin Savage, Gabrielle Séjourné, Dhanesh Sivadasan Bindu, Elke Ausloos, Hanna Elzbieta Grzesik, Hanne Dhondt, Nina Schoonvliet, Chris Van den Haute, Joris Van Asselberghs, Marta Montpeyó Garcia-Moreno, Keimpe Wierda, Veerle Baekelandt, Konrad Platzer, Kevin Rostasy, Kai Lee Yap, Jan Eggermont, Matthew G Holt, Cagla Eroglu, Peter Vangheluwe.
      Polyamines, such as spermidine, are essential regulators of brain development, yet how cells control their uptake and extracellular levels remains unclear. Here we show that ATP13A4, a transport protein enriched in glia and prominently expressed in astrocytes, governs brain polyamine balance. Using biochemical, cellular, and animal models, we find that ATP13A4 imports polyamines into cells and thereby limits their availability outside cells. Loss of ATP13A4 simplifies astrocyte morphology and increases the excitatory connections, or synapses, that astrocytes promote between neurons; adding spermidine reproduces these effects, identifying extracellular spermidine as a synapse-promoting signal. In mice lacking Atp13a4, brain polyamines are redistributed, with reduced levels in the cortex and accumulation in cerebrospinal fluid. This is accompanied by excess excitatory synapses, delayed early development, and mild, female-biased behavioral changes in adulthood. Rare ATP13A4 variants linked to neurodevelopmental disorders disrupt its function. Thus, astrocytic polyamine clearance via ATP13A4 tunes extracellular spermidine to shape synapse formation during development.
    DOI:  https://doi.org/10.1038/s41467-026-76132-z
  11. Nat Commun. 2026 08 03. pii: 9338. [Epub ahead of print]17(1):
    Maternal metabolic stress regulates progeny intestinal stem cell niche signaling through heritable changes in redox metabolites.
    Helin Hocaoglu, Shenlu Qin, Leah Eller, Farhan Abu, Benjamin Ohlstein, Lei Wang, Matthew H Sieber.
      Maternal metabolic stress is a major determinant of progeny health and disease susceptibility, yet the mechanisms linking germline metabolism to lifelong changes in tissue physiology remain poorly defined. Here, we show that maternal metabolic stress alters the cellular composition of the progeny intestinal epithelium through a conserved metabolic pathway. Germline metabolic dysfunction depletes NAD⁺ in mature oocytes, reprogramming progeny redox metabolism and impairing the methionine cycle. This metabolic shift reduces protein levels of the Notch ligand Delta, disrupting intestinal stem cell niche signaling and altering progeny intestinal physiology. Across insect and mammalian models, our findings reveal that maternal metabolic health has conserved effects on progeny metabolism and intestinal function. Together, this work identifies heritable redox-metabolic changes as a mechanistic link between maternal metabolic stress, stem cell regulation, and intestinal disease susceptibility.
    DOI:  https://doi.org/10.1038/s41467-026-76249-1
  12. Proc Natl Acad Sci U S A. 2026 Sep 08. 123(36): e2617638123
    Design and structural basis of selective nonsteroidal inhibitors of aster cholesterol trafficking.
    Hyunsoo Kim, Beatriz Romartinez-Alonso, Xu Xiao, Yajing Gao, John Paul Kennelly, Alessandra Ferrari, Rui Li, Liujuan Cui, Emily Whang, John W R Schwabe, Michael E Jung, Peter Tontonoz.
      Aster proteins (Aster-A, -B, and -C) are crucial for transporting cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER). Asters are expressed in a cell type-specific manner across tissues. Their global disruption leads to varied physiological outcomes given the diverse roles of cholesterol throughout the body. We previously identified sterol analogs, such AI-3d, that inhibit all three Aster proteins. However, their utility is limited by toxicity and off-target effects. Here, we report the development of nonsteroidal Aster inhibitors that are active in cells and in vivo, using binding-guided design to generate compounds with isoform-selective affinities. We found that YKJ-124 is a low-toxicity, Aster-A-preferring inhibitor that elevates PM-accessible cholesterol in primary T cells and potentiates store-operated Ca2+ entry in Th17 cells, phenocopying Aster-A deficiency. YKJ-300 and YKJ-305 selectively target Aster-C; cocrystal structures and point mutation studies reveal a Ser477-dependent hydrogen bond (Gly in Aster-A/B) that underlies this specificity. We also explored the in vivo consequences of pharmacologic Aster-C inhibition. YKJ-305 treatment of mice blunted fasting-induced hepatic cholesterol transport and cholesterol ester formation, accompanied by compensatory activation of the SREBP2 pathway. Last, we also identify broader-spectrum inhibitors (YKJ-86) and dual Aster-A/C inhibitors (YKJ-262) that drive PM cholesterol accumulation in fibroblasts and human intestinal enteroids. Together, these chemical probes enable isoform-resolved manipulation of Aster-dependent cholesterol trafficking and provide a foundation for developing Aster-targeted therapies for cholesterol dysregulation.
    Keywords:  cholesterol; lipid transport; small molecule inhibitors
    DOI:  https://doi.org/10.1073/pnas.2617638123
  13. J Cell Biochem. 2026 Sep;127(9): e70120
    H3K18 Lactylation Promotes Cell Proliferation in T-Cell Acute Lymphoblastic Leukemia.
    Lingling Feng, Xia Jin, Juan Zhang, Zong Zhai, Xiaohua Zhang, Yi Wang.
      The Warburg effect-induced lactate production in T-cell acute lymphoblastic leukemia (T-ALL) cell proliferation is well established, however, the role of lactate-mediated protein lactylation in this process remains poorly understood. In this study, we demonstrated that inhibiting lactate levels through the lactate dehydrogenase A (LDHA) inhibitor significantly reduced both cell proliferation and protein lactylation levels in T-ALL cells. Lactate deficiency led to a marked decrease in protein lactylation, accompanied by impaired cell proliferation. Meanwhile, lactate deficiency also induced the S‑phase cell cycle arrest and reduced DNA synthesis, which collectively impaired cell proliferation. Mechanistically, we observed that the decreased expression of lactylation in histone H3 at lysine 18 (H3K18lac) reduced the enrichment of this mark on the promoter region of neurotrophic receptor tyrosine kinase 3 (NTRK3), which supported the cell proliferation of T-ALL cells. Moreover, the overexpression of NTRK3 rescued the lactate deficiency-induced proliferation inhibition of T-ALL cells. Furthermore, exogenous lactate supplementation dramatically restored the decreased cell proliferation in T-ALL cells and restored H3K18lac levels. Our findings reveal a novel role of lactate-mediated protein lactylation in regulating T-ALL cell proliferation.
    Keywords:  H3K18lac; T‐ALL; cell proliferation; lactate; lactylation
    DOI:  https://doi.org/10.1002/jcb.70120
  14. Proc Natl Acad Sci U S A. 2026 Sep 08. 123(36): e2531151123
    Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.
    Zhengyang Zhang, Liwei Zhang, Peng An, Xu Zhang, Yi Xia, Yunlu Kang, Xiaoxia Chen, Rongrong Hua, Yinhua Zhu, Yanling Hao, Yuan Huang, Yongting Luo, Junjie Luo, Guisheng Wang.
      Simultaneously profiling mitochondrial DNA (mtDNA) heteroplasmy and phenotypic variability at the single-cell level remains a challenge due to the absence of integrated methods that map mitochondrial genotypes alongside their functional states. We introduce human single-cell mitochondrial phenotype-coupled mtDNA sequencing (scMPCDS), a platform that quantifies mtDNA mutations and heteroplasmy together with mitochondrial membrane potential and reactive oxygen species within individual cells. Unlike bulk sequencing or separate single-omics techniques, scMPCDS directly correlates mitochondrial genomic instability with functional outcomes. Using this approach, we demonstrate that DdCBE-mediated mtDNA editing induces cell-specific off-target mutations in the mitochondrial genome, which coincide with diverse phenotypic changes. Applying scMPCDS to HeLa cells and clear cell renal cell carcinoma tissues, we identify single-cell subpopulations exhibiting distinct mtDNA mutation burdens and altered bioenergetic profiles, implicating potential mitochondrial heterogeneity-driven tumor evolution. Overall, scMPCDS serves as a versatile tool to unravel mitochondrial genotype-phenotype relationships at the single-cell level in both normal and disease states, thereby advancing precise mitochondrial diagnostics and therapeutics.
    Keywords:  cancer; mitochondrial phenotype; mtDNA editing; mtDNA heteroplasmy; single cell
    DOI:  https://doi.org/10.1073/pnas.2531151123
  15. J Neurosci. 2026 Sep 03. pii: e0515262026. [Epub ahead of print]
    Mitochondrial calcium, a potential sensor for homeostatic synaptic plasticity.
    Dobromila Pekala, Maurice Safar, Madeline Lampert, Duc Doung, Stephanie Zlatic, Victor Faundez, Peter Wenner.
      Neural function is maintained through homeostatic mechanisms that are engaged following perturbations to the nervous system. Homeostatic plasticity is thought to be critical for establishing and stabilizing appropriate levels of network function. Neurons are proposed to detect deviations in activity through intracellular calcium signaling, such that changes in calcium levels initiate compensatory mechanisms that restore activity and calcium to baseline. This sensing process is generally assumed to occur in the cytoplasm, however, recent work suggests that it may reside inside mitochondria. We test this in the chick embryo (either sex) spinal cord. We show that perturbations known to induce homeostatic plasticity preferentially alter the mitochondrial proteome, including components of the tricarboxylic acid (TCA) cycle, a pathway sensitive to calcium entry into mitochondria. We then tested whether calcium influx into the mitochondrial matrix contributes to the induction of homeostatic plasticity in motoneurons. Pharmacological blockade of the mitochondrial calcium uniporter (MCU), which mediates calcium entry into the matrix, produced a robust and sustained increase in spontaneous network activity (SNA). Using Ru265 to inhibit MCU function, we confirmed a reduction in mitochondrial calcium, while cytoplasmic calcium levels were largely unchanged or slightly elevated. MCU blockade was accompanied by an increase in excitatory synaptic strength consistent with homeostatic synaptic plasticity. The underlying mechanisms overlapped with those previously described in this preparation following activity or neurotransmitter blockade. Together, these findings support a model in which mitochondria contribute to the initiation of homeostatic synaptic plasticity, potentially by sensing changes in calcium transients within the mitochondrial matrix.Significance Statement Homeostatic plasticity is thought to play a critical role in maintaining circuit function. Although substantial progress has been made in identifying the mechanisms underlying the expression of homeostatic plasticity, the upstream triggers remain poorly understood. Cytoplasmic calcium has been proposed as a key signal in the detection of perturbations in neural circuit activity and in initiating compensatory responses. Here, we present findings consistent with the idea that the sensor for network activity and homeostatic synaptic plasticity tracks mitochondrial calcium. Identifying the sensor that initiates homeostatic mechanisms will be essential for understanding the functional objectives of this form of plasticity and may provide a foundation for pharmacologically targeting this pathway in conditions characterized by altered network activity.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0515-26.2026
  16. Cell. 2026 Sep 03. pii: S0092-8674(26)00869-X. [Epub ahead of print]189(18): 5482-5484
    Metabolite buffering of labile iron governs ferroptosis.
    Amalia H Megarioti, James A Olzmann.
      Iron abundance alone does not determine ferroptosis sensitivity. In this issue of Cell, Sharma and colleagues identify polyamines as endogenous metabolic buffers that reduce the chemical accessibility of labile iron, revealing an unexpected function for one of the cell's most abundant metabolite classes while raising new questions about the organization of intracellular iron metabolism.
    DOI:  https://doi.org/10.1016/j.cell.2026.07.037
  17. ACS Sens. 2026 Aug 28. 11(8): 6840-6851
    A Fluorescent RNA-Based Genetically Encoded Mg2+ Sensor Allows Robust Detection of Mg2+ in Live Cells.
    Xin Xie, Bibi Zhang, Mingyan Liu, Yuzheng Zhao, Linyong Zhu, Xianjun Chen, Yi Yang.
      Magnesium plays crucial roles in many biological processes and the stabilization of biomolecules, including DNA, RNA, and proteins. Despite significant progress, however, our understanding of how cells regulate Mg2+ homeostasis and transport remains incomplete. One of the goals is to develop approaches for detecting Mg2+ dynamics with high spatial and temporal resolution. Herein, we describe the development of MagFR, a ratiometric Mg2+ sensor based on Pepper and Clivia fluorescent RNAs. In this sensor, Pepper fluorescence is highly Mg2+ dependent, and Clivia fluorescence acts as the normalizer. MagFR has favourable properties, including a large dynamic range, pH insensitivity, and high selectivity, allowing robust detection of Mg2+ in both live bacterial and mammalian cells. By targeting MagFR to distinct subcellular compartments in mammalian cells, we observed that the free cytoplasmic Mg2+ concentration is slightly higher than that in the nucleoplasm. We demonstrated that mammalian cells maintain Mg2+ homeostasis even under conditions of elevated extracellular Mg2+, revealing the robustness of intracellular regulatory mechanisms governing Mg2+ balance. MagFR also enabled real-time detection of cellular Mg2+ dynamics following ATP depletion. Overall, this study offers a robust and versatile tool for imaging Mg2+ dynamics in cells, which will be useful for elucidating the functionality and mechanism of Mg2+ homeostasis underlying diverse cellular processes.
    Keywords:  fluorescent RNA; genetically encoded; magnesium; real-time; sensor
    DOI:  https://doi.org/10.1021/acssensors.6c00673
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