bims-celmim 2026-04-26 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2026–04–26
eighteen papers selected by
Marc Segarra Mondejar, AINA

Deletion of Mitochondrial Calcium Uniporter Enhances Calcium Signals by Slowing Calcium Clearance and Triggers Adaptive Transcriptomic Remodeling.
Dual-Response and Dual-Targeting Probe Based on the Quinolinothiazole Salt Capable of Decoding Cellular Stress and Cellular State.
ORP10 Maintains Mitochondrial Energy Metabolism by Modulating BCR-Evoked Ca2+ Signaling in Diffuse Large B-Cell Lymphoma Cells.
The Mitochondrial NAD Transporter SLC25A51 in Adipocytes Regulates Adipose Tissue Mitochondrial Function and Systemic Metabolism During Aging.
Fusing imaging and metabolic modeling via multimodal deep learning in ovarian cancer.
Precision Visualization of Tumor Microenvironment via a Lysosome-Anchored Molecular Rotor with Viscosity-Triggered Fluorescence Ignition.
Alzheimer's disease: disrupted communication between the endoplasmic reticulum and mitochondria.
Lipid droplet biogenesis as a metabolic switch regulating ferroptosis sensitivity in cancer cells.
Metabolic Pathways Regulate Cardiovascular Toxicity in Cancer Immunotherapy.
Identification and functional analysis of NAD+ metabolism-related gene NT5E in pulmonary hypertension.
SEC62 at mitochondria-associated membranes drives MASH progression by suppressing ATAD3B-mediated mitochondrial quality control.
Renal coenzyme A (CoA) production from VB5 fuels stem cell proliferation and tumor growth.
Synthetic multicolor antigen-stabilizable nanobody platform for intersectional labeling and functional imaging.
Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging.
Polyamine homeostasis in Caenorhabditis elegans relies primarily on transport.
Senescent cells acquire resistance to cystine deprivation-induced ferroptosis via the PPARα-PDK4-phosphorylated PDH axis.
Tumor suppressor candidate 1 (TUSC1) drives oxidative phosphorylation and tumor cell death in colorectal cancer.
Oxidative stress-induced mitochondrial fragmentation inhibits CREB-mediated PV regulation and facilitates caspase-3-mediated PV neuronal degeneration following status epilepticus.

J Biol Chem. 2026 Apr 17. pii: S0021-9258(26)00345-5. [Epub ahead of print] 111473

Deletion of Mitochondrial Calcium Uniporter Enhances Calcium Signals by Slowing Calcium Clearance and Triggers Adaptive Transcriptomic Remodeling.

Rajesh Bhardwaj, Abdull J Massri, Gary S Bird, Anant B Parekh.

  Mitochondrial Ca2+ uptake via the mitochondrial Ca2+ uniporter (MCU) following store-operated Ca2+ entry (SOCE) supports cellular bioenergetics, yet how mitochondria shape SOCE and cytosolic Ca2+ signaling remains incompletely understood. Combining gene deletion and functional Ca2+ imaging techniques with a rigorous transcriptomic filter, we find larger cytosolic Ca2+ signals in CRISPR/Cas9-generated Mcu knockout cells. This increase arises primarily from slower cytosolic Ca2+ clearance rather than increased store-operated Ca2+ release-activated Ca2+ (CRAC) channel activity. Compensatory upregulation of cytosolic Ca2+ regulators, such as the plasma membrane Ca2+ ATPase (PMCA) pump that extrudes excess cytosolic Ca2+, is insufficient to restore normal Ca2+ homeostasis. Re-expression of wild-type MCU restored the cytosolic Ca2+ dynamics but a channel pore-dead MCU mutant did not. Deletion of Mcu resulted in major alterations in the transcriptome and re-expression of the protein significantly restored 15% of more than 200 common genes that showed differential expression in two independent knockout clones. Our results identify a set of candidate MCU-dependent genes that may contribute to the regulation of cellular Ca2+ signaling, and show how cytosolic Ca2+ signals can be enhanced in the absence of MCU without an increase in CRAC channel activity.

Keywords:  Ca(2+) release-activated Ca(2+) (CRAC) channel; Calcium homeostasis; Cytosolic calcium clearance; Mitochondrial calcium uniporter (MCU); Plasma membrane Ca(2+) ATPase (PMCA); Store-operated calcium entry (SOCE); Transcriptomics

DOI:  https://doi.org/10.1016/j.jbc.2026.111473
Anal Chem. 2026 Apr 23.

Dual-Response and Dual-Targeting Probe Based on the Quinolinothiazole Salt Capable of Decoding Cellular Stress and Cellular State.

Hong-Di Xu, Qi Lin, Wen-Pei Ni, Jian-Feng Ge, Ru Sun.

The functional state of subcellular organelles served as a fundamental indicator of the cellular health. However, conventional fluorescent probes were largely limited to single-parameter detection, failing to capture coordinated interorganellar dynamics during pathological processes. Here, we developed a novel fluorescent probe, QTNP, based on a quinolinethiazolium scaffold. QTNP featured a large Stokes shift (∼179 nm in Toluene) and dual-response capability, allowing simultaneous sensing of the local pH and nucleic acid activity. The limit of detections (LOD) toward DNA and RNA were calculated to be 1.43 μg/mL and 0.89 μg/mL, respectively, indicating the high sensitivity of QTNP. Furthermore, QTNP achieved dual targeting of mitochondria and nucleoli. Cell imaging displayed QTNP dynamically decoded cellular stress responses: it exhibited a 1.8-fold fluorescence enhancement in CCCP-induced mitochondrial dysfunction and showed significant, reversible quenching (6.0-fold decrease in total intensity) during ferroptosis, which was fully reversible upon the addition of Fer-1. Notably, based on its sensitive response to nucleic acid activity across different physiological states, QTNP reliably distinguished normal, cancerous, and senescent cells via baseline fluorescence intensity, showing 15 to 20-fold stronger signals in cancerous cells compared to normal cells. Therefore, this work provides a versatile tool for studying organelle interactions and cellular states in living systems.

DOI: https://doi.org/10.1021/acs.analchem.5c07794
FASEB J. 2026 May 15. 40(9): e71836

ORP10 Maintains Mitochondrial Energy Metabolism by Modulating BCR-Evoked Ca2+ Signaling in Diffuse Large B-Cell Lymphoma Cells.

Jieke Cui, Yu Chang, Hongwen Li, Silin Gan, Weimin Wang, Xueyan Cao, Qiyao Pu, Baohong Yue, Jiwei Li.

  The oxidative phosphorylation diffuse large B-cell lymphoma (Oxphos DLBCL) subtype is characterized by increased oxidative phosphorylation, but the mechanism underlying energy metabolism in Oxphos DLBCL cells is not well understood. Here, we first confirmed that oxysterol-binding protein-related protein 10 (ORP10) was highly expressed in Oxphos DLBCL cells tested and that ORP10 knockdown clearly inhibited Oxphos DLBCL cell tested proliferation in vitro and in vivo, and increased cell death. After screening interacting proteins, we found that ORP10 directly interacted with inositol 1,4,5-trisphosphate (IP3) receptor 1 (IP3R1), and that ORP10 knockdown reduced cytosolic and mitochondrial parallel Ca2+ spike oscillations, the oxygen consumption rate (OCR), and intracellular ATP levels, but had no impact on lactic acid production. In addition, ORP10 knockdown enhanced autophagic cell death in Oxphos DLBCL cells tested. These data support a novel model in which ORP10 associates with IP3R1 and is required for robust IP3R1-dependent Ca2+ responses, which maintain mitochondrial energetics in Oxphos DLBCL cells tested. Thus, ORP10 may represent a promising metabolic vulnerability marker of Oxphos DLBCL cells tested.

Keywords:  Ca2+ signaling; IP3R1; ORP10; Oxphos DLBCL; mitochondrial energetics

DOI:  https://doi.org/10.1096/fj.202504497R
Aging Cell. 2026 May;25(5): e70509

The Mitochondrial NAD Transporter SLC25A51 in Adipocytes Regulates Adipose Tissue Mitochondrial Function and Systemic Metabolism During Aging.

Daiki Kojima, Keisuke Yaku, Shotaro Kosugi, Ryunosuke Mitsuno, Kenji Kaneko, Yoshinaga Kawano, Akihito Hishikawa, Seiya Mizuno, Manami Katoh, Akiko Satoh, Shinya Toyokuni, Tatsuhiko Azegami, Kenichiro Kinouchi, Shintaro Yamaguchi, Hiroshi Itoh, Takeshi Kanda, Toshimasa Yamauchi, Takashi Nakagawa, Kaori Hayashi, Jun Yoshino.

  Nicotinamide adenine dinucleotide (NAD) is a classical coenzyme regulating cellular energy metabolism. Emerging evidence demonstrates the causal relationship between defective NAD metabolism and various age-associated diseases. The major purpose of the present study was to investigate the role of adipocyte mitochondrial NAD biology in age-associated metabolic diseases. To this end, we focused on solute carrier family 25 member 51 (SLC25A51), a recently identified mitochondrial NAD transporter. We found that aging was associated with decreased adipose tissue SLC25A51 expression in both humans and mice. We next generated and analyzed novel knockout and overexpression models, which we have named adipocyte-specific Slc25a51 knockout (ASKO) and Slc25a51 overexpressing (ASLO) mice. ASKO mice had a marked decrease in adipose tissue mitochondrial NAD levels and exhibited age-associated systemic metabolic complications, such as obesity, glucose intolerance, insulin resistance, hyperinsulinemia, metabolic inflexibility, dyslipidemia, and hepatosteatosis. Mechanistically, loss of Slc25a51 reduced mitochondrial respiratory function, fatty acid oxidation capacity, and adiponectin production in adipose tissue, likely contributing to the development of systemic metabolic complications. Conversely, ASLO mice were protected from obesity and insulin resistance caused by aging. In conclusion, our results provide novel mechanistic and therapeutic insights into understanding the critical role of adipocyte mitochondrial NAD transporter SLC25A51 in the pathophysiology of age-associated metabolic diseases, particularly obesity and insulin resistance.

Keywords:  NAD; adipocyte; aging; insulin resistance; obesity

DOI:  https://doi.org/10.1111/acel.70509
Cell Syst. 2026 Apr 22. pii: S2405-4712(26)00076-1. [Epub ahead of print] 101594

Fusing imaging and metabolic modeling via multimodal deep learning in ovarian cancer.

Noushin Eftekhari, Suraj Verma, Aninda Saha, Guido Zampieri, Saladin Sawan, Annalisa Occhipinti, Claudio Angione.

  Integrating genotype (e.g., transcriptomics), phenotype (e.g., imaging), and tumor microenvironment (e.g., metabolomics) is crucial to elucidating the molecular basis of ovarian cancer. However, there is a lack of robust multimodal integration methods when only a limited number of common samples is available. Here, we generate patient-specific metabolic models starting from transcriptomics data and integrate them with imaging data. We show that this multimodal integration-never attempted before-improves survival estimation and enables a mechanistic interpretation of the predictions. We assess the robustness of our approach with different combinations of transcriptomics, fluxomics, and 3D computerized tomography (CT) imaging data, correctly stratifying patients based on risk. Fusing metabolic modeling with imaging and transcriptomics significantly improves model accuracy compared with widely used transcriptomics-imaging approaches and elucidates critical metabolic reactions. Our approach is general and can be applied to other cancer types where coupled imaging-transcriptomics data are available. A record of this paper's transparent peer review process is included in the supplemental information.

Keywords:  CT scan; imaging; machine-learning; metabolic modeling; metabolism; multimodality; ovarian cancer; personalized medicine; radiomics; survival

DOI:  https://doi.org/10.1016/j.cels.2026.101594
Anal Chem. 2026 Apr 18.

Precision Visualization of Tumor Microenvironment via a Lysosome-Anchored Molecular Rotor with Viscosity-Triggered Fluorescence Ignition.

Ning Ding, Bochao Chen, Feifei Jiang, Yifan Zhong, Xinyuan Jin, Lin Zhang, Xingyue Li, Jin Zhou.

Intracellular viscosity is a key biomarker of the tumor microenvironment. However, most existing probes lacked tumor-targeting capabilities, limiting the accuracy of tumor detection and imaging analysis. Herein, we present a new fluorescent probe (NM-Lys), engineered for the highly selective and sensitive sensing of intracellular viscosity. Operating through a restricted intramolecular motion mechanism, NM-Lys exhibited a remarkable fluorescence enhancement (up to 21-fold) at 645 nm in high-viscosity environments. NM-Lys demonstrated outstanding selectivity for viscosity against potential interferents. Furthermore, NM-Lys could target the lysosomes and monitor the dynamic changes in lysosomal viscosity under oleic acid stimulation. Finally, by encapsulating NM-Lys into folic acid-functionalized liposomes, we designed a folic acid receptor-targeted nanoprobe (Lip-NM-FA), which ultimately facilitated the high-contrast visualization of tumor boundaries in a xenograft mouse model. This formulation achieved high-contrast fluorescence imaging of tumors in living mice by specifically targeting the high-viscosity microenvironment of tumor tissues. This research established NM-Lys as a robust analytical tool for monitoring tumors.

DOI: https://doi.org/10.1021/acs.analchem.6c02089
J Neurol. 2026 Apr 20. pii: 283. [Epub ahead of print]273(5):

Alzheimer's disease: disrupted communication between the endoplasmic reticulum and mitochondria.

Jiafu Guo, Ziying Yang, Shiyan Luo, Chenxi Li, Shijun Xu.

  Alzheimer's disease (AD) remains a major, intractable neurodegenerative disorder and a serious threat to human health, characterized by a protracted clinical course, gradual progression, and irreversible cognitive decline. The current therapeutic landscape is characterized by a lack of disease-modifying agents, making the pursuit of early, effective interventions a global priority. Endoplasmic reticulum-mitochondria contact sites (ERMCs), also termed mitochondria-associated ER membranes (MAMs), constitute critical platforms for interorganellar communication, enabling material exchange and signal transduction. Key functions regulated at these junctions include calcium (Ca2+) homeostasis, mitochondrial dynamics, and lipid synthesis/transfer. Growing evidence implicates dysregulated ERMCs in the pathogenesis of neurodegenerative diseases, including AD and Parkinson's disease (PD). Recent advances in understanding the physiological and pathological roles of ERMCs have further illuminated their multifaceted contribution to AD, spanning amyloid-β (Aβ) production, Ca2+ signaling, energy and lipid metabolism, mitochondrial integrity, and endoplasmic reticulum stress (ERs). This review synthesizes current knowledge on ERMCs as a pivotal communication hub in AD and underscores their promising potential as targets for novel therapeutic strategies. Deeper insights into this axis may inform future approaches to improve clinical outcomes.

Keywords:  Alzheimer’s disease; Ca2+ ; ERMCs; Lipid metabolism; Mitochondria

DOI:  https://doi.org/10.1007/s00415-026-13822-0
FEBS J. 2026 Apr 24.

Lipid droplet biogenesis as a metabolic switch regulating ferroptosis sensitivity in cancer cells.

Abdulsamie Hanano, Amal Yousfan.

  Fatty acids (FAs) are essential for cellular growth and homeostasis; however, their excessive accumulation induces lipotoxicity. To prevent FA-induced damage, eukaryotic cells sequester surplus FAs within cytosolic lipid droplets (LDs), dynamic organelles central to lipid storage, metabolism, and signaling. Emerging evidence indicates that LDs suppress ferroptosis, an iron-dependent programmed cell death, by channeling polyunsaturated fatty acids (PUFAs) away from membrane phospholipids, thereby limiting lipid peroxidation. Nonetheless, the molecular mechanisms linking LD biogenesis to ferroptosis susceptibility remain poorly defined. In a recent study published in The FEBS Journal, Kump et al., provided mechanistic insights into how triacylglycerol (TGs) biosynthesis and LD assembly regulate ferroptosis in cancer cells as a function of PUFA availability. Here, we discuss and contextualize their principal findings.

Keywords:  Acyl‐CoA diacylglycerol acyltransferase; ferroptosis; lipid droplets; lipid peroxidation; polyunsaturated fatty acids

DOI:  https://doi.org/10.1111/febs.70567
Cancer Lett. 2026 Apr 21. pii: S0304-3835(26)00294-6. [Epub ahead of print] 218531

Metabolic Pathways Regulate Cardiovascular Toxicity in Cancer Immunotherapy.

Zeying Li, Kai Yang, Fangli Jiang, Jie Mei, Tianyu Zeng, Xiwen Zhao, Yan Liang, Xiang Huang, Yongmei Yin.

  Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, yet their clinical application is constrained by a critical trade-off between potent antitumor efficacy and off-target cardiovascular toxicity. This adverse effect underscores a fundamental biological dilemma: how tumor immunotherapy disrupts cardiovascular homeostasis. Immune cells within the cardiovascular system undergo metabolic adaptations after immune therapy. This intricate crosstalk has brought metabolic checkpoints to the forefront of research. In this review, we systematically outline the features of tumor-associated metabolic remodeling and shared roles in cardiac metabolism and immunometabolism. We elucidate ICIs initiate a cascade of events leading to cardic dysfunction through metabolic signal pathways. Furthermore, we propose that the strategic integration of cutting-edge technologies including spatial metabolomics to enable precise reprogramming of metabolic networks will ultimately decouple the efficacy of cancer immunotherapy from its associated toxicities.

Keywords:  Cardiovascular toxicity; Immune therapy; Immunometabolism; Metabolic checkpoint; Spatial metabolomics; Tumor

DOI:  https://doi.org/10.1016/j.canlet.2026.218531
Front Genet. 2026 ;17 1787122

Identification and functional analysis of NAD+ metabolism-related gene NT5E in pulmonary hypertension.

Yanan Chu, Jinxiu Yang, Tianxin Ye, Fangcong Yu, Qian Wang, Jingming Zhuo.

   Background: Pulmonary hypertension (PH) is a severe progressive disease characterised by elevated pulmonary vascular resistance and right ventricular hypertrophy. Increasing evidence has highlighted the vital role of nicotinamide adenine dinucleotide (NAD+) metabolism in cardiovascular disease. However, the role of NAD+ metabolism-related genes (NMRGs) in PH remains unclear. In this study, we aimed to identify novel NMRGs as biomarkers in PH.
Methods: Using the Gene Expression Omnibus database and Limma R package, we identified differentially expressed genes (DEGs) of PH and downloaded NMRGs from Kyoto Encyclopedia of Genes and Genomes and Reactome databases. Candidate NMRGs were subsequently identified by overlapping DEGs, NMRGs, and module genes obtained by weighted gene co-expression network analysis. The diagnostic value of these candidate NMRGs was evaluated using receiver operator characteristic (ROC) curve analysis, and gene set enrichment analysis (GSEA) was performed to explore the functional roles of hub genes. CIBERSORT algorithm was employed to assess immune cell infiltration in the PH microenvironment. Finally, the functional role of target genes in PH was validated through in vitro cellular experiments.
Results: Through comprehensive bioinformatics analyses across multiple datasets, we identified two NMRGs: NT5E and CD38. ROC analysis confirmed the higher predictive accuracy of NT5E, with area under the ROC curve values reaching 0.891 and 0.894 in GSE113439 and GSE53408 datasets, respectively. GSEA revealed that patients with high NT5E expression exhibited significant enrichment of PH-related biological functions and pathways. Given the relationship between NAD+ and immunity, immune infiltration analysis was performed, which showed a close association between NT5E expression and plasma cells and eosinophils in the PH microenvironment. In vitro experiments further showed that NT5E was significantly upregulated in a PH cell model, and knockdown of NT5E attenuated hypoxia-induced proliferation, resistance to apoptosis, and migratory ability of pulmonary arterial smooth muscle cells.
Conclusion: Based on bioinformatics analysis and in vitro validation, we confirmed that NMRGs affect PH progression, with NT5E showing potential as a novel diagnostic marker and therapeutic target in PH.

Keywords:  GEO; NAD+; NT5E; WGCNA; machine learning; pulmonary hypertension

DOI:  https://doi.org/10.3389/fgene.2026.1787122
Metabolism. 2026 Apr 17. pii: S0026-0495(26)00133-2. [Epub ahead of print]180 156623

SEC62 at mitochondria-associated membranes drives MASH progression by suppressing ATAD3B-mediated mitochondrial quality control.

Junchao Lin, Tong Wu, Chen Wang, Wei Zhou, Yutong Liu, Gang Yang, He Zhou, Jingyan Luo, Zhenzhen Fan, Yu Da, Jie He, Bing Xu, Mingzhuo Jiang, Daiming Fan, Kaichun Wu, Jie Liang.

   BACKGROUND: The progression of metabolic dysfunction-associated steatohepatitis (MASH) involves chronic, irreversible inflammatory responses linked to intracellular organelle dysfunction. While endoplasmic reticulum (ER) stress and mitochondrial impairment are recognized as critical drivers, the precise molecular mechanisms governing inter-organelle communication in this disease context remain incompletely understood.
AIM: This study aimed to investigate the role of the ER transmembrane protein SEC62 in MASH pathogenesis. Specifically, it sought to determine whether SEC62 expression is altered in MASH, define its functional impact on disease phenotypes, and elucidate the mechanistic pathway through which it regulates mitochondrial homeostasis and inflammation.
RESULTS: SEC62 was upregulated in both human and mouse MASH livers. Hepatocyte-specific SEC62 overexpression worsened hepatic steatosis, inflammation, and mitochondrial damage, whereas SEC62 knockout ameliorated these features. Mechanistically, SEC62 interacted directly with ATAD3B at the mitochondria-associated membranes (MAMs) interface, leading to the significant downregulation of ATAD3B expression. This SEC62-ATAD3B axis resulted in defective mitophagy, increased mitochondrial reactive oxygen species (ROS) production, and amplified inflammatory responses.
CONCLUSION: Our results demonstrate that SEC62 is a novel regulator of MAMs that drives MASH progression. By interacting with and suppressing ATAD3B, SEC62 disrupts mitochondrial quality control, leading to oxidative stress and inflammation. Together, these findings define a specific molecular mechanism of organelle interplay in MASH and position SEC62 as a potential therapeutic target for intervention.

Keywords:  ATAD3B; Endoplasmic reticulum; FOXO3a; Metabolic-associated steatohepatitis; Mitochondria; SEC62

DOI:  https://doi.org/10.1016/j.metabol.2026.156623
Nat Commun. 2026 Apr 18.

Renal coenzyme A (CoA) production from VB5 fuels stem cell proliferation and tumor growth.

Ting Miao, Ying Liu, Mujeeb Qadiri, Amaury Dasseux, John M Asara, Yanhui Hu, Xiaomei Sun, Luz Del Carmen Pliego-Alcántara, Christian C Dibble, Norbert Perrimon.

Coenzyme A (CoA), derived from Vitamin B5 (VB5; also called pantothenate), is essential for lipid metabolism, energy production, and cell proliferation. While the intracellular functions of CoA are well-characterized, much less is known about its tissue‑specific regulation and systemic physiological roles. Here, using Drosophila melanogaster, we uncover a gut-renal circuit in which dietary VB5 fuels CoA biosynthesis specifically in the Malpighian tubules (MTs, the fly kidney), non‑autonomously impacting gut homeostasis. We show that, in the MTs, Myc boosts renal CoA production by directly upregulating the pantothenate kinase Fbl (human PANK1-3 ortholog) and downregulating CG5828, which we characterize as the functional ortholog of the metabolite phosphatase and CoA synthesis suppressor PANK4 (dPANK4). Elevated CoA biosynthesis enhances mevalonate-isoprenoid pathway activity in the gut, promoting intestinal stem cell proliferation. We further demonstrate that renal CoA production is required for gut tumor growth in a fly model. Consistently, MYC and genes within the CoA-isoprenoid axis display strong association with clinical outcomes in human cancers. Together, our findings establish that Myc-driven CoA metabolism generates an inter‑organ signal that couples VB5 availability to stem cell control and tumor growth, and identify the CoA-isoprenoid axis as a targetable metabolic vulnerability in cancer.

DOI: https://doi.org/10.1038/s41467-026-71716-1
Nat Methods. 2026 Apr 22.

Synthetic multicolor antigen-stabilizable nanobody platform for intersectional labeling and functional imaging.

Natalia V Barykina, Erin M Carey, Olena S Oliinyk, Juliana M Mendonça-Gomes, Sofia de Oliveira, Axel Nimmerjahn, Vladislav V Verkhusha.

We present a synthetic tool kit of antigen-stabilizable fluorescent nanobodies (VIS-Fbs) spanning the entire visible spectrum from 450 nm to 660 nm. By engineering over 20 fluorescent proteins (FPs) and biosensors into 8 nanobodies, we established a generalizable design of VIS-Fbs, which fluoresce brightly only upon binding to cognate antigens. Our synthetic approach includes constitutive, photoactivatable and photoswitchable FPs, as well as intensiometric FP-based biosensors. VIS-Fbs carrying biosensors enable simultaneous monitoring of two metabolites at confined locations, while FP-based VIS-Fbs targeting biosensors allow ratiometric functional imaging in mouse brain. We further used VIS-Fbs to track endogenous β-catenin dynamics in zebrafish embryos during normal development and under Wnt-β-catenin signaling modulation. VIS-Fbs provide background-free visualization of intracellular proteins, multicolor detection of multiple antigens and selective targeting of defined cell populations and compartments. This synthetic biology-driven platform enables precise studies of protein dynamics, cellular processes and complex biological systems with high specificity and minimal background.

DOI: https://doi.org/10.1038/s41592-026-03056-3
Nat Commun. 2026 Apr 18. pii: 3589. [Epub ahead of print]17(1):

Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging.

Tetiana Poliezhaieva, Yuting Li, Prerana Shrikant Chaudhari, Ulas Isildak, Pol Alonso-Pernas, Isabela Santos Valentim, Fengting Su, Lilia Espada, Melike Bayar, Li Fu, Andreas Koeberle, Handan Melike Dönertaş, Maria A Ermolaeva.

Mitochondrial dysfunction is a prominent hallmark of aging contributing to the decline of metabolic plasticity in late life. While genetic distortions of mitochondrial integrity elicit premature aging, the mechanisms leading to "natural" aging of mitochondria are less clear. Here we use proteomics, lipidomics, genetics and functional tests in wild type Caenorhabditis elegans and long-lived clk-1(qm30) and isp-1(qm150) mitochondrial mutants to identify molecular pathways that support longevity amid persistent mitochondrial inefficiency. These tests and subsequent transcriptomics and metabolomics analyses in humans reveal aging-associated decline of phosphatidylcholine synthesis as a trigger of mitochondrial network disruption, which contributes to mitochondrial dysfunction during normal aging. Moreover, ectopic boosting of phosphatidylcholine levels via diet restores late life mitochondrial integrity in vivo in nematodes and reinstates metabolic resilience in human cell culture tests. We thus describe a previously unrecognized natural driver of mitochondrial decline in aging that is malleable by dietary interventions.

DOI: https://doi.org/10.1038/s41467-026-71508-7
Cell Rep. 2026 Apr 17. pii: S2211-1247(26)00361-X. [Epub ahead of print]45(4): 117283

Polyamine homeostasis in Caenorhabditis elegans relies primarily on transport.

Cindy Chang, Ankur Jain.

  Polyamines are essential metabolites present in all cells, but their regulation in vivo remains poorly understood. Little is known about whether tissues maintain distinct polyamine setpoints, how these setpoints are established, or whether such differences underlie selective vulnerability in disease. Here, we applied single-cell polyamine measurements in living Caenorhabditis elegans to map tissue polyamine levels and their regulatory dependencies. Three principles emerge: (1) across differentiated tissues, steady-state polyamine pools are maintained primarily by transporter-mediated import rather than de novo synthesis. (2) The intestine functions as a systemic regulator: perturbing intestinal polyamines affects organism-wide levels, and intestine-specific rescue restores systemic balance. (3) Neurons maintain markedly low cytoplasmic polyamine pools and undergo subtype-specific developmental reprogramming, switching polyamine acquisition strategies as they mature. These findings define core principles of tissue-specific polyamine regulation in vivo and provide a framework for developing therapeutic strategies to restore polyamine balance.

Keywords:  C. elegans; CP: Metabolism; Polyamines; metabolism; tissue-specific regulation

DOI:  https://doi.org/10.1016/j.celrep.2026.117283
FEBS Lett. 2026 Apr 19.

Senescent cells acquire resistance to cystine deprivation-induced ferroptosis via the PPARα-PDK4-phosphorylated PDH axis.

Shiho Machii, Kazushi Morimoto, Pakawit Lerksaipheng, Mirinthorn Jutanom, Ken-Ichi Yamada.

  Cellular senescence, a state of irreversible cell cycle arrest, is implicated in age-related diseases. While it is well known that senescent cells resist apoptosis, studies on their resistance to ferroptosis are limited and not fully understood. Senescent cells remain sensitive to ferroptosis induced by direct inhibition of glutathione peroxidase 4 (GPX4) but resist ferroptosis from cystine starvation, suggesting a role for mitochondrial metabolism. Here, we found that this resistance is mediated by peroxisome proliferator-activated receptor α (PPARα)-dependent upregulation of pyruvate dehydrogenase kinase 4 (PDK4), which inactivates pyruvate dehydrogenase (PDH) and suppresses mitochondria-derived reactive oxygen species, a key driver of ferroptosis. Our findings identify the PPARα-PDK4-PDH axis as a metabolic switch regulating ferroptosis sensitivity in senescent cells and provide insight into the senescence-ferroptosis interaction.

Keywords:  PDH; PDK4; PPARα; cellular senescence; cystine deprivation; ferroptosis; mitochondrial function

DOI:  https://doi.org/10.1002/1873-3468.70332
Apoptosis. 2026 Apr 20. pii: 130. [Epub ahead of print]31(5):

Tumor suppressor candidate 1 (TUSC1) drives oxidative phosphorylation and tumor cell death in colorectal cancer.

Janvie Manhas, Ruchi Bhardwaj, Sagar Tyagi, Ramani Shyam Kapuganti, Anushree Bharadwaj, Jaydeep Sharma, Gunjan Sharma, Diksha Joshi, Ayushi Jain, Priyanka Mani, S V S Deo, Rajinder Parshad, Prasenjit Das, Archna Singh, Sam J Mathew, Sudip Sen, Jayanth Kumar Palanichamy.

  Tumor Suppressor Candidate-1 (TUSC1), located at chromosome 9p21.2, resides within a region frequently deleted in human malignancies, yet its role in colorectal cancer (CRC) remains undefined. We investigated TUSC1 expression and function using integrated clinical, transcriptomic, metabolic, and in-vivo approaches. Immunohistochemical analysis of 145 CRC specimens revealed a significant loss of TUSC1 protein compared to normal colon, concordant with TCGA-COAD/READ RNA-Seq datasets. DepMap CRISPR fitness screens demonstrated that TUSC1 is non-essential for baseline proliferation, supporting a tumor suppressor-like profile. Lentiviral re-expression of TUSC1 in low-expressing CRC cell lines (HCT116, SW480) induced broad transcriptomic remodeling, including suppression of PI3K-Akt-mTOR signaling and stemness programs, with concomitant enrichment of oxidative phosphorylation (OXPHOS) pathways. Quantitative proteomics and phospho-western analyses confirmed attenuation of PI3K-Akt signaling. TUSC1 overexpression led to increased mitochondrial respiration, Complex I activity, and mitochondrial mass without significant changes in glycolytic flux. It also led to elevated mitochondrial ROS levels and induced G2/M arrest and apoptosis. Antioxidants partially rescued mitochondrial ROS-dependent cytotoxicity in HCT116 cells, whereas SW480 cells displayed a more limited redox rescue. TUSC1 also reduced cancer stem cell markers, impaired clonogenicity, enhanced 5-fluorouracil sensitivity, and suppressed tumor growth in xenograft models. These findings establish TUSC1 as a metabolic tumor suppressor in CRC that attenuates PI3K-Akt signaling, enhances mitochondrial oxidative metabolism, and promotes ROS-mediated tumor cell death. This study provides the first mechanistic insight into TUSC1's function in cancer, and its restoration or therapeutic induction of oxidative metabolic stress may represent a strategy for targeting CRCs.

Keywords:  Colorectal cancer; Oxidative phosphorylation; TUSC1; Tumor suppressor

DOI:  https://doi.org/10.1007/s10495-026-02336-9
Neuropharmacology. 2026 Apr 22. pii: S0028-3908(26)00163-2. [Epub ahead of print] 110990

Oxidative stress-induced mitochondrial fragmentation inhibits CREB-mediated PV regulation and facilitates caspase-3-mediated PV neuronal degeneration following status epilepticus.

Ji-Eun Kim, Su Hyeon Wang, Tae-Cheon Kang.

  Parvalbumin (PV)- expressing neurons (PV neurons) are a subpopulation of γ-aminobutyric acid (GABA)-ergic interneurons that are highly vulnerable to oxidative stress. Although mitochondrial homeostasis is an essential housekeeping function for maintaining PV expression level, the underlying mechanisms of PV downregulation caused by aberrant mitochondrial dynamics are largely unknown. In this study, using an in vivo male rat model, we found that oxidative stress induced by L-buthionine sulfoximine (BSO) reduced PV expression and cAMP-response-element-binding protein (CREB) serine (S) 133 phosphorylation through cyclin-dependent kinase 5 (CDK5)-dynamin-related protein 1 (DRP1)-mediated mitochondrial fission within hippocampal PV neurons under normal control conditions. These effects were ameliorated by roscovitine (a CDK5 inhibitor) or mitochondrial division inhibitor-1 (Mdivi-1, an inhibitor of mitochondrial fission). Similar to BSO, WY14643-induced mitochondrial fission decreased PV expression and CREB S133 phosphorylation in PV neurons. Furthermore, CREB knockdown also led to PV downregulation without altering CDK5 activity or mitochondrial dynamics. Notably, these treatments did not lead to PV neuronal degeneration. In a pilocarpine-induced status epilepticus (SE) model, however, massive PV neuronal degeneration was observed accompanied by decreased CREB S133 phosphorylation and excessive mitochondrial fragmentation. N-acetylcysteine (NAC), roscovitine and Mdivi-1 attenuated SE-induced PV neuronal degeneration by preserving CREB S133 phosphorylation and mitochondrial integrity. These findings indicate that the CDK5-DRP1-CREB pathway may evoke PV downregulation under sublethal oxidative stress and lead to irreversible PV neuronal degeneration under severe pathological conditions such as SE. Therefore, our findings suggest that this signaling pathway may be a therapeutic target to preserve PV neurons in neurological and psychiatric diseases.

Keywords:  BSO; ROS; apoptosis; caspase-3; epilepsy; parvalbumin; pilocarpine

DOI:  https://doi.org/10.1016/j.neuropharm.2026.110990