bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–04–05
eighteen papers selected by
Marc Segarra Mondejar, AINA
  1. Mechanosensory channels mediate ER Ca2+ transients to trigger assembly of autophagosome initiation sites for degradation of ER subdomains.
  2. Microscopy in mitochondrial research - a comprehensive review.
  3. Lysosome: a critical hub for ferroptosis regulation.
  4. Lactate Facilitates the Survival and Invasion of Pancreatic Cancer Cells Under Glucose Deprivation.
  5. STUB1-VCP/p97 complex regulates mitophagy via fine-tuning of PINK1 levels.
  6. Dysregulation of a novel autophagosome-mitochondria contact contributes to autophagy dysfunction and neurodegeneration in tauopathy.
  7. Mitochondrial NAD kinase Pos5 is required for CoQ biosynthesis in yeasts.
  8. Pearling drives mitochondrial DNA nucleoid distribution.
  9. Aberrant amino acid-sensing promotes immunotherapy resistance via the inflammatory cytokine-ZBTB5-mTORC1 axis.
  10. Regulation of neuronal invasion of small cell lung cancer by STMN2/β-alanine-controlled metabolic reprogramming.
  11. NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions.
  12. Natural photosynthetic system for restoring homeostasis of animal organelle interaction network.
  13. Revitalizing p-GSK-3β via cysteine sulfenylation promotes hepatic insulin resistance by differentially regulating glycogenesis and gluconeogenesis.
  14. Spatially-guided metabolomics profiling of metabolic regions in human tumor tissues.
  15. A phosphorous-based dendrimer targets mitochondria and normalizes the keratinocyte proliferation/differentiation balance to improve psoriasis.
  16. From Cancer, Malate-Aspartate Shuttle, RNA Replicase, and mtDNA to Trypanosomes and Back to Cancer Again.
  17. Direct observation of cation-dependent polarisation switching dynamics in fluorite ferroelectrics.
  18. Lactylation of SOD1 promotes oxidative damage in IVDD.
  1. Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00158-9. [Epub ahead of print]86(7): 1377-1396.e6
    Mechanosensory channels mediate ER Ca2+ transients to trigger assembly of autophagosome initiation sites for degradation of ER subdomains.
    Xiaoli Ma, Zhiyang Cheng, Hongyu Zhao, Huan Zhang, Ke Xiao, Jiali Xie, Yun Feng, Chun Yang, Yujie Feng, Xi Wang, Yaozu Xiang, Junjie Hu, Qiaoxia Zheng, Wei Ji, Hong Zhang.
      ER-phagy involves the selective autophagosomal engulfment of ER fragments, but the signaling events, selection mechanisms, and membrane source of ER-phagic autophagosomes remain elusive. Here, using state-of-the-art super-resolution multi-SIM imaging, we reveal that stresses (prolonged starvation, cholesterol dyshomeostasis, and high-Ca2+ insults) trigger the expansion of sheet ER subdomains containing high levels of luminal Ca2+ in mammalian cells, which are subsequently degraded by ER-phagy. Autophagosome formation and sequestration of ER sheets require the concerted actions of FAM134B and lipidated LC3, whereas the autophagy proteins ATG14 and ATG9 are partially dispensable. Electron microscopy and cryo-electron tomography show that the membranes of autophagosomes enclosing high-Ca2+-containing ER sheets are directly remodeled from the ER. The ER-localized cation channels PIEZO1 and TRPV1 are enriched at and mediate Ca2+ transients from high-Ca2+-containing ER sheets, triggering liquid-liquid phase separation of the autophagosome-initiating FIP200 complex to initiate ER-phagy. Thus, distinct mechanisms are employed for the formation of high-Ca2+-containing ER-enclosing autophagosomes and non-selective autophagosomes.
    Keywords:  Ca(2+); ER-phagy; FAM134B; FIP200; PIEZO1; TRPV1
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.002
  2. J Cell Sci. 2026 Mar 15. pii: jcs263933. [Epub ahead of print]139(6):
    Microscopy in mitochondrial research - a comprehensive review.
    Prasanna Katti, Prasanna Venkhatesh, C Nivedya, Andrea Marshall, Amber Crabtree, Zahra Elly Soltani, Olga Korolkova, Vineeta Sharma, Suraj Thapliyal, Karthik Naik, Kit Neikirk, Rodolpho Ornitz Oliveira Souza, Sepiso K Masenga, Nelson Wandira, Magdalene Ameka, Okwute M Ochayi, Christian A Combs, Lucy Collinson, Nalan Liv, Antentor Hinton.
      Mitochondria are highly dynamic, double-membrane organelles that play integral roles beyond energy production. Mitochondria adapt their morphology to meet diverse cellular demands, and highly plastic mitochondrial networks interact and communicate with various cellular components to maintain cellular health. Advances in both light and electron microscopy (EM) have greatly enhanced our understanding of mitochondrial structure and function. However, the small diameter of mitochondrial tubules, often near the diffraction limit of light, poses challenges for visualizing submitochondrial structures and protein distributions with conventional microscopy. Recently, super-resolution microscopy has offered unprecedented insights into mitochondrial dynamics, interactions and architecture. In this Review, we discuss how imaging techniques have advanced our understanding of mitochondrial biology. We critically assess the contributions of two-dimensional EM to elucidating the native architecture of cristae and respiratory chain complexes. Additionally, we explore how three-dimensional EM and super-resolution methods have reshaped our comprehension of mitochondrial network dynamics, heterogeneity and interactions with other cellular components. Finally, we discuss the strengths and limitations of various approaches, considering their potential to overcome current challenges and open new avenues in mitochondrial research, and illuminate how advanced microscopy continues to drive discoveries in mitochondrial biology with implications for metabolic diseases and aging.
    Keywords:  CLEM; Confocal; EM; Mitochondria; Super-resolution microscopy; Volume EM
    DOI:  https://doi.org/10.1242/jcs.263933
  3. Trends Cell Biol. 2026 Mar 30. pii: S0962-8924(26)00038-3. [Epub ahead of print]
    Lysosome: a critical hub for ferroptosis regulation.
    Xin Chen.
      Ferroptosis is an iron-dependent programmed cell death that involves lipid peroxidation. Ferroptosis represents a critical process underlying tumorigenesis and multiple pathological disorders. Recently, lysosomes have been found to orchestrate ferroptotic signaling, linking iron metabolism, oxidative homeostasis, and selective autophagy. Furthermore, lysosomal membrane disruption leads to the release of intraluminal iron and cathepsins, thereby facilitating ferroptotic damage, whereas lysosomal exocytosis acts in the opposite direction to limit ferroptosis. Therefore, pharmacological modulation of lysosomal activities could be used to treat drug-resistant tumors or protect normal tissues against ferroptosis-related injuries. In this review, we summarize how lysosomes control ferroptosis, focusing on the regulation through lysosomal contents, pH, degradation processes, and exocytosis. We also discuss possible therapeutics that target lysosomes to modulate ferroptosis-associated diseases.
    Keywords:  LMP; autophagy; ferritinophagy; ferroptosis; iron; lysosome
    DOI:  https://doi.org/10.1016/j.tcb.2026.03.007
  4. FASEB J. 2026 Apr 15. 40(7): e71726
    Lactate Facilitates the Survival and Invasion of Pancreatic Cancer Cells Under Glucose Deprivation.
    Fan Wang, Ping Hu, Shengbo Han, Ya Zhang, Yang Li, Wenfeng Zhuo, Yong Zhao, Yan Huang, Guozheng Lv, Hongda Wang, Gang Zhao.
      Lactate has been considered as a tumor-promoting metabolite, however, its functional roles in pancreatic cancer (PC) have not yet been fully elucidated. Here, we explored the roles of lactate on the proliferation and invasion of PC cells under glucose deprivation. We found that lactate enhanced PC cells' proliferation and invasion under glucose deprivation, but not in normal conditions. The Cancer Genome Atlas (TCGA) Pancreatic Adenocarcinoma (PAAD) dataset showed that monocarboxylic acid transporter 1 (MCT1), a lactate transporter, was overexpressed and correlated with poor prognosis in PC patients. Additionally, knockdown or inhibition of MCT1 distinctively attenuated lactate-induced proliferation and invasion of PC cells under glucose deprivation by suppressing their tricarboxylic acid (TCA) cycle. Importantly, the MCT1 inhibitor AZD3965 synergistically enhanced the anticancer effects of the glycolysis inhibitor 2-DG. Taken together, our results demonstrate that MCT1-mediated lactate influx sustains PC proliferation under glucose starvation, and combined inhibition of MCT1 and glycolysis could be leveraged for treatment of PC.
    Keywords:  MCT1; TCA; lactate; metastasis; proliferation
    DOI:  https://doi.org/10.1096/fj.202503162RR
  5. Cell Rep. 2026 Mar 27. pii: S2211-1247(26)00261-5. [Epub ahead of print]45(4): 117183
    STUB1-VCP/p97 complex regulates mitophagy via fine-tuning of PINK1 levels.
    Jin-Yi Lin, Ze-Bo Huang, Shi-Qi Zhang, Yong Wu, Ling-Jun Cheng, Xiangzheng Gao, Sofie Lautrup, Shu-Qin Cao, Junping Pan, Dade Rong, Ruixue Ai, Hayden Weng Siong Tan, Liming Wang, Haihe Wang, Han-Ming Shen, Evandro F Fang, Guang Lu.
      PINK1 is a master regulator of PINK1-parkin-mediated mitophagy, a key process for maintaining mitochondrial homeostasis. The precise regulation of PINK1 is therefore essential for orchestrating mitophagy. While proteolytic processing of PINK1 and degradation of cleaved PINK1 via the N-end rule under basal conditions have been extensively characterized, the mechanisms governing full-length PINK1 degradation upon mitochondrial damage remain enigmatic. Here, we demonstrate that PINK1 undergoes ubiquitination and proteasomal degradation during mitophagy through the coordinated action of STUB1 and VCP/p97. Depletion of STUB1 stabilizes full-length PINK1, which paradoxically impairs mitophagy through the acceleration of parkin degradation. At the organismal level, the STUB1-VCP axis plays an important role in neuronal mitophagy-related memory and learning capacities in the roundworm C. elegans. Congruently, this axis is impaired in the postmortem brain tissues from patients with Alzheimer's disease compared with cognitively normal controls. Collectively, our findings support STUB1-VCP as a molecular calibrator that fine-tunes full-length PINK1 levels to enable efficient mitophagy and maintain mitochondrial homeostasis.
    Keywords:  Alzheimer’s disease; CP: metabolism; CP: molecular biology; PINK1; STUB1; VCP/p97; autophagy; mitophagy; parkin; ubiquitination-proteasome system
    DOI:  https://doi.org/10.1016/j.celrep.2026.117183
  6. bioRxiv. 2026 Mar 25. pii: 2026.03.23.713823. [Epub ahead of print]
    Dysregulation of a novel autophagosome-mitochondria contact contributes to autophagy dysfunction and neurodegeneration in tauopathy.
    Nuo Jia, Hongyuan Guan, Yantao Zuo, Yu Young Jeong, Niharika Amireddy, Gavesh Rajapaksha, Cuauhtemoc Ulises Gonzalez, Nora Jaber, Yun-Kyung Lee, Marialaina Nissenbaum, David J Margolis, Wei Dai, Alexander W Kusnecov, Qian Cai.
      Mitochondria engage in extensive communication with other organelles through membrane contacts. Perturbed mitochondria-organelle interactions are indicated in a variety of neurodegenerative diseases, but the underlying mechanisms remain poorly understood. Here, we report a new class of mitochondria-organelle communication: autophagosome/autophagic vacuole (AV)-mitochondria (Mito) contact, which exhibits hyper-tethering in tauopathy neurons, consequently hampering AV retrograde transport. Such defects are attributed to accelerated turnover of the contact release factor TBC1D15, triggered by mitochondrial bioenergetic deficit-induced hyperactivity of the AMP-activated protein kinase (AMPK). Increasing TBC1D15 levels or repressing AMPK activity normalizes AV-Mito contact release and restores retrograde transport of AVs, thereby increasing autophagic cargo clearance and reducing tau burden in tauopathy axons. Furthermore, overexpression of TBC1D15 enhances autophagic clearance and attenuates tau pathology, alleviating neurodegeneration and cognitive dysfunction in tauopathy mice. Taken together, our study provides new insights into AV-Mito contact dysregulation in tauopathy-related autophagy failure, laying the groundwork for the development of potential therapeutics to combat tauopathy diseases.
    DOI:  https://doi.org/10.64898/2026.03.23.713823
  7. PLoS One. 2026 ;21(4): e0346295
    Mitochondrial NAD kinase Pos5 is required for CoQ biosynthesis in yeasts.
    Shogo Nishihara, Ikuhisa Nishida, Yasuhiro Matsuo, Tomohiro Kaino, Makoto Kawamukai.
      Coenzyme Q (CoQ) is an essential component of the electron transport chain, and ten genes involved in CoQ biosynthesis have been identified in Schizosaccharomyces pombe. To gain further insight into CoQ biosynthesis, we screened the Bioneer gene-deletion library and found that the Δpos5 strain produced only 0.2-fold of the wild-type CoQ10 level. Pos5 shares homology with Saccharomyces cerevisiae Pos5 (ScPos5), a mitochondrial NADH (or NAD+) kinase that generates NADPH (or NADP+). Heterologous expression of ScPOS5 in the S. pombe Δpos5 strain recovered CoQ content to 0.9-fold of the wild-type level, indicating functional conservation of Pos5 between the two yeasts. Consistently, CoQ6 level in ΔScpos5 was decreased to 0.2-fold of that in the wild-type strain. The Δpos5 strain exhibited several phenotypes characteristic of CoQ-deficient S. pombe, including inability to grow on non-fermentable carbon sources, hypersensitivity to oxidative stress, and high sulfide production. Among CoQ biosynthetic enzymes, Coq6 monooxygenase is thought to utilize NADPH. Supplementation with VA or PHB partially restored CoQ production in the Δpos5 strain, while overexpression of coq6 had negligible effect. These findings suggest that Pos5 is required for the earlier step of CoQ biosynthesis.
    DOI:  https://doi.org/10.1371/journal.pone.0346295
  8. Science. 2026 Apr 02. 392(6793): 102-109
    Pearling drives mitochondrial DNA nucleoid distribution.
    Juan C Landoni, Matthew D Lycas, Josefa Macuada, Willi Stepp, Roméo Jaccard, Christopher J Obara, Andrew S Moore, David Hoffman, Jennifer Lippincott-Schwartz, Wallace Marshall, Gabriel Sturm, Suliana Manley.
      The distribution of mitochondrial DNA-containing nucleoids is essential for mitochondrial function and genome inheritance; however, no known mechanisms can explain nucleoid segregation or their regular positioning. In this work, we found that mitochondria frequently undergo a reversible biophysical instability termed "pearling," transforming from a tubular into a regularly spaced beads morphology. Physiological pearling imposed a characteristic length scale and simultaneously mediated nucleoid disaggregation and established internucleoid distancing with high precision. Pearling onset was triggered by calcium influx, whereas the density of lamellar cristae invaginations modulated pearling prevalence and preserved nucleoid spacing following recovery. The dysregulation of mitochondrial calcium influx or inner membrane cristae integrity caused aberrant nucleoid clustering. Our results identify pearling as a mechanism governing nucleoid distribution and inheritance and offer insights into its regulation.
    DOI:  https://doi.org/10.1126/science.adu5646
  9. Nat Cell Biol. 2026 Apr 03.
    Aberrant amino acid-sensing promotes immunotherapy resistance via the inflammatory cytokine-ZBTB5-mTORC1 axis.
    Junyu Xiang, Tao Wang, Shuoran Tian, Jinyang Li, Mengyun Luo, Yuzhu Wang, Aibei Du, Xu Chen, Fanxuan Tian, Lei Wang, Yongchao Zhang, Mengyi Han, Wenqing Hou, Xinyu Wang, Tao Hou, Qin Liu, Dongfeng Chen, Liangzhi Wen, Zhongyi Qin, Xianfeng Li, Cong Jiang, Qiaoqiao Zhang, Pengda Liu, Xiuwu Bian, Wenyi Wei, Bin Wang.
      Acute activation of mTORC1 by amino acids (AAs) is pivotal for growth regulation, yet it remains unclear how the intracellular nutrient-sensing machinery might be rewired by environmental cues to execute distinct functions. Here we report that, despite nutrient insufficiency, cancer-intrinsic AA-sensing mTORC1 signalling is hijacked by inflammatory cytokines in the tumour microenvironment (TME). ZBTB5 translates inflammatory signals to restore mTORC1 pathway via disrupting the GATOR1 complex. Mechanistically, inflammatory cues promote phosphorylation of ZBTB5-S127, thereby recruiting the Cullin3ZBTB5 E3 ubiquitin ligase to degrade NPRL2 within GATOR1 and reactivate mTORC1 signalling. Consequently, tumoural AA uptake is boosted to exacerbate nutrient restriction and death of CD8+ T cells, leading to immunoevasion, tumour progression and inferior response to immune-checkpoint inhibitors. As such, blocking ZBTB5-pS127 ameliorates primary and acquired resistance to checkpoint blockade. Thus, targeting aberrant nutrient-sensing via the ZBTB5-pS127-mTORC1 axis represents a proof-of-concept strategy to sensitize cancer immunotherapy by alleviating AA restriction in the TME.
    DOI:  https://doi.org/10.1038/s41556-026-01926-8
  10. Cell Rep. 2026 Mar 28. pii: S2211-1247(26)00286-X. [Epub ahead of print]45(4): 117208
    Regulation of neuronal invasion of small cell lung cancer by STMN2/β-alanine-controlled metabolic reprogramming.
    Yan Zhou, Runbo Zhong, Yanwei Zhang, Michael R Shurin, Galina V Shurin, Liwen Xiong, Tianqing Chu, Baohui Han, Haohua Teng, Yu Yang, Erpeng Wu, Chi Zhang, Lincheng Zhang, Wanting Liu, Yuqing Lou, Jun Lu, Yongjie Wang, Hua Zhong.
      Small cell lung cancer (SCLC) exhibits a high incidence of perineural invasion (PNI), a clinical feature associated with poor prognosis. Here, we establish PNI as an independent adverse prognostic factor in a surgical SCLC cohort. We further show that the neural microenvironment upregulates stathmin-2 (STMN2) in SCLC cells. STMN2, in a concentration-dependent manner, activates the β-alanine metabolic pathway, leading to intracellular β-alanine accumulation, which enhances tumor cell migration and invasion. In vivo, STMN2 knockdown suppresses neural invasion, an effect reversible upon β-alanine supplementation. This work defines a neural-STMN2-β-alanine-invasion axis that drives PNI in SCLC, providing mechanistic insights and highlighting a promising metabolic vulnerability for therapeutic intervention.
    Keywords:  CP: cancer; CP: neuroscience; SCLC; invasiveness; perineural invasion; stathmin-2
    DOI:  https://doi.org/10.1016/j.celrep.2026.117208
  11. Nat Metab. 2026 Apr 01.
    NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions.
    Megan D Radyk, Barbara S Nelson, Mariana Tannus Ruckert, Christopher J Halbrook, Mengrou Shan, Jonathan M Alektiar, Brooke L Lavoie, Lucie Salvatore, Wei Yan, Matthew D Perricone, Kathryn Buscher, Alexander Wood, Hanna S Hong, Peter Sajjakulnukit, Li Zhang, Gabriel Corfas, Filip Bednar, Timothy L Frankel, Marina Pasca di Magliano, Justin A Colacino, Yatrik M Shah, Howard C Crawford, Costas A Lyssiotis.
      Acinar-to-ductal metaplasia (ADM) is a reversible cell state that facilitates pancreas repair following injury. Oncogenic KRAS mutations can progress ADM to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). However, the metabolic alterations in these precancerous lesions are understudied. Here, we identify global changes in central carbon metabolism genes and metabolites during ADM formation. In particular, NRF2-target genes are significantly induced in ADM. Among these, we focus on genes encoding NADPH-producing enzymes glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1), which participate in the regulation of oxidative stress. In mouse models of pancreatic tumourigenesis, G6PD deficiency or Me1 loss increases reactive oxygen species and lipid peroxidation, which is accompanied by accelerated formation of ADM and PanIN lesions. Notably, Me1 loss, but not G6PD deficiency, promotes faster PDAC progression. We demonstrate that oxidative stress is required for ADM, as pharmacological antioxidant treatment attenuates ADM progression in vivo and ex vivo. Conversely, depleting the antioxidant glutathione promotes precancerous lesions in primary human acinar cells and in mice. Together, our findings shed light on metabolic reprogramming in the precancerous pancreas.
    DOI:  https://doi.org/10.1038/s42255-026-01496-x
  12. Nat Commun. 2026 Mar 31. pii: 3087. [Epub ahead of print]17(1):
    Natural photosynthetic system for restoring homeostasis of animal organelle interaction network.
    Chen Xia, Zhanqiu Dai, Yongcheng Wang, Jiachen Yu, Zijie Wang, Zhenxiang Huang, Kaifeng Pan, Ke Yang, Yiyu Chen, Peiyu Zhong, Chenhui Gu, Shunwu Fan, Xianfeng Lin, Pengfei Chen.
      Disruption of organelle interactions due to metabolic stress is a crucial factor in the pathological processes of many degenerative diseases. Compared with animal cells, the participation of chloroplasts enables plant cells to show defensive adaptation under stress. Therefore, delivering plant-derived photosynthetic systems into animal cells may help to establish a more stable organelle interaction network. Here, we show that plant-derived photosynthetic systems can effectively restore homeostasis of the interaction network of animal organelles. Specifically, plant-derived nanothylakoid units provide energy to animal cells, regulate intracellular Ca2+ homeostasis, increase endoplasmic reticulum (ER) lipid unsaturation and global membrane fluidity, reduce abnormal contact between mitochondria and ER, and alleviate mitochondrial dysfunction. By combining implantable light-emitting diodes with wireless charging, we expand photosynthesis therapy, enabling treatments for deeper tissues. This study provides a proof-of-concept for disease treatment based on the regulation of organelle interaction networks by natural photosynthetic systems and establishes a therapeutic approach for treating deep tissues.
    DOI:  https://doi.org/10.1038/s41467-026-69825-y
  13. Nat Metab. 2026 Apr 02.
    Revitalizing p-GSK-3β via cysteine sulfenylation promotes hepatic insulin resistance by differentially regulating glycogenesis and gluconeogenesis.
    Jie Chen, Zhuohang Liu, Jian Gu, Yishen Jiang, Kexin Cao, Nannan Zhou, Yabo Zhou, Zhenfeng Wang, Li Zhou, Jin Yu, Xu Sun, Tao Li, Lu Zhang, Tianning Huang, Dianheng Wang, Chaoqi Zhang, Ke Tang, Jingwei Ma, Huafeng Zhang, Jiadi Lv, Bo Huang.
      The role of hepatic insulin resistance (HIR) in the development of fatty liver, diabetes and cardiovascular diseases is well known, yet the molecular basis of HIR remains unclear, limiting targeted therapeutic strategies. Here we show that insulin signalling-inactivated phosphorylated GSK-3β (p-GSK-3β) is revitalized via reactive oxygen species-mediated sulfenylation, leading to glycogenesis termination and gluconeogenesis initiation, two hallmarks of HIR. Mechanistically, sulfenylated or 'oxidatively activated' p-GSK-3β regains the enzymatic activity to phosphorylate liver glycogen synthase, thereby blocking glucose storage. This activated p-GSK-3β can further phosphorylate insulin-suppressed Forkhead box O1, thus liberating its transcriptional activity to promote the expression of gluconeogenic enzymes. Notably, this dual-pathway mechanism is conserved in clinically relevant human liver samples and organoids. These findings elucidate the molecular mechanism by which HIR is formed and provide potential strategies against HIR by targeting sulfenylated or 'oxidatively activated' p-GSK-3β.
    DOI:  https://doi.org/10.1038/s42255-026-01507-x
  14. Mol Syst Biol. 2026 Apr 01.
    Spatially-guided metabolomics profiling of metabolic regions in human tumor tissues.
    Jia-Ying Joey Lee, Jingtao Zhang, Sin-Chi Chew, Shihleone Loong, Liang Xu, Jia-Wen Carmen Kong, Fedor Grigoryev, Alexander Yaw-Fui Chung, Jin-Yao Teo, Peng-Chung Cheow, Glenn Bonney, Brian K P Goh, Wei-Qiang Leow, Yulan Wang, Lit-Hsin Loo, Pierce Kah-Hoe Chow.
      Bulk high-resolution mass spectrometry provides sensitive and global snapshots of metabolites involved in cancer metabolism. However, intratumoral heterogeneity obscures the cellular origins of detected metabolites, making it difficult to identify reproducible and predictive metabolic markers. Here, we present "Spatially guided MEtabolomics (SgME) profiling", a multi-modal metabolomics data analysis approach that delineates and maps metabolic regions (MERs), including overlapping regions, within tumor tissues. We applied SgME profiling to human hepatocellular carcinoma (HCC) tumors and refined potential RNA markers that were also found in previous transcriptomics or bioinformatics studies to those specifically associated with malignant regions. We further estimated that more than 50% of the highly abundant metabolites detected in bulk tumors originated from the non-malignant MERs and are therefore unlikely to be predictive and/or reproducible markers. Importantly, SgME profiling also revealed new potential metabolic markers that were not apparent in bulk analysis because they increased in low-grade tumor regions but declined sharply in necrotic regions. Together, these findings show that SgME profiling overcomes key limitations of conventional metabolomics profiling by enabling more granular, spatially resolved metabolic characterization.
    Keywords:  Hepatocellular Carcinoma; Mass Spectrometry Imaging; Metabolic Heterogeneity; Spatial Metabolomics
    DOI:  https://doi.org/10.1038/s44320-026-00205-w
  15. PLoS One. 2026 ;21(3): e0343926
    A phosphorous-based dendrimer targets mitochondria and normalizes the keratinocyte proliferation/differentiation balance to improve psoriasis.
    Emily Clement, Ranime Jebbawi, Abdelouahd Oukhrib, Hélène Labie, Maëlys Le Moal, Séverine Fruchon, Stéphanie Cassel, Anne-Marie Caminade, Cédric-Olivier Turrin, Muriel Blanzat, Michel Simon, Rémy Poupot.
      Psoriasis vulgaris is a common chronic inflammatory skin disease associated with hyperproliferation and defective differentiation of keratinocytes. Despite new effective treatments using biologicals targeting key cytokines or their receptors, innovative therapeutic approaches remain to be discovered. Here, psoriasis-like imiquimod-induced skin lesions in mice were improved when topically treated with a nano-sized, phosphorus-based dendrimer capped with azabisphosphonate groups, so-called IMD-006, and previously known as ABP dendrimer. This effect was confirmed using ex vivo and in vitro human psoriasis models generated by adding T helper (Th)1-type and Th17-type inflammatory cytokines to skin explants and reconstructed epidermises, in which topically-applied IMD-006 normalized keratinocyte proliferation and differentiation. In 2D keratinocyte cultures, IMD-006 also decreased proliferation whilst promoting differentiation. It was internalized by keratinocytes and distributed to mitochondria. After treatment with IMD-006, changes to the morphology of the mitochondrial network, increases in mitochondrial ROS levels, and co-localization of mitochondria with lysosomes suggest it promotes mitochondrial degradation, a key step in keratinocyte differentiation. Therefore, our results show that IMD-006 could be a promising candidate for the topical treatment of psoriasis.
    DOI:  https://doi.org/10.1371/journal.pone.0343926
  16. Annu Rev Biochem. 2026 Apr 01.
    From Cancer, Malate-Aspartate Shuttle, RNA Replicase, and mtDNA to Trypanosomes and Back to Cancer Again.
    Piet Borst.
      I studied medicine to become an endocrinologist but ended up in biochemistry. As a graduate student, I studied tumor mitochondria and discovered the malate-aspartate shuttle (the major route in animal cells for shuttling reducing equivalents into mitochondria). As a postdoc in New York, I switched to the replication of RNA bacteriophages, and on my return to Amsterdam, I started on mitochondrial biogenesis and discovered the circular mitochondrial DNAs (mtDNAs) of animal mitochondria and yeast. I also tackled trypanosomatids, major parasites of humans, in which we characterized their exotic mtDNA networks and discovered the glycosome, an organelle containing most of the glycolytic system. We helped to unravel the mechanism of antigenic variation in African trypanosomes and even discovered a new base, base J, in the DNA of trypanosomatids.After moving to the Netherlands Cancer Institute, I combined the trypanosomatids with a project on mechanisms of multidrug resistance in cancer cells. In particular, studying mice with one or more disrupted ABC transporter genes resulted in interesting findings in drug pharmacokinetics and in the elucidation of the cause of two inborn errors.
    DOI:  https://doi.org/10.1146/annurev-biochem-051424-083457
  17. Nat Commun. 2026 Mar 30. pii: 2660. [Epub ahead of print]17(1):
    Direct observation of cation-dependent polarisation switching dynamics in fluorite ferroelectrics.
    Kousuke Ooe, Yufan Shen, Kazuki Shitara, Rintaro Maki, Shunsuke Kobayashi, Yuichi Shimakawa, Daisuke Kan, Joanne Etheridge.
      Fluorite ferroelectrics are exciting candidates for next-generation non-volatile memory devices because their unique ferroelectric mechanism, which arises from unconventional oxygen displacements, permits ferroelectricity with minimal thickness constraints. However, the polarisation switching mechanism remains the subject of intense debate due to a limited understanding of the atomic-scale dynamics which are extremely challenging to detect and measure. Here, we observe directly the polarisation switching pathways by visualising oxygen site dynamics in ZrO2 and Hf0.5Zr0.5O2 freestanding membranes using an advanced atomic-column imaging technique-optimum bright-field scanning transmission electron microscopy. We observe that the 180° and 90° polarisation pathways involve different nonpolar intermediate states with distinct spatial scales. Coupled with density functional theory, we also reveal how different cation species in fluorite oxides impact the accessible polarisation switching pathways. Our atomic-level insights into the polarisation switching dynamics open new avenues for the advanced engineering of fluorite ferroelectric materials and resulting memory devices.
    DOI:  https://doi.org/10.1038/s41467-026-70593-y
  18. Nat Rev Rheumatol. 2026 Apr 02.
    Lactylation of SOD1 promotes oxidative damage in IVDD.
    Jessica McHugh.
      
    DOI:  https://doi.org/10.1038/s41584-026-01369-3
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