bims-celmim 2026-06-28 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2026–06–28
23 papers selected by
Marc Segarra Mondejar, AINA

Revealing the spatiotemporal dynamics of methionine metabolism with a genetically encoded single-fluorophore biosensor.
Mitochondrial Ca2+ signaling: A metabolic rheostat defining tumor and immune cell fate.
Robust and sensitive ELISA detection of total and activated PRKN.
De novo pyrimidine synthesis controls germinal center B cell and plasma cell fates and systemic autoimmunity.
PIGBOS-CLCC1 interaction shapes cellular calcium dynamics and energy metabolism.
GPAM mediates mitochondrial dysfunction and the progression of alcoholic liver disease through lipid remodeling.
The metabolic basis of regulated cell death.
Mitochondria: from powerhouses of cells to hubs in antitumor immunity.
Pan-cancer analysis reveals the prognostic relevance of NUP54 and its association with HIF-1α-related glycolytic phenotypes in lung adenocarcinoma.
Rosindol: A fluorogen for the quantitative measurement of reactive oxygen species in living cells.
Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation.
PIKfyve influences inter-organelle contacts with lysosomes to modulate the endoplasmic reticulum.
Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
Universal Pressure-Loading Device for Live-Cell Imaging under Sustained Physiological Mechanical Stress.
Targeting DGAT1 reprograms lipid landscape and restores CD8⁺ T cell immunity in pancreatic cancer.
Targeting mitochondria as a potential therapeutic strategy against radioresistance in cancer.
Targeting mitochondrial α-ketoglutarate sequestration disables dual oncogenic drivers and metabolic adaptability in pancreatic ductal adenocarcinoma.
p53 overrides METTL5 loss-induced tumor suppression via mitochondrial respiration.
Reductive carboxylation via isocitrate dehydrogenase 1 supports cardiac metabolic adaptation during oncometabolic stress.
NDUFA4L2 acts as a mitochondrial checkpoint against ferroptosis in hypoxic clear cell renal cell carcinoma.
A ratiometric fluorescent reporter of mitochondrial sodium.
ALDOC modulates astrocytic glycolysis and AMPK/mTOR/HIF-1α signaling in Alzheimer's disease.
Sequential changes in calcium transients during M phase regulate cardiomyocyte proliferation.

bioRxiv. 2026 Jun 09. pii: 2026.06.05.730515. [Epub ahead of print]

Revealing the spatiotemporal dynamics of methionine metabolism with a genetically encoded single-fluorophore biosensor.

Katarina A Cohen, Arnav Jhawar, Gilberto Garcia, Naiara Goni, Megan Chen, Athena Alcala, Ryo Higuchi-Sanabria, Danielle L Schmitt.

Methionine is an essential amino acid, used for protein synthesis, redox homeostasis, and methylation reactions throughout the cell. However, the compartmentalized dynamics of methionine have remained elusive, due to a lack of available tools to measure methionine with high spatial and temporal resolution. To address this limitation, we have developed a single fluorescent protein-based methionine optical reporter (Meteor) which reports subcellular changes in methionine with high dynamic range. Using Meteor, we demonstrate the subcellular uptake of methionine in multiple cell lines into several locations, including the mitochondrial matrix. Furthermore, we use Meteor to illuminate the dynamics of the methionine cycle in the cytoplasm and nucleus, finding cancer cells can rapidly increase methionine from metabolic precursors in both locations. Finally, demonstrated that Meteor can be used to visualize methionine dynamics in vivo using Caenorhabditis elegans . Thus, we have developed a new tool to measure methionine dynamics across scales with high dynamic range and spatiotemporal resolution.

DOI: https://doi.org/10.64898/2026.06.05.730515
Trends Immunol. 2026 Jun 25. pii: S1471-4906(26)00137-7. [Epub ahead of print]

Mitochondrial Ca2+ signaling: A metabolic rheostat defining tumor and immune cell fate.

Amélie E Bura, Andrea Rolong, Christophe Paget, Maxime Guéguinou.

  Mitochondrial calcium (mtCa2+) has long been framed as a bioenergetic regulator, yet evidence redefines it as a relevant immunometabolic switch. Within the tumor microenvironment, the mitochondrial calcium uniporter (MCU) complex and the NCLX-TMEM65 efflux axis maintain a 'Goldilocks zone' of Ca2+ homeostasis. This can be exploited by cancer cells to sustain oxidative phosphorylation and tricarboxylic acid-derived oncometabolite production, including succinate, fumarate, and 2-hydroxyglutarate, while imposing ionic and nutrient constraints on infiltrating immune cells. Chronic mtCa2+ overload in effector T cells drives mitochondrial dysfunction and exhaustion, while oxidative phosphorylation-dependent Ca2+ flux enforces the acquisition of an immunosuppressive profile in macrophages. Disrupting these tumor-immune ionic imbalances through selective MCU modulation or efflux pathway targeting offers a strategy to restore immune surveillance and/or enhance immune checkpoint inhibitor therapies.

Keywords:  T cells; cancer; immune checkpoint blockade; immunometabolism; mitochondrial calcium signaling; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.it.2026.05.012
Autophagy. 2026 Jun 24.

Robust and sensitive ELISA detection of total and activated PRKN.

Jens O Watzlawik, Bernardo A Bustillos, Claudia Rodriguez Martinez, Dennis W Dickson, Zbigniew K Wszolek, Owen A Ross, Wolfdieter Springer, Fabienne C Fiesel.

  Parkinson disease (PD) is closely linked to disruptions in mitochondrial quality control, a process regulated by the ubiquitin kinase PINK1 and the E3 ubiquitin ligase PRKN/parkin. Upon mitochondrial damage, PINK1 phosphorylates ubiquitin, which in turn recruits and activates PRKN. Full activation of PRKN is mediated by PINK1-dependent phosphorylation of PRKN at serine 65, which leads to widespread ubiquitination of mitochondrial substrates and amplifies the mitophagy response. Disruption of this pathway results in mitochondrial accumulation, oxidative stress, and neuronal death, all key mechanisms of PD pathogenesis. Genetic studies have shown biallelic loss-of-function mutations in PRKN are the most common cause of early-onset PD. Although the role of haploinsufficiency remains under investigation, PRKN protein becomes insoluble and inactive with aging or post-translational modifications, indicating that functional protein levels are a key determinant of disease risk. Reliable quantification of total and activated PRKN in samples has not been feasible, limiting research and clinical assessment. To address this, we developed and validated knockout (KO)-verified sandwich ELISA assays that quantify both total PRKN and PINK1-phosphorylated p-S65-PRKN. These assays provide absolute quantification of PRKN, improving functional diagnosis, and patient stratification in PD. Application of these methods established the concentration of PRKN in cells and in brain and revealed significant effects of a common genetic PRKN variant, further highlighting the importance of determining functional PRKN protein levels. The developed immunoassays complement previously established PINK1 and p-S65-Ub measurements, enhancing mechanistic insight into mitophagy and enabling effective monitoring of PD therapies and other neurodegenerative diseases.

Keywords:  Autophagy; P-S65-PRKN; PARK2; PINK1; biomarker; mitochondria; mitophagy; parkin; parkinson disease; ubiquitin

DOI:  https://doi.org/10.1080/15548627.2026.2694658
Cell Rep. 2026 Jun 22. pii: S2211-1247(26)00665-0. [Epub ahead of print]45(7): 117587

De novo pyrimidine synthesis controls germinal center B cell and plasma cell fates and systemic autoimmunity.

Julia L Weber, Tien Bui, Keomonyroth Nuon, Adam J Fike, Sophia M Crocker, Kristen N Bricker, Anju Maharjan, Wujuan Zhang, Aaron R Goldman, Sathi Babu Chodisetti, Ziaur S M Rahman.

  Whether and how pyrimidine metabolites promote systemic autoimmunity is unknown. Here, metabolomics and 15N-amide glutamine tracing show enhanced flux through de novo pyrimidine synthesis in systemic lupus erythematosus (SLE)-prone B cells. Temporal inhibition of pyrimidine synthesis dampens SLE-prone but not foreign antigen-specific germinal center (GC), plasma cell (PC), and antibody responses. Uridine monophosphate synthase (UMPS) conditional deletion, however, reveals a B cell-intrinsic requirement of de novo pyrimidine synthesis in foreign antigen-driven and SLE-prone GC, PC, and antibody responses and kidney immune complex deposition. Metabolomics, mitochondrial stress test, metabolic flow cytometry, glycolytic rate assay, and RNA sequencing highlight the importance of pyrimidine synthesis in promoting aerobic glycolysis and oxidative phosphorylation in SLE-prone B cells. De novo pyrimidine synthesis helps SLE-prone B cells maintain heightened metabolic state and expression of metabolic regulator, cMYC. Mechanistically, mTORC1 and S6K1 downstream of TLR7 and CD40 signaling in B cells promote pyrimidine synthesis by activating CAD, a rate-limiting enzyme of this pathway.

Keywords:  CAD; CP: Immunology; UMPS; autoantibody; autoimmunity; germinal center; mTORC1; plasma cell; pyrimidine metabolism

DOI:  https://doi.org/10.1016/j.celrep.2026.117587
Cell Commun Signal. 2026 Jun 25.

PIGBOS-CLCC1 interaction shapes cellular calcium dynamics and energy metabolism.

Seemanti Aditya, Amal Kanti Bera.

  PIGBOS is a recently identified 54-amino acid microprotein localized to the mitochondrial outer membrane and implicated in the endoplasmic reticulum (ER) stress response. Here, we identify a previously unrecognized role for PIGBOS in cellular Ca2+ homeostasis. Manipulation of PIGBOS expression in HEK293T cells revealed that PIGBOS enhances Ca2+ signaling by promoting ER Ca2+ release through inositol 1,4,5-trisphosphate (IP3) receptors and subsequent mitochondrial Ca2+ uptake in response to histamine stimulation. In contrast, siRNA-mediated depletion or genetic ablation of PIGBOS markedly attenuated these responses. PIGBOS influenced Ca2+ transfer from the ER to mitochondria without affecting direct mitochondrial Ca2+ uptake and also promoted store-operated Ca2+ entry. Functional analyses demonstrated that the interaction of PIGBOS with the ER-resident chloride channel CLCC1 via its C-terminal region is required for this activity. Network analysis predicted a direct association between PIGBOS and CLCC1, as well as indirect connections with core Ca2+ signaling components, including IP3 receptors, STIM1, Orai1, and SERCA, whose expression was altered upon modulation of PIGBOS abundance. Loss of PIGBOS impaired mitochondrial respiration, reduced ATP production, and increased reactive oxygen species. Together, these findings establish PIGBOS as a key regulator of ER-mitochondrial Ca2+ signaling that couples Ca2+ dynamics to mitochondrial bioenergetics and cellular stress responses.

Keywords:  CLCC1; Calcium signaling; Microprotein; PIGBOS

DOI:  https://doi.org/10.1186/s12964-026-03027-3
Sci Adv. 2026 Jun 26. 12(26): eaef1896

GPAM mediates mitochondrial dysfunction and the progression of alcoholic liver disease through lipid remodeling.

Zibin Zhan, Xuewen Liu, Zehua Li, Xueyan Qiao, Shuo Li, Yu Gong, Luping Yang, Yi Gao, Xianfeng Xia, Kunhao Bai, Fanhong Zeng, Jun Weng.

Lipid metabolic disorders and mitochondrial dysfunction are key and core pathological processes that contribute to the progression of alcoholic liver disease (ALD). However, the effects of lipid metabolism disorders on mitochondrial dysfunction in patients with ALD remain unknown. Here, we demonstrated that glycerol-3-phosphateacyltransferase (GPAM) expression was down-regulated in patients with ALD and associated with ALD progression. Dysregulation of GPAM, a triglyceride synthetase, reshaped lipid metabolism by increasing the levels of toxic lipids such as ceramide and lysophosphatidylcholine and reducing the levels of mitochondrial structural lipids such as cardiolipin. These changes resulted in abnormal mitochondrial dynamics, impaired mitophagy, and dysfunctional mitochondrial respiration, which induced activation of the cGAS-STING pathway. This activation resulted in the accumulation of inflammatory infiltrates, triggering the ALD process in mice. However, the reexpression of GPAM in vivo and in vitro and in hepatic organoids alleviated the development of ALD. This study aimed to determine whether GPAM is a potential therapeutic agent and assess the close relationship between lipid metabolism disorders and mitochondrial dysfunction in patients with ALD.

DOI: https://doi.org/10.1126/sciadv.aef1896
Cell Metab. 2026 Jun 25. pii: S1550-4131(26)00227-5. [Epub ahead of print]

The metabolic basis of regulated cell death.

Jiao Liu, Jiayi Wang, Rui Kang, Guido Kroemer, Daolin Tang.

Regulated cell death (RCD) has long been conceptualized as a genetically encoded signaling process, yet its outcome is ultimately dictated by cellular metabolism. Here, we propose that cellular metabolism functions as a gatekeeper of RCD, establishing permissive or restrictive states that determine cell fate. Bioenergetic capacity, redox balance, lipid composition, and metal availability impose metabolic constraints that bias cells toward survival or distinct death modalities. At the systems level, organelle-resolved metabolism and inter-organelle communication coordinate the spatial control of death processes. We further position RCD pathways along a metabolic continuum, ranging from energy-dependent apoptosis to chemistry-driven ferroptosis. This framework explains the plasticity of death responses and suggests that metabolic reprogramming can redirect cell fate. Targeting metabolic dependencies thus offers a strategy to control cell death in disease.

DOI: https://doi.org/10.1016/j.cmet.2026.06.001
Front Immunol. 2026 ;17 1852236

Mitochondria: from powerhouses of cells to hubs in antitumor immunity.

Xiaofeng Li, Yanfeng Shi, Yan Zhao, Gengjun Zhu, Lifang Jin.

  While immune checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapies constitute the cornerstone of current immunotherapy, their efficacy is often limited by, most notably, the immunosuppressive tumor microenvironment. Recently, mitochondria are recognized as pivotal metabolic-immune hubs that critically support tumor progression, metastasis, and immune evasion. However, this insight has not yet translated into a clear understanding of the underlying mechanisms or their therapeutic potential. This review summarizes the role of mitochondria in cellular metabolic regulation, with a focus on mitochondrial-mediated metabolic reprogramming in cancer and immune cells within the tumor microenvironment. We then discuss therapeutic opportunities to potentiate antitumor immunity by targeting mitochondrial reprogramming in cancer and CAR-T cells. Finally, we offer a forward-looking perspective on emerging mitochondria-targeted strategies, such as mitochondrial vaccines, precise mtDNA editing, and engineered mitochondrial transplantation.

Keywords:  CAR-T; antitumor immunity; metabolic reprogramming; mitochondria; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1852236
Cell Signal. 2026 Jun 25. pii: S0898-6568(26)00352-9. [Epub ahead of print] 112697

Pan-cancer analysis reveals the prognostic relevance of NUP54 and its association with HIF-1α-related glycolytic phenotypes in lung adenocarcinoma.

Peng Cheng, Chengru Song, Qian Han, Hongjie Yang, Ruitai Fan.

  The role of the nuclear pore protein NUP54 in tumorigenesis and progression remains unclear. By integrating multiomics data from TCGA, GTEx, CPTAC, and other sources, in this study, the first pan-cancer landscape of NUP54 was systematically delineated: its mRNA and protein expression levels are significantly upregulated in most types of cancer, including lung adenocarcinoma, hepatocellular carcinoma, and gastric cancer. It has a high diagnostic value across several types of cancer, including cholangiocarcinoma and pancreatic cancer. Its prognostic value has high tissue specificity: serving as an independent risk factor in low-grade glioma, lung adenocarcinoma, and pancreatic cancer, while protecting against renal clear cell carcinoma. Focusing on lung adenocarcinoma, multi-cohort clinical assessment, single-cell transcriptomics analysis, and functional experiments confirmed that high expression of NUP54 is an independent predictor of poor patient prognosis and significantly promotes the proliferation of cancer cells, colony formation, and in vivo tumorigenesis. NUP54 activates the HIF-1α signaling pathway to upregulate key glycolytic molecules LDHA, PKM2, and GLUT1, thereby driving glucose uptake, lactate production, and high ATP levels to promote metabolic reprogramming. This NUP54-associated phenotype was attenuated by the HIF-1α inhibitor PX-478 in vitro and in vivo. Overall, this study identifies NUP54 as a potential prognostic biomarker in LUAD and suggests that the NUP54/HIF-1α/glycolysis-related pathway may represent a biological mechanism worthy of further investigation.

Keywords:  Glycolysis; HIF-1α signaling pathway; Lung adenocarcinoma; Metabolic reprogramming; NUP54; Prognostic marker; pan-cancer analysis

DOI:  https://doi.org/10.1016/j.cellsig.2026.112697
bioRxiv. 2026 Jun 09. pii: 2026.06.04.730197. [Epub ahead of print]

Rosindol: A fluorogen for the quantitative measurement of reactive oxygen species in living cells.

Andrew Monnone, Molly Nicknish, Juan Jaramillo Montezco, Christine Sanganoo, Nalin Aggarwal, Arista Luong, Scott Schaus, Mark Grinstaff.

Reactive oxygen species (ROS) are key mediators of disease, yet accurate characterization in living systems remains challenging because current probes lack oxidation specificity and produce nonlinear, pH-dependent signals. Here we introduce Rosindol, a novel thioacetal-based fluorogenic probe that overcomes these limitations. Rosindol undergoes an umpolung oxidation in the presence of ROS to generate fluorescence, displaying dose-linear responses to H 2 O 2 , O 2 •⁻, OH•, and HOCl with minimal background signal. Unlike conventional probes, Rosindol is pH-independent, photostable, water soluble, and agnostic to glucose concentration, esterase expression, and ambient oxygen. Validation in human cells-including PMA-stimulated neutrophils and SOD knockout models-confirms accurate detection of cytosolic and mitochondrial ROS. In pancreatic cancer cells, Rosindol reveals a fourfold increase in mitochondrial O 2 •⁻ generation capacity via Complex I of the electron transport chain. Glucose stimulation induces twofold higher ROS generation in malignant cells, highlighting a connection between Warburg metabolism and the etiology of oxidative stress in pancreatic cancer. These studies illustrate the utility of Rosindol to provide valuable insight to oxidative stress processes in complex biological environments.

DOI: https://doi.org/10.64898/2026.06.04.730197
Cell Commun Signal. 2026 Jun 22.

Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation.

Qingqi Zhang, Junyan Gao, Yiting Yang, Ping Guo, Huiqin Gao, Shuaiyong Zhao, Shuanglin Zhang, Yaping Shi, Guanxing Xie, Yutong Han, Hao Liu, Yunzeng Zou.

  Mitochondria-associated endoplasmic reticulum membrane (MAM), which serves as a signaling hub for interactions between the endoplasmic reticulum (ER) and mitochondria, dynamically coordinates innate immune processes by regulating calcium homeostasis, lipid metabolism, mitochondrial dynamics, mitochondrial protein modifications, and autophagy. MAM regulates calcium homeostasis to govern mitochondrial energy metabolism and inflammasome activation; maintains lipid metabolism for membrane integrity to support antiviral signaling pathways; controls mitochondrial fission and fusion dynamics, processes that are closely associated with mitochondrial DNA (mtDNA) release; regulates mitochondrial protein modifications to fine-tune the function of proteins localized at MAM; and facilitates the clearance of damaged mitochondria and leaked mtDNA through autophagy. Most critically, MAM dysfunction and innate immune dysregulation form a vicious cycle: immune activation disrupts MAM integrity, and MAM abnormalities exacerbate the release of mitochondrial damage-associated molecules, continuously driving overactivation of pathways such as inflammasomes and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, thereby promoting the development of autoimmune diseases. This review synthesizes current literature on the molecular mechanisms by which MAM regulates innate immunity. We summarize how disruptions in MAM-mediated mitochondrial homeostasis contribute to innate immune imbalance. By integrating these findings, we highlight potential intervention nodes. This underscores the clinical relevance of targeting MAM in immune-related pathological conditions.

Keywords:  Innate immunity; Mitochondria-associated endoplasmic reticulum membrane (MAM); Mitochondrial homeostasis; MtDNA

DOI:  https://doi.org/10.1186/s12964-026-03013-9
J Cell Biol. 2026 Sep 07. pii: e202507087. [Epub ahead of print]225(9):

PIKfyve influences inter-organelle contacts with lysosomes to modulate the endoplasmic reticulum.

Nicala Jenkins, Zainab Adamji, Maria R Narciso, Nourhan R Almasri, Sharifa Lomiyev, Roberto J Botelho.

Lysosomes clear unwanted cellular material delivered by constant membrane fusion. Membrane fission is thus required to balance lysosome size, number, and composition. PIKfyve is a lipid kinase that converts phosphatidylinositol-3-phosphate [PtdIns(3)P] to phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P2] and promotes lysosome fission since lysosomes coalesce into larger, but fewer, organelles in its absence. Here, we reveal a role for PIKfyve in regulating ER dynamics. We show the ER is less reticulated and motile in cells inhibited for PIKfyve. Partly, this arises because lysosomes cluster perinuclearly and are less motile, which appears to arrest ER hitchhiking, a process in which lysosomes pull and form ER tubules. Secondly, the ER morphology is distorted because of hyper-tethering of protrudin, an ER transmembrane protein, to lysosomes via excess PtdIns(3)P and protrudin's FYVE domain. Our findings reveal that PIKfyve balances phosphoinositides at ER-lysosome contact sites to govern ER properties and have significant implications for our understanding of PIKfyve function and of diseases linked to its dysfunction.

DOI: https://doi.org/10.1083/jcb.202507087
bioRxiv. 2026 Jun 10. pii: 2026.06.09.730804. [Epub ahead of print]

Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.

Michel Thiebaut de Schotten, Cynthia C Liu, Catherine Kelly, Ke Bo, Tor D Wager, Eugene V Mosharov, Martin Picard.

Mitochondria support the bioenergetic processes that enable brain function and cognition, but we have lacked a label-free, non-invasive approach to explore how brain mitochondria are linked to ageing, disease, and cognition in humans. A recently introduced MitoBrainMap neuroimaging framework predicts mitochondrial features from magnetic resonance data alone, potentially bridging cellular biology with macroscale brain organization. Here, we tested whether this framework captures meaningful age- and pathology-related mitochondrial variation. Consistent with existing literature, we find that MR-predicted mitochondrial density and tissue respiratory capacity consistently declined with age, whereas mitochondrial respiratory capacity-an index of mitochondrial quality-was relatively preserved across the lifespan. Moreover, the relations among specific mitochondrial features predicted from our algorithm were consistent with their biological organization, supporting preliminary construct validity for MR-predicted mitochondrial features. In patients with rare mitochondrial diseases, predicted maps revealed region-specific alterations in mitochondrial density and respiratory chain components, particularly the expected compensatory upregulation of complex II, but not of other mitochondrial genome-encoded components. Finally, the MR-based mitochondrial features were associated with the energetic stress marker GDF15 measured in blood, as well as with cognitive performance measures, linking the novel predictions of brain mitochondria to systemic stress and behavior. These findings introduce a first-generation, label-free, neuroimaging-based mitochondrial mapping as a non-invasive window into living human brain mitochondria.

DOI: https://doi.org/10.64898/2026.06.09.730804
J Vis Exp. 2026 Jun 02.

Universal Pressure-Loading Device for Live-Cell Imaging under Sustained Physiological Mechanical Stress.

Wei Yan, Yixi Zhang, Lu Yang, Yuqin Jiang, Qin Yang, Lingyi Jiang, Haocheng Bian, Xiang Qin, Tingting Li, Yiyao Liu, Shun Li.

This protocol describes a hydrostatic pressure-loading device that facilitates real-time microscopic observation of adherent cells during sustained hydrostatic pressure stimulation, and is compatible with 3.5 cm commercial cell culture dishes. The apparatus consists of an airtight culture chamber fabricated from an aluminum base, an optically transparent poly(methyl methacrylate) cover, gas inlet/outlet ports integrated into the cover, and a sealed observation window. By connecting to a regulated gas source, the device maintains a stable hydrostatic pressure (0-200 kPa, adjustable) while enabling continuous phase-contrast or fluorescence imaging. Using this pressure-loading device, pressure-induced dose-dependent effects on cell phenotype and behaviors, such as morphology, proliferation, and migration, can be recorded. Furthermore, fluorescent signals can also be recorded in real time. Here, pressure-triggered Ca2⁺ signaling heterogeneity and dynamics in breast cancer MDA-MB-231 cells and cervical cancer HeLa cells were observed and quantified by inverted fluorescence microscopy using time-lapse imaging. This platform integrates mechanical loading with live‑cell imaging to overcome limitations of conventional endpoint systems, providing a universal tool for mechanobiological studies.

DOI: https://doi.org/10.3791/70868
Nat Commun. 2026 Jun 25.

Targeting DGAT1 reprograms lipid landscape and restores CD8⁺ T cell immunity in pancreatic cancer.

Zhongkun Liu, Lang Chen, Tong Zhang, Yuliang Wang, Panpan Ma, Xiangwei Zhang, Ronghui Liu, Ruiying Zhang, Xuanhao Zhang, Qingqing Su, Jinyan Huang, Da Wang, Qi Zhang, Cunqi Ye, Yun-Hua Liu.

Lipid accumulation is a hallmark of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment, yet effective strategies to reprogram this lipid-rich niche and restore anti-tumor immunity remain limited. Here, we show that diacylglycerol O-acyltransferase 1 (DGAT1) as a tumor-intrinsic metabolic checkpoint that promotes immune evasion. DGAT1 inhibition rewires tumor lipid metabolism by promoting increased fatty acid uptake and redistribution, thereby depleting extracellular free fatty acids that impair CD8⁺ T cell function. Mechanistically, decreased palmitate availability alleviates endoplasmic reticulum stress, preserves FOXO1 activity, and supports stem-like CD8⁺ T cell differentiation. This competitive lipid remodeling enhances memory potential, restrains terminal exhaustion, and sensitizes PDAC tumors to PD-1 checkpoint blockade in vivo. Together, our findings identify tumor-immune lipid crosstalk as a key barrier to effective immunity in PDAC and establish DGAT1 as a promising therapeutic target to restore T cell function and improve immunotherapy response.

DOI: https://doi.org/10.1038/s41467-026-74315-2
Front Oncol. 2026 ;16 1849057

Targeting mitochondria as a potential therapeutic strategy against radioresistance in cancer.

Nazia Nazam, Shaikh Sadiya, Saba Khan, Aroonima Misra, Niti Sureka, Kirti Panwar, Neelam Sahani, Sufian Zaheer.

  Radioresistance remains a major barrier to effective cancer therapy, contributing to tumor persistence, recurrence, and poor clinical outcomes. Increasing evidence identifies mitochondria as central regulators of radiation response through their multifaceted roles in cellular bioenergetics, redox homeostasis, mitochondrial DNA (mtDNA) maintenance, apoptotic signaling, and mitochondrial dynamics. Radioresistant tumor cells undergo profound metabolic reprogramming characterized by enhanced oxidative phosphorylation (OXPHOS), glycolytic plasticity, glutaminolysis, and pentose phosphate pathway activation, enabling sustained ATP generation, antioxidant defense, and efficient DNA repair under radiation stress. In parallel, mitochondrial reactive oxygen species (ROS) signaling is tightly modulated by antioxidant systems including glutathione, superoxide dismutase, catalase, and NRF2-driven pathways, thereby limiting radiation-induced oxidative injury. Alterations in mitochondrial fusion and fission dynamics, particularly Drp1-mediated fission, further support tumor survival by promoting mitophagy, metabolic adaptation, and resistance to apoptosis. Additionally, enhanced mtDNA repair and mitochondrial biogenesis preserve mitochondrial integrity in irradiated cancer cells. Dysregulation of mitochondria-mediated intrinsic apoptotic pathways, including aberrant expression of Bcl-2 family proteins, further facilitates evasion of radiation-induced cell death. This review comprehensively examines the molecular mechanisms by which mitochondria contribute to tumor radioresistance and critically discusses emerging mitochondria-targeted therapeutic strategies aimed at improving radiosensitivity. These include OXPHOS inhibitors, glycolytic and glutaminase inhibitors, ROS-modulating agents, mitochondrial dynamics regulators, nanoparticle-based mitochondrial targeting systems, and combinatorial approaches integrating radiotherapy with immunotherapy or DNA damage response inhibitors. By integrating mechanistic insights with emerging preclinical and clinical evidence, this review highlights mitochondria as actionable therapeutic vulnerabilities and underscores the translational potential of mitochondrial-targeted radiosensitization strategies for improving outcomes in resistant malignancies.

Keywords:  cancer; mitochondria; radioresistance; radiosensitization; radiotherapy

DOI:  https://doi.org/10.3389/fonc.2026.1849057
Cell Death Dis. 2026 Jun 25.

Targeting mitochondrial α-ketoglutarate sequestration disables dual oncogenic drivers and metabolic adaptability in pancreatic ductal adenocarcinoma.

Yeting Xu, Hongjiang Guo, Shengxi Li, Yucheng Wang, Yinghao Cao, Lin Wang, Qiuxia Chen, Ziyi Qin, Jiaxing Qiu, Yuhan Liu, Yunfan Li, Jiaming Zou, Yingying Wang, Kaihan Zhang, Rui Ju, Lei Guo.

Pancreatic ductal adenocarcinoma (PDAC) exhibits hyperactive mitochondrial metabolism, yet how this rewiring spatially restricts the availability of metabolites for oncogenic signaling and drives systemic metabolic dysregulation in PDAC remains unknown. Here, we identify enhanced mitochondrial α-ketoglutarate (α-KG) sequestration as a key metabolic vulnerability in PDAC. Using multi-omics, preclinical models, and clinical correlation analyses, we identified elevated mitochondrial metabolic gene expression in PDAC. Moreover, higher expression of dihydrolipoamide succinyltransferase (DLST) correlates with poorer PDAC prognosis, suggesting the role of mitochondrial α-KG sequestration in PDAC progression. Targeting mitochondrial respiration with the complex I inhibitor carboxyamidotriazole orotate (CTO) redirected α-KG flux from mitochondrial sequestration, and increased α-KG-dependent m6A demethylation of MYC mRNA and HIF-1α hydroxylation. Combining CTO or α-KG dehydrogenase complex inhibitor devimistat with an α-KG analog (dimethyl α-KG) amplified c-Myc/HIF-1α suppression. Consequently, prolonged CTO exposure downregulated multiple metabolic pathways (glycolysis, pentose phosphate pathway, fatty acid synthesis) regulated by c-Myc/HIF-1α, and significantly delayed PDAC progression in vitro and in vivo. Our work first identify a novel mechanism whereby mitochondrial metabolism drives systemic metabolic dysregulation in PDAC through the sequestration of α-KG, and establishes "redirecting α-KG flux from mitochondrial sequestration" as a strategy to disable PDAC's metabolic adaptability. The orotate salt form of carboxyamidotriazole effectively disrupts mitochondrial α-KG sequestration to suppresses PDAC growth at a dose equivalent to the clinically tested level.

DOI: https://doi.org/10.1038/s41419-026-09016-1
Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2604695123

p53 overrides METTL5 loss-induced tumor suppression via mitochondrial respiration.

Guozhi Li, Qiujie Li, Jun Zhang, Yifei Huang, Wenjun Tao, Yali Cheng, Jiaju Sun, Jingying Yuan, Rui Zhang, Xiao-Min Liu, Jun Zhou.

  The tumor suppressor p53 is pivotal in repressing tumorigenesis under physiological conditions. Paradoxically, we find that wild-type (WT) p53 plays an oncogenic role in relieving METTL5 depletion-caused cancer regression by sustaining mitochondrial respiration. The methyltransferase METTL5 is upregulated in non-small cell lung cancer (NSCLC) and associated with advanced tumor grade and poor prognosis. Depletion of METTL5 impairs NSCLC cell proliferation and migration in vitro and in vivo, with p53-null cells displaying enhanced sensitivity. While METTL5-depletion inhibits cytoplasmic translation in both p53-WT and p53-null cells, only cells lacking p53 exhibit severe tumor regression due to defective mitochondrial protein synthesis and consequent respiratory dysfunction. Mechanistically, p53 binds 5'UTR of TOMM40, the crucial gatekeeper of mitochondrial protein import, to enforce its exclusion from translation. METTL5 loss promotes p53 nuclear retention via inhibiting MDM2-mediated p53 ubiquitination, alleviating its translational suppression of TOMM40, and supporting oxidative phosphorylation. Remarkably, the combination targeting of p53 and METTL5 synergistically attenuates the proliferation and migration in p53-WT cancer cells. Our study elucidates the essential role of p53 in supporting tumor viability upon METTL5 deficiency by maintaining mitochondrial respiration. Meanwhile, it provides a molecular foundation for developing therapeutic strategies regarding cancers with WT p53.

Keywords:  METTL5; lung cancer; mitochondrial respiration; p53; protein synthesis

DOI:  https://doi.org/10.1073/pnas.2604695123
bioRxiv. 2026 Jun 10. pii: 2026.06.06.727699. [Epub ahead of print]

Reductive carboxylation via isocitrate dehydrogenase 1 supports cardiac metabolic adaptation during oncometabolic stress.

Kyoungmin Kim, Tanvi Shankar, Yaqi Gao, Ian K Williamson, Nathaniel Snyder, Evan P Kransdorf, Ralph DeBerardinis, Heinrich Taegtmeyer, Brandon Faubert, Anja Karlstaedt.

Background: Cardiovascular disease and cancer are the two leading causes of morbidity and mortality worldwide. Metabolic dysregulation of cancer cells extends beyond the tumor microenvironment and increases the risk for cardiovascular diseases. One common somatic mutation in cancer cells affects isocitrate dehydrogenase (IDH) 1 and 2, which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the cytosol and mitochondria, respectively. IDH1 and 2 mutations cause the production of the oncometabolite D-2-hydroxyglutarate (D2-HG), which allosterically inhibits α-ketoglutarate dehydrogenase (α-KGDH) and is associated with reduced cardiac contractile function.
Methods: We combined stable isotope tracer studies with computational modeling to investigate the fundamental role of IDH isoforms in cardiac adaptation under oncometabolic stress.
Results: We uncovered an unexpected cardiac phenotype that expands the role of IDH1 in the heart beyond oxidative metabolism. We quantified the stable isotopomer distributions from glucose and glutamine in perfused working rat hearts and isolated adult ventricular cardiomyocytes using mass spectrometry-based metabolomics. Our analysis revealed that defective mitochondrial metabolism causes the redirection of carbon flux from oxidative towards reductive pathways. Reductive carboxylation of α-KGDH increases glutamine uptake and glutamine-derived citrate formation in working rat heart perfusions and cultured adult mouse ventricular cardiomyocytes. To identify which IDH isoform is responsible for redirecting carbon flux, we developed knockout models of IDH1, IDH2, and IDH3 in adult mouse ventricular cardiomyocytes. Loss of IDH1 expression impaired the reductive formation of citrate and caused functional defects in cardiomyocytes. Lastly, epigenetic analyses of histone marks revealed that IDH1 induces widespread alterations in histone acetylation and tri-methylation.
Conclusion: Our results highlight a novel role for IDH1 in cardiac metabolism and transcriptional control of metabolic adaptation to tumor-mediated stress and provide evidence that reductive-citrate formation may induce epigenetic modifications in the heart.

DOI: https://doi.org/10.64898/2026.06.06.727699
Cell Signal. 2026 Jun 22. pii: S0898-6568(26)00341-4. [Epub ahead of print] 112686

NDUFA4L2 acts as a mitochondrial checkpoint against ferroptosis in hypoxic clear cell renal cell carcinoma.

Xin Sun, Qirui Zhou, Yayun Wu, Weiwei Qian, Jiaxing Ma, Tao Zhang.

  This study aimed to define the functional role of the HIF-1α target gene NDUFA4L2 in clear cell renal cell carcinoma (ccRCC), specifically its regulation of mitochondrial function and the ferroptosis cell death pathway. Through TCGA data analysis and in vitro and in vivo models, we confirmed that HIF-1α induces NDUFA4L2 expression and mitochondrial localization. Using shRNA-mediated knockdown combined with rescue experiments employing the ferroptosis inhibitor ferrostatin-1 and the mitochondrial antioxidant mitoTEMPO, we demonstrated that silencing NDUFA4L2 triggered mitochondrial lipid peroxidation, altered mitochondrial ultrastructure, and suppressed proliferation via a mitochondria-associated ferroptotic mechanism. Mechanistically, NDUFA4L2 functioned parallel to Lactate Dehydrogenase B (LDHB); their genetic or pharmacological co-inhibition synergistically enhanced ferroptosis and suppressed cell viability in vitro and tumor growth in vivo, associated with elevated ferroptosis markers (PTGS2, 4-HNE). Furthermore, NDUFA4L2 knockdown sensitized tumors to radiotherapy by amplifying ferroptotic cell death. In conclusion, NDUFA4L2 is a critical suppressor of mitochondria-associated ferroptosis in ccRCC, acting cooperatively with LDHB to maintain redox homeostasis, and targeting the NDUFA4L2/LDHB axis represents a promising therapeutic strategy, particularly in combination with radiotherapy.

Keywords:  Clear cell renal cell carcinoma (ccRCC); Ferroptosis; Lipid peroxidation; Mitochondria; NDUFA4L2

DOI:  https://doi.org/10.1016/j.cellsig.2026.112686
Nat Chem Biol. 2026 Jun 22.

A ratiometric fluorescent reporter of mitochondrial sodium.

Koushambi Mitra, Soyoung Kim, Daphne Oettinger, Sanjeev Uthishtran, Qian Zhao, Aneesh Tazhe Veetil, Joseph R Ramirez, Hening Lin, Senthil Arumugam, Yamuna Krishnan.

Cells cope with salt stress, hypoxia or elevated cytosolic Ca2+ by regulating their mitochondrial Na+ levels. The discovery of the mitochondrial Na+/Ca2+ exchanger and its disease relevance has revealed the need to map mitochondrial Na+ in situ. Here we describe a ratiometric fluorescent reporter for Na+, denoted MitRatiNa, that reports mitochondrial Na+ levels independent of membrane potential and in diverse cell lines. Na+ in individual mitochondria varies greatly and, depending on cell type, can be as low as 1-5 mM or as high as 40 mM on average. We demonstrate that mitochondrial Na+ increases during cytosolic Ca2+ elevation, inhibition of glycolysis or respiration. Mitochondria in skin fibroblasts from healthy humans show a high Na+ population that disappears in fibroblasts of persons with mitochondrial diseases. The newfound ability to map absolute Na+ at the resolution of single mitochondria enables the dissection of regulatory mechanisms for mitochondrial Ca2+ and Na+ and potential identification of new therapeutic avenues.

DOI: https://doi.org/10.1038/s41589-026-02253-7
Front Neurosci. 2026 ;20 1847340

ALDOC modulates astrocytic glycolysis and AMPK/mTOR/HIF-1α signaling in Alzheimer's disease.

Zhenyuan Zhang, Yanmei Bai, Xiangjian Zhang, Jian Zhang, Guofeng Yang.

   Aims: Astrocytes provide crucial metabolic support for neurons and undergo significant metabolic changes in Alzheimer's disease (AD). Aldolase C (ALDOC), an astrocyte-enriched glycolytic enzyme, may play a role in this process. This study aimed to investigate whether ALDOC modulates astrocytic metabolism to support neuronal energy supply in patients with AD and to assess its therapeutic potential.
Methods: Hippocampal and cortical tissues from 6-month-old APP/PS1 and wild-type mice were subjected to western blotting, qPCR, and immunofluorescence staining for ALDOC and glycolytic proteins. An in vitro AD model was created using oligomeric β-amyloid (oAβ)-treated SVGp12 astrocytes. ALDOC was overexpressed or knocked down via plasmid or siRNA. Downstream effects on AMPK/mTOR/HIF-1α signaling and the expression of glycolytic markers (LDHA and PKM2) were evaluated by western blot and qPCR, as well as by lactate/ATP assays and extracellular acidification rate (ECAR) measurements. Neuron-astrocyte interactions were assessed in an SVGp12/SH-SY5Y coculture. Furthermore, the ability of magnesium ions to restore ALDOC expression was tested.
Results: ALDOC was specifically expressed in astrocytes but was downregulated in APP/PS1 mice, accompanied by reduced HIF-1α and LDHA levels, suggesting glycolytic impairment. Similar downregulation occurred in oAβ-treated SVGp12 cells. ALDOC overexpression was associated with altered AMPK/mTOR/HIF-1α signaling, enhanced glycolysis, and increased lactate and ATP production, whereas its knockdown had the opposite effects. These outcomes appeared to depend on HIF-1α, as suggested by the rescue experiments. In coculture, ALDOC overexpression in astrocytes supported neuronal metabolic function. Moreover, magnesium ions restored ALDOC activity and glycolysis in oAβ-treated astrocytes.
Conclusion: These results suggest that ALDOC is downregulated in APP/PS1 mice and is associated with glycolytic impairment. In oAβ-treated astrocytes, ALDOC appears to regulate glycolysis through the AMPK/mTOR/HIF-1α axis and may support neuronal energy via the lactate shuttle. Magnesium ions appear to offer a potential strategy for addressing the metabolic deficits in AD.

Keywords:  Alzheimer’s disease (AD); aldolase C (ALDOC); astrocytes; glycolysis; hypoxia-inducible factor-1α (HIF-1α); metabolic regulation

DOI:  https://doi.org/10.3389/fnins.2026.1847340
J Cell Biol. 2026 Aug 03. pii: e202505134. [Epub ahead of print]225(8):

Sequential changes in calcium transients during M phase regulate cardiomyocyte proliferation.

Honghai Liu, Niyatie Ammanamanchi, Jocelyn D Mich-Basso, Brian K Panama, Yao Li, Winston Huang, Dena Almeida, Christopher M Lewarchik, Brendan Lo, Yijen Wu, Michael Gotthardt, Michael I Kotlikoff, Wolfgang Baehr, Randall Rasmusson, Guy Salama, Bernhard Kühn.

Heart muscle growth and regeneration require the proliferation of cardiomyocytes. Rapid pulsatile increases in cytosolic Ca2+ concentration, called calcium transients (CaTs), trigger cardiomyocyte contractions, but how cardiomyocytes adapt Ca2+ signaling during proliferation is largely unknown. Here, we show that cardiomyocyte proliferation requires changes in Ca2+ signaling. Cardiomyocytes undergo a sequence of CaT changes during M phase: CaT amplitudes begin to decline in prometaphase, reach a minimum in metaphase, rise during anaphase, and return to the original state in daughter cardiomyocytes. Spindle poles show decreased Ca2+ levels during prometaphase and metaphase. Localized reduction of Ca2+ levels at spindle poles is mediated by dynein 1-dependent SERCA2a accumulation. Active cyclin-dependent kinase 1 (CDK1) induces both the decrease in CaT amplitudes and the accumulation of SERCA2a at the spindle poles, whereas CDK1 inhibition reverses these effects. Forcing an increase in cytosolic Ca2+ levels by blocking SERCA2a during prometaphase and metaphase disrupts mitosis and produces binucleated cardiomyocytes, underscoring the essential role of Ca2+ signaling changes for cardiomyocyte proliferation.

DOI: https://doi.org/10.1083/jcb.202505134