bims-celmim 2025-07-27 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2025–07–27
nineteen papers selected by
Marc Segarra Mondejar

Metabolic adaptations of brain metastasis.
Metastatic breast cancer cells are selectively dependent on the mitochondrial cristae-shaping protein OPA1.
Development of novel mitochondrial pyruvate carrier inhibitors for breast cancer treatment.
Metabolic reprogramming in breast cancer: Pathways driving progression, drug resistance, and emerging therapeutics.
Metabolic Effects of Succinate Dehydrogenase Loss in Cancer.
Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex.
Metabolic regulation of key developmental events during mammalian embryogenesis.
High altitude induces a shift from complex I to complex II in the brain mitochondria of newborn and adult mice.
In vivo measurement of an Apelin gradient with a genetically encoded APLNR conformation biosensor.
Altered fatty acid oxidation via CPT1A promotes epithelial-to-mesenchymal transition in ovarian cancer.
Exploiting genetic and environmental vulnerabilities to target DHODH in CNS tumors.
Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis.
De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma.
The metabolic significance of ATP-citrate lyase in cancer: insights into glutamine-fuelled citrate biosynthesis and tumour progression.
Ultra-Photostable Fluorescent Boron-Bridged Near-Infrared Probes to Reveal New Mode of Lipid Droplet-Mitochondria Interaction at STED Super-Resolution.
Relative adenosine production assay suitable for 2D and 3D tumor cell culture.
RIPK4-mediated MFN2 degradation drives osteogenesis through mitochondrial fragmentation and restricts myelopoiesis by blocking mitochondrial transfer.
Metabolomic profiles impacted by brief mindfulness intervention with contributions to improved health.
Marker-independent vibrational spectroscopy imaging recognizes the hypoxia effect in the human brain endothelium.

Nat Rev Cancer. 2025 Jul 24.

Metabolic adaptations of brain metastasis.

Pravat Kumar Parida, Srinivas Malladi.

Brain metastases remain a major clinical challenge, characterized by high mortality rates and often limited therapeutic options. The cellular and molecular processes that drive brain metastases are highly intricate, underscored by dynamic metabolic adaptations that enable tumour cells to thrive in the unique microenvironment of the brain. Emerging clinical and preclinical evidence reveals that these metabolic adaptations are not uniform but vary based on the tumour's tissue of origin, oncogenomic landscape and capacity to endure nutrient stress. Notably, proliferative and dormant metastatic cells within the brain exhibit distinct metabolic profiles, highlighting the complexity of targeting these cells. Key metabolic pathways, including glucose, fatty acid and amino acid metabolism, are co-opted not only to sustain cancer cell survival and growth but also to modulate interactions with resident brain cells, reshaping their function to support metastasis. Importantly, this metabolic heterogeneity underscores the inadequacy of a one-size-fits-all therapeutic approach. Here, we review the adaptive metabolic reprogramming that facilitates brain metastases and discuss emerging strategies to tailor interventions aimed at preventing and treating overt brain metastases.

DOI: https://doi.org/10.1038/s41568-025-00848-1
Cell Death Dis. 2025 Jul 21. 16(1): 539

Metastatic breast cancer cells are selectively dependent on the mitochondrial cristae-shaping protein OPA1.

Antigoni Diokmetzidou, Aurora Maracani, Anna Pellattiero, Mauricio Cardenas-Rodriguez, Erwan A Rivière, Luca Scorrano.

In breast cancer, the inner mitochondrial membrane fusion protein Optic Atrophy 1 (OPA1) is upregulated and its inhibition reverses acquired chemoresistance. However, it remains unclear whether OPA1 inhibition also targets normal breast cells. We show that OPA1 upregulation is a hallmark of metastatic breast cancer cells, which are selectively susceptible to OPA1 inhibition compared to isogenic normal or localized tumor cells. In an isogenic model spanning normal, transformed, and metastatic breast cancer cells, levels of Mitofusin 1 (MFN1) progressively declined while dynamin related protein 1 (DRP1) became increasingly active, correlating with fragmented mitochondria during cancer progression. Meanwhile, OPA1 levels were elevated in invasive cells characterized by mitochondrial fragmentation, tight cristae, and high respiration. OPA1 deletion selectively reduced metastatic cells mitochondrial respiration, proliferation, and migration. Specific OPA1 inhibitors MYLS22 and Opitor-0 diminished migration and increased death of metastatic cells, underscoring OPA1 as a selective vulnerability of metastatic breast cancer.

DOI: https://doi.org/10.1038/s41419-025-07878-5
J Biol Chem. 2025 Jul 16. pii: S0021-9258(25)02336-1. [Epub ahead of print] 110486

Development of novel mitochondrial pyruvate carrier inhibitors for breast cancer treatment.

Tanner J Schumacher, Zachary S Gardner, Jon Rumbley, Conor T Ronayne, Venkatram R Mereddy.

  Reprogrammed metabolism of cancer cells offers a unique target for pharmacological intervention. The mitochondrial pyruvate carrier (MPC) plays important roles in cancer progression by transporting cytosolic pyruvate into the mitochondria for use in the TCA cycle. In the current study, a series of novel fluoro-substituted aminocarboxycoumarin derivatives have been evaluated for their mitochondrial pyruvate carrier (MPC) inhibition properties. Our studies indicate that the aminocarboxycoumarin template elicits potent MPC inhibitory characteristics, and specifically, structure activity relationship studies show that the N-methyl-N-benzyl structural template provides the optimal inhibitory capacity. Further respiratory experiments demonstrate that candidate compounds specifically inhibit pyruvate driven respiration without substantially affecting other metabolic fuels, consistent with MPC inhibition. Further, computational inhibitor docking studies illustrate that aminocarboxycoumarin binding characteristics are nearly identical to that of classical MPC inhibitor UK5099 bound to human MPC, recently determined by cryoEM. The lead candidate C5 elicits cancer cell proliferation inhibition specifically in monocarboxylate transporter 1 (MCT1) expressing murine breast cancer cells 4T1 and 67NR, consistent with its ability to accumulate intracellular lactate. In vivo tumor growth studies illustrate that C5 significantly reduces the tumor burden in two syngeneic murine tumor models with 4T1 and 67NR cells. These studies provide novel MPC inhibitors with potential for anticancer applications in MCT1 expressing breast cancer tumor models.

Keywords:  aminocarboxycoumarin; breast cancer; mitochondrial pyruvate carrier; tumor metabolism

DOI:  https://doi.org/10.1016/j.jbc.2025.110486
Biochim Biophys Acta Rev Cancer. 2025 Jul 21. pii: S0304-419X(25)00138-6. [Epub ahead of print]1880(5): 189396

Metabolic reprogramming in breast cancer: Pathways driving progression, drug resistance, and emerging therapeutics.

Pankaj Garg, Gargi Singhal, David Horne, Ravi Salgia, Sharad S Singhal.

  Breast cancer (BC), one of the most frequent causes of cancer-related death in women, is known to be a highly heterogeneous disease in regard to molecular subtypes, which seem to possess different metabolic profiles. Aberrant metabolism is well understood as one of the hallmarks of cancer and it contributes to BC progression, therapeutic resistance, and metastasis. Here, we analyze BC metabolism and how certain cancer types, such as hormone receptor-positive, HER2-positive, and triple-negative BC, use glycolysis, lipid metabolism, amino acid compulsion, and mitochondrial biogenesis to feed and proliferate. These metabolic hallmarks, in the context of the tumor microenvironments, are illustrated to highlight the metabolic byproducts that are derived from reprogrammed pathways and are vital to immunosuppression and tumor survival under low oxygen and nutrient availability. Furthermore, we emphasize novel trends in anticancer drugs designed to strike on these metabolic dependencies to suppress tumor growth. In addition to summing up current knowledge about metabolic reprogramming in BC, this review reveals new targets for specific treatments that might enhance prognosis in certain types of BC. This review aims to bridge basic scientific insights and clinical perspectives, guiding future metabolic interventions in BC toward clinically relevant, subtype-specific therapeutic strategies.

Keywords:  Biomarker driven therapies; Breast cancer; Metabolic pathway inhibition; Metabolic reprogramming; Therapeutic resistance; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2025.189396
J Cell Physiol. 2025 Jul;240(7): e70066

Metabolic Effects of Succinate Dehydrogenase Loss in Cancer.

Adam Chatoff, Daniel S Kantner, Nathaniel W Snyder, Lori Rink.

  Succinate dehydrogenase (SDH) is both Complex II in the electron transport chain (ETC) and a key metabolic enzyme in the tricarboxylic acid cycle. SDH is a heterotetrameric enzyme consisting of four subunits SDHA, SDHB, SDHC, and SDHD, all encoded in the nuclear genome. In addition, the SDH complex requires two assembly factors, SDHAF1 and SDHAF2, which are required for assembly of SDHA and SDHB onto the inner mitochondrial-embedded subunits SDHC and SDHD. Once assembled, SDH catalyzes the conversion of succinate to fumarate coupled to the reduction of ubiquinone to ubiquinol via FAD/FADH2 and ultimately the generation of ATP via ATP synthase through a functioning ETC. Given the unique dual metabolic role of SDH, loss of activity results in major metabolic rewiring, potentially uncovering metabolic vulnerabilities that could be targeted for pharmacological manipulation in disease states. SDH is a tumor suppressor and SDH-loss is a driver of oncogenesis for cancers including pheochromocytomas, paragangliomas, gastrointestinal stromal tumors, and clear cell renal cell carcinomas. SDH deficiency also plays a role in the pathogenesis in non-neoplastic diseases, including Leigh syndrome and other neurometabolic disorders. Considering the implications of SDH function in both normal physiology and disease, understanding SDH function has fundamental and translational implications. This review seeks to summarize SDH deficiency, focusing on the role SDH plays in metabolism, the metabolic consequences of SDH deficiency, the proteomic consequences of SDH loss, thereby highlight potential therapeutic vulnerabilities in SDH-deficient cells.

Keywords:  Complex II; clear cell renal cell carcinoma; electron transport chain; gastrointestinal stromal tumors; leigh syndrome; pheochromocytomas/paragangliomas; succinate dehydrogenase; tricarboxylic acid cycle

DOI:  https://doi.org/10.1002/jcp.70066
Nat Commun. 2025 Jul 21. 16(1): 6700

Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex.

Yingyuan Sun, Yaru Wang, Zheng Xing, Dongyu Li, Rong Wang, Baozhi Chen, Ning Zhou, Alyssa Ayala, Benjamin P Tu, Xiaofeng Qi.

The Mitochondrial Pyruvate Carrier (MPC) bridges cytosolic and mitochondrial metabolism by transporting pyruvate into mitochondria for ATP production and biosynthesis of various essential molecules. MPC functions as a heterodimer composed of MPC1 and MPC2 in most mammalian cells. Here, we present the cryogenic electron microscopy (cryo-EM) structures of the human MPC1-2 complex in the mitochondrial intermembrane space (IMS)-open state and the inhibitor-bound in the mitochondrial matrix-open state. Structural analysis shows that the transport channel of MPC is formed by the interaction of transmembrane helix (TM) 1 and TM2 of MPC1 with TM2 and TM1 of MPC2, respectively. UK5099, a potent MPC inhibitor, shares the same binding site with pyruvate at the matrix side of the transport channel, stabilizing MPC in its matrix-open conformation. Notably, a functional W82F mutation in MPC2 leads to the complex in an IMS-open conformation. Structural comparisons across different conformations, combined with yeast rescue assays, reveal the mechanisms of substrate binding and asymmetric conformational changes in MPC during pyruvate transport across the inner mitochondrial membrane (IMM) as well as the inhibitory mechanisms of MPC inhibitors.

DOI: https://doi.org/10.1038/s41467-025-61939-z
Nat Cell Biol. 2025 Jul 22.

Metabolic regulation of key developmental events during mammalian embryogenesis.

Yuyan Xu, Wei Xie, Jin Zhang.

Metabolic regulation is critical in embryonic development and influences key processes such as fertilization, zygotic genome activation, cell compaction, implantation, gastrulation and organ development. Here we explore the interplay between metabolism and embryonic development in the context of important sequential key embryonic events, highlighting the orchestration of developmental processes by various metabolites and signalling molecules. Key metabolites, including glucose, fatty acids and amino acids, act as modulators of developmental processes, while also serving as energy sources and building blocks for cellular structures. Understanding the intricate relationship between metabolism and embryogenesis may provide insights into developmental disorders and potential therapeutic interventions.

DOI: https://doi.org/10.1038/s41556-025-01720-y
J Exp Biol. 2025 Jul 22. pii: jeb.250422. [Epub ahead of print]

High altitude induces a shift from complex I to complex II in the brain mitochondria of newborn and adult mice.

Maud Demarest, Fernanda Aliaga-Raduan, Christian Arias-Reyes, Marcelino Gonzales, Edith M Schneider Gasser, Jorge Soliz, Vincent Joseph.

  Species living at high altitude (HA) often exhibit optimized oxygen utilization at adulthood, however, the plasticity of metabolic pathways during postnatal development remains unclear. Because mice, but not rats are commonly found at HA, we investigated mitochondrial oxygen consumption rates (OCR) in the cerebral cortex across postnatal development and at adulthood at sea level (SL, Quebec, Canada) under normoxia or hypoxia (13.5% O2), and at HA (La Paz, Bolivia, 3600m) after 50 generations of residency. At postnatal day 7 (P7), 14 (P14), 21 (P21) and in adults (P60-90), fresh tissue samples were used to assess mitochondrial OCR under states of proton LEAK (OCRLEAK(N)) and oxidative phosphorylation (OXPHOS) using substrates for complex I (N pathway - OCRN), complex II (S pathway - OCRS), and complexes I+II (NS pathways - OCRNS). Our results showed 1) At HA, rats exhibit higher OCR at P7, P14, and at adulthood compared to their SL counterparts, and 2) HA residency induces a shift from the N pathway to the S pathway at all ages in mice. Finally, these responses were absent in SL animals exposed to postnatal hypoxia, highlighting the importance to study HA-living species. These findings emphasize key metabolic shifts, with implications for understanding responses to hypoxia in species showing divergent success at HA.

Keywords:  Brain cortex; High altitude; Mitochondria; Postnatal development; Rodents.

DOI:  https://doi.org/10.1242/jeb.250422
Nat Commun. 2025 Jul 21. 16(1): 6682

In vivo measurement of an Apelin gradient with a genetically encoded APLNR conformation biosensor.

Lukas Herdt, Hannes Schihada, Michael Kurz, Sebastian Ernst, Jean Eberlein, Peter Kolb, Cornelius Krasel, Moritz Bünemann, Christian S M Helker.

The Apelin receptor (APLNR), a class A G-protein coupled receptor, plays a crucial role during cardiovascular development and tumor angiogenesis. To understand its spatiotemporal activity in health and disease is fundamental for the development of drugs to manipulate its activation state. To obtain this understanding, here we develop a tool box of various APLNR conformation biosensors, based on FRET, BRET and the conformation-sensitive fluorophore circularly permuted GFP (cpGFP), with further focus on its in vivo application. We demonstrate the functionality of our biosensors by pharmacological characterization and signal transduction analysis in vitro. Two APLNR-cpGFP biosensors show superior signal-to-noise ratio and are further analyzed for their in vivo applicability. In zebrafish embryos, APLNR-cpGFP biosensors are able to bind both endogenous ligands, Apelin and Apela, and visualize endogenous Aplnr activity in growing blood vessels. Moreover, we are able to measure an Apelin ligand gradient across cellular distances in vivo. Hence, these APLNR conformation biosensors are powerful tools to resolve the spatiotemporal Apelin signaling activity in health and disease.

DOI: https://doi.org/10.1038/s41467-025-61781-3
FEBS J. 2025 Jul 24.

Altered fatty acid oxidation via CPT1A promotes epithelial-to-mesenchymal transition in ovarian cancer.

Suman Pakhira, Sib Sankar Roy.

  Metabolic alterations are increasingly recognized as fundamental features of cancer. Recent studies have highlighted the involvement of altered fatty acid oxidation (FAO) at different stages of tumor development. As the rate-limiting enzyme of FAO, CPT1 plays a crucial role in these metabolic adaptations in cancer cells. However, the regulation of CPT1 expression and activity in tumor cells still requires detailed investigation. Our studies reveal that CPT1A, a variant of CPT1, is significantly upregulated in ovarian cancer (OC) and correlates with poor prognosis. Inhibition of CPT1A, either by siRNA-mediated knockdown or by etomoxir, reduces the migratory and invasive properties of the OC cells. CPT1A exerts these effects by modulating the expression of epithelial-to-mesenchymal transition (EMT)-associated genes at transcriptional and protein levels. Growth factors such as transforming growth factor beta (TGFβ) are abundant in the tumor microenvironment and modulate the metabolic profile of tumors, thereby promoting EMT. Our findings demonstrate that TGFβ treatment increases the rate of FAO in ovarian cancer cells. Mechanistically, TGFβ mediates this effect by enhancing CPT1A expression and its enzymatic activity in OC cells through an AMPK-dependent pathway. Additionally, we identified NRF2 as a potential transcriptional regulator of CPT1A within the context of TGFβ-AMPK signaling. Finally, inhibiting CPT1A successfully attenuates TGFβ-induced EMT in ovarian cancer cells. Cumulatively, our study underscores the role of CPT1A-mediated FAO in facilitating ovarian cancer progression through TGFβ-induced EMT.

Keywords:  CPT1A; EMT; FAO; TGFβ; ovarian cancer

DOI:  https://doi.org/10.1111/febs.70193
Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdaf149

Exploiting genetic and environmental vulnerabilities to target DHODH in CNS tumors.

Eli E Bar, Julie-Aurore Losman.

  This review explores innovative therapeutic strategies for treating central nervous system (CNS) tumors by targeting their unique metabolic dependencies. This approach marks a significant departure from traditional cytotoxic treatments, focusing instead on the metabolic vulnerabilities created by the tumor's microenvironment and genetic profile. A key area of interest is the de novo pyrimidine synthesis pathway, which is crucial for DNA and RNA synthesis, DNA repair, and protein glycosylation. We highlight the potential of dihydroorotate dehydrogenase (DHODH) inhibitors, which have shown promising anti-tumor activity in preclinical models. The blood-brain barrier, while a challenge for drug delivery, may enhance the efficacy of these inhibitors by maintaining a unique metabolic environment in the brain. Specific brain tumors, such as glioblastoma multiforme, MYC-amplified medulloblastoma, and IDH mutant gliomas, exhibit heightened sensitivity to DHODH inhibition. We suggest that the unique metabolic environment of the brain could make DHODH a more effective therapeutic target for brain tumors compared to other cancer types. Despite the speculative nature of these findings, the compelling preclinical data warrant further investigation into brain-penetrant DHODH inhibitors for CNS malignancies.

Keywords:  CNS tumors; DHODH inhibitors; brain tumors; metabolic vulnerabilities; pyrimidine synthesis

DOI:  https://doi.org/10.1093/noajnl/vdaf149
Cell Rep. 2025 Jul 21. pii: S2211-1247(25)00803-4. [Epub ahead of print]44(8): 116032

Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis.

Louise Nuyttens, Marah Heyerick, Geike Heremans, Elise Moens, Maxime Roes, Céline Van Dender, Liesbet De Bus, Johan Decruyenaere, Jan Dewaele, Jolien Vandewalle, Claude Libert.

  Sepsis, killing 11 million people yearly, is associated with increased production of lactate-a metabolite mechanistically linked to mortality-complicating glucose administration in sepsis. To understand the mechanism behind hyperlactatemia, we applied the cecal ligation and puncture (CLP) model and studied all pyruvate processing routes in liver mitochondria during acute sepsis. Our data suggest that mitochondrial pyruvate-driven respiration is nearly nonexistent in sepsis, not due to insufficient pyruvate uptake or carboxylation, but due to a dysfunctional pyruvate dehydrogenase complex (PDC). Septic mitochondria compensate via glutamate-mediated tricarboxylic acid (TCA) anaplerosis, simultaneously converting some pyruvate into alanine via enhanced mitochondrial glutamic pyruvate transaminase (GPT2) activity. PDC dysfunction is not caused by PDC inactivation per se but by a shortage of its cofactor, thiamine pyrophosphate (TPP). TPP supplementation restores pyruvate oxidation and protects mice from sepsis. TPP also allows safe glucose administration in mice, leading to a robust TPP-plus-glucose therapy.

Keywords:  CP: Metabolism; CP: Microbiology; lactate; mitochondria; pyruvate; sepsis; thiamine

DOI:  https://doi.org/10.1016/j.celrep.2025.116032
EMBO Mol Med. 2025 Jul 24.

De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma.

Duo Xu, Yanyun Gao, Shengchen Liu, Shiyuan Yin, Tong Hu, Haibin Deng, Tuo Zhang, Balazs Hegedüs, Thomas M Marti, Patrick Dorn, Shun-Qing Liang, Ralph A Schmid, Ren-Wang Peng, Yongqian Shu.

  Pleural mesothelioma (PM) is one of the deadliest cancers, with limited therapeutic options due to its therapeutically intractable genome, which is characterized by the functional inactivation of tumor suppressor genes (TSGs) and high tumor heterogeneity, including diverse metabolic adaptations. However, the molecular mechanisms underlying these metabolic alterations remain poorly understood, particularly how TSG inactivation rewires tumor metabolism to drive tumorigenesis and create metabolic dependencies. Through integrated multi-omics analysis, we identify for the first time that NF2 loss of function defines a distinct PM subtype characterized by enhanced de novo pyrimidine synthesis, which NF2-deficient PM cells are critically dependent on for sustained proliferation in vitro and in vivo. Mechanistically, NF2 loss activates YAP, a downstream proto-oncogenic transcriptional coactivator in the Hippo signalling pathway, which in turn upregulates CAD and DHODH, key enzymes in the de novo pyrimidine biosynthesis pathway. Our findings provide novel insights into metabolic reprogramming in PM, revealing de novo pyrimidine synthesis as a synthetic lethal vulnerability in NF2-deficient tumors. This work highlights a potential therapeutic strategy for targeting NF2-deficient mesothelioma through metabolic intervention.

Keywords:  De Novo Pyrimidine Synthesis; Metabolic Diversity; Neurofibromin 2 (NF2); Pleural Mesothelioma (PM); Synthetic Lethality

DOI:  https://doi.org/10.1038/s44321-025-00278-4
Med Oncol. 2025 Jul 19. 42(8): 349

The metabolic significance of ATP-citrate lyase in cancer: insights into glutamine-fuelled citrate biosynthesis and tumour progression.

Mohammed Bader, Omar Galy, Mohamed Babiker, Loai Eletr, Mustafa Saeed, Obai Suliman, Muzamil Mahdi Abdel Hamid.

  ATP-citrate lyase (ACLY) is a major metabolic enzyme involved in the citrate to acetyl-CoA conversion, connecting glycolysis with lipid biosynthesis. More evidence has been given for its cancer metabolic role, but its patterns of expression and prognostic value in various cancers remain unclear, particularly in the process of cancer metabolic reprogramming, a feature of cancer progression and drug resistance. We performed a pan-cancer analysis of ACLY expression in six tumour types, bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and liver hepatocellular carcinoma (LIHC), using public databases like TIMER, GEPIA, UALCAN, and cBioPortal. GEPIA and UALCAN were utilized for evaluating prognostic significance, and GEO datasets for external validation. ACLY was consistently overexpressed in reprogrammed cancers (BLCA, BRCA, KIRC, KIRP, and LIHC) (P < 0.05 to P < 0.001) but appreciably downregulated in KICH, a metabolically quiescent cancer. ACLY overexpression was associated with poor prognosis in LIHC and KICH (P = 0.011 and P = 0.0081, respectively) but surprisingly associated with better survival in KIRC (P < 0.0001). Genomic alterations in ACLY were rare (< 4%) across all cancers. The findings were validated by multiple GEO datasets: GSE41804 (LIHC), GSE 3167 (BLCA), GSE 22820 (BRCA), GSE 53757 (KIRC), GSE15641 (KIRP), and GSE15641 (KICH). Conclusion: ACLY expression agrees with the metabolic phenotype of most tumours and has different prognostic implications. Overexpression in metabolically active cancers and association with poor outcomes, namely in LIHC, emphasizes its potential for therapeutic targeting as a tumour metabolic status biomarker. Downregulation in KICH, on the other hand, agrees with evidence of metabolic stability in certain cancers. These findings might be used in the direction of metabolism-based therapeutic approaches and risk stratification in oncology.

Keywords:  ATP-citrate lyase (ACLY); Cancer metabolism; Metabolic reprogramming

DOI:  https://doi.org/10.1007/s12032-025-02909-9
Anal Chem. 2025 Jul 22.

Ultra-Photostable Fluorescent Boron-Bridged Near-Infrared Probes to Reveal New Mode of Lipid Droplet-Mitochondria Interaction at STED Super-Resolution.

Mingyue Cao, Xiaoming Zhu, Yunting Liu, Yangang Su, Xinru Hu, Zhiqiang Liu, Xiaoqiang Yu.

Interactions between lipid droplets (LDs) and mitochondria are vital for maintaining the cellular metabolism and energy homeostasis. However, visualizing these interaction dynamics at a high resolution in live cells is still very challenging. Here, a boron-bridged near-infrared probe (QI-BF) was developed specifically for low-power stimulated emission depletion (STED) super-resolution imaging of LDs. QI-BF exhibited excellent photostability and enabled continuous scanning of 1000+ frames using a STED laser (0.96 MW cm-2, 775 nm), without significant fluorescence decay. Furthermore, dynamic dual-color STED super-resolution visualization of the morphological interactions between LDs and mitochondria was achieved with the aid of commercial mitochondrial dyes. For the first time, the dynamic process of mitochondrial wrapping around the LDs and LD-mediated mitochondria tubulation were successfully captured. This study sheds light on developing ultraphotostable organic fluorescent probes for versatile low-power STED nanoscopy.

DOI: https://doi.org/10.1021/acs.analchem.5c02739
Methods Cell Biol. 2025 ;pii: S0091-679X(25)00006-8. [Epub ahead of print]196 171-176

Relative adenosine production assay suitable for 2D and 3D tumor cell culture.

Apple Hui Min Tay, Andreas Lundqvist.

  Adenosine (ADO), an anti-inflammatory and immunosuppressive metabolite, plays a crucial role in mediating purinergic signaling alongside adenosine triphosphate (ATP) and adenosine monophosphate (AMP) within the tumor microenvironment. Dysregulated ADO signaling has been implicated in tumor immune evasion and progression, highlighting the importance of measuring ADO production. This method chapter presents a protocol for assessing ADO levels in both two- and three- dimensional tumor cell culture conditions. The protocol employs a competitive AMP blockade strategy, where excessive AMP is introduced to inhibit CD73-mediated conversion of AMP to ADO, enabling the quantification of relative ADO production. Given ADO's potent immunosuppressive properties and its influence on various immune responses, accurate measurement of ADO production is crucial for understanding its role in tumor immune evasion and for guiding the development of targeted immunotherapeutic strategies.

Keywords:  Adenosine; CD73; Cancer; Immune evasion; Tumor microenvironment

DOI:  https://doi.org/10.1016/bs.mcb.2025.01.006
Nat Commun. 2025 Jul 19. 16(1): 6666

RIPK4-mediated MFN2 degradation drives osteogenesis through mitochondrial fragmentation and restricts myelopoiesis by blocking mitochondrial transfer.

Peng Ding, Xing Wang, Chuan Gao, Yuehan Wei, Gan Li, Wenlei Zhu, Ni Wang, Wan Fu, Qihang Fang, Meng Yao, Yigang Huang, Chenyi Jiang, Youshui Gao, Jing Zhang, Junjie Gao, Qing Zhong, Changqing Zhang.

Human RIPK4 mutation leads to Bartsocas-Papas syndrome (BPS), characterized by severe skin, craniofacial and limb abnormalities. Currently, our understanding of RIPK4's function has focused on epidermal differentiation and development, whether RIPK4 regulates skeletal homeostasis remains largely elusive. Herein, through global RIPK4 ablation in adult mice, we demonstrate that RIPK4 deficiency leads to osteoporosis, promotes myeloid-biased hematopoiesis and osteolineage RIPK4 plays a crucial role in bone formation and myeloid hematopoiesis. Further detailed investigation pinpoints that RIPK4 interacts with mitochondrial fusion protein MFN2 in a kinase-dependent manner. RIPK4 facilitates the phosphorylation of MFN2, which subsequently undergoes degradation through the proteasome pathway and disrupts the dynamic equilibrium of mitochondrial fission and fusion. Additionally, we also show that osteolineage RIPK4 maintains bone marrow myelopoiesis by MFN2-mediated mitochondrial transfer. More interestingly, while osteocytic RIPK4 could modestly influence the osteogenesis, it is insufficient to sustain bone marrow myelopoiesis owing to the limited amount of mitochondria transfer. These findings decipher the essential role of RIPK4 in maintaining skeletal homeostasis and unveil an unappreciated mechanism of RIPK4-MFN2 axis in regulating osteogenesis and bone marrow myelopoiesis.

DOI: https://doi.org/10.1038/s41467-025-61808-9
Sci Rep. 2025 Jul 25. 15(1): 27022

Metabolomic profiles impacted by brief mindfulness intervention with contributions to improved health.

Yi-Yuan Tang, Jeffrey S Patterson, Rongxiang Tang, Jinhua Chi, Ngoc Bao Phuong Ho, Dorothy D Sears, Haiwei Gu.

  Mounting evidence indicates that mindfulness-based interventions improve physical and mental health. However, whether brief mindfulness intervention supports health benefits by regulating metabolic profiles is poorly understood. To address this gap, this randomized controlled trial compared ten 1-hour sessions of integrative body-mind training (IBMT) with relaxation training (RT) in 42 participants. Untargeted metabolomics was performed on fasting serum samples to investigate the physiological effects of the interventions on metabolic profiles. After IBMT, significant increases were observed in glycine derivatives, glutamate, and tetrahexosylceramide, while multiple sulfur containing compounds decreased. In contrast, RT yielded no significant intervention effects. A direct comparison between IBMT and RT revealed significant group differences in the levels of glycine, phosphatidylcholine, phosphatidylethanolamine, phosphoglycerol, phosphatidylserine, sphingomyelin derivatives, and α-linolenic acid. Further, pathway and enrichment analyses confirmed the effects of IBMT on amino acid and lipid metabolism with significant alterations to sphingolipid, α-linolenic acid, and linoleic acid metabolism as well as histidine and pyruvate metabolism. These findings suggest that IBMT can reprogram key metabolic pathways. In conclusion, this study offers insights into how a brief mindfulness intervention modulates metabolic profiles and highlights the potential of mindfulness-based interventions to promote health through metabolic regulation. These findings may guide the development of future mindfulness-based health promotion strategies.

Keywords:  Amino acid metabolism; Integrative body-mind training; Lipid metabolism; Metabolomics; Physical and mental health; Relaxation training

DOI:  https://doi.org/10.1038/s41598-025-12067-7
Sci Rep. 2025 Jul 18. 15(1): 26112

Marker-independent vibrational spectroscopy imaging recognizes the hypoxia effect in the human brain endothelium.

Aleksandra Pragnąca, Anna Antolak, Zuzanna J Krysiak, Monika Leśniak, Agata Borkowska, Robert Zdanowski, Kamilla Malek.

  Brain microvascular endothelial cells experience hypoxic conditions in several neurodegenerative disease processes and the underlying mechanisms still need to be explored. Current imaging modalities and biochemical assays require many specific markers that should be detected to identify the hypoxic response, especially at a level of single cells. This study presents a single-cell molecular imaging approach utilizing Fourier-Transform Infrared and Raman spectroscopy. Those methods enable the simultaneous detection of proteins, lipids, and nucleic acids encoded in their unique vibrational fingerprints. By establishing ratiometric estimators, we measured upregulated lipid metabolism, structural changes of proteins and asses DNA:RNA ratio at the single-cell level induced by oxygen depletion. Moreover, this approach allows for analyzing changes within specific cellular compartments, including nuclei, providing a comprehensive understanding of how hypoxia affects cellular functions and metabolism. Our findings pave the way for future investigations into the cellular adaptations to hypoxia in brain endothelial cells, potentially revealing novel therapeutic targets for neurodegenerative diseases.

Keywords:  Brain endothelium; FTIR and Raman spectroscopy imaging; Hypoxia; Spectral markers

DOI:  https://doi.org/10.1038/s41598-025-11000-2