bims-celmim 2025-08-03 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2025–08–03
sixteen papers selected by
Marc Segarra Mondejar

The impact of ERUPR on mitochondrial integrity mediated by PDK4.
SIRT3 deficiency aggravates mitochondrial metabolic disorder and podocyte injury in DKD via MPC2 acetylation.
MGlu5 Dependent Mitochondrial Translocation of PKCδ: A Mechanism Raising Astrocytic Oxidative Metabolism in Response to Extracellular Glutamate.
Role of mitochondrial Ca2+ in stroke: From molecular mechanism to treatment strategy (Review).
Rab14 promotes Parkin mediated mitophagy.
PDK1-dependent metabolic reprogramming regulates stemness and tumorigenicity of osteosarcoma stem cells through ATF3.
STIM-IP3R crosstalk regulates migration of breast cancer cells.
MEANtools integrates multi-omics data to identify metabolites and predict biosynthetic pathways.
From lactate to lactylation: potential targets for the treatment of neurodegenerative diseases.
Endoplasmic reticulum-mediated organelle crosstalk in kidney disease.
PDE4D Regulates Mitochondrial Homeostasis and Adult Hippocampal Neurogenesis via the cAMP/CREB Signaling Pathway in Chronic Stress-Induced Depressive-Like Behavior.
Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure.
PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth.
A diagnostic algorithm for inherited metabolic disorders using untargeted metabolomics.
Pyruvate kinase M2 activation maintains mitochondrial metabolism by regulating the interaction between HIF-1α and PGC-1α in diabetic kidney disease.
Filamentation of hCTPS1 with CTP.

Cell Death Dis. 2025 Jul 29. 16(1): 573

The impact of ERUPR on mitochondrial integrity mediated by PDK4.

Priyanka Mallick, Sebabrata Maity, Rupsha Mondal, Trina Roy, Puyam Milan Meitei, Shashank Saxena, Bhavani Shankar Sahu, Oishee Chakrabarti, Saikat Chakrabarti.

ER and mitochondrial stress are often interconnected and considered major contributors to aging as well as neurodegeneration. Coordinated induction of ERUPR and mitoUPR has been observed in diabetes and pulmonary disorders. However, in the context of aging and neurodegeneration, regulation of this intra-organellar crosstalk has remained relatively elusive. Here, we demonstrate that pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial protein, accumulates at the ER-mitochondrial contact sites (MAMs) during ER stress. Classically, PDK4 is known to phosphorylate PDHA1 (pyruvate dehydrogenase E1 subunit alpha 1) and plays a significant role in regulating the oxidative phosphorylation-driven ATP production. In this study, we propose a non-canonical kinase-independent function of PDK4; we show that it acts as a connecting link between ERUPR and mitoUPR, with significance in aging and Alzheimer's disease (AD) associated neurodegeneration. Transcriptomics analyses show increased PDK4 levels upon drug-induced ER stress. We detect elevated PDK4 levels in lysates from human AD patient and mouse models as well as in ex vivo AD models. Additionally, exogenous expression of PDK4 was found to refine ER-mitochondria communication, significantly altering mitochondrial morphology and function. Further, we also observe defective autophagic clearance of mitochondria under such conditions. It is prudent to suggest that elevated PDK4 levels could be one of the key factors connecting ERUPR with mitoUPR, a phenotypic contributor in aging and in AD-like neurodegenerative disorders.

DOI: https://doi.org/10.1038/s41419-025-07743-5
Cell Signal. 2025 Jul 29. pii: S0898-6568(25)00444-9. [Epub ahead of print]135 112029

SIRT3 deficiency aggravates mitochondrial metabolic disorder and podocyte injury in DKD via MPC2 acetylation.

Jun Feng, Ling Feng, Yu Yan, Huiluan Ye, Kaiyue Tang, Xiaohua Guo, Yiqiong Ma.

   BACKGROUND: Diabetic kidney disease (DKD) is a chronic disease characterized by high prevalence and mortality rates. Podocyte injury and mitochondrial metabolic disorder are crucial in its progression. Sirtuin3 (SIRT3), a mitochondrial NAD+-dependent deacetylase, exerts renoprotective effects in various kidney pathologies by modulating the acetylation status and activity of energy metabolism related substrates. However, its specific roles in podocytes homeostasis during DKD progression remain unclear. We previously reported the role and acetylation level of mitochondrial pyruvate carrier 2 (MPC2) in DKD, but the regulatory mechanism between SIRT3 and MPC2 has not been elucidated. This study aims to investigate the effect of SIRT3 on mitochondrial reprogramming in podocytes and explore the association between SIRT3 and MPC2 during DKD progression.
RESULT: SIRT3 expression was downregulated in hyperglycemia-induced podocytes in vivo and in vitro. SIRT3 deficiency aggravated podocyte apoptosis and mitochondrial homeostasis dysregulation, as evidenced by increased ROS production, decreased mitochondrial membrane potential and diminished ATP level. However, the overexpression of SIRT3 alleviated these alterations. In addition, we identified a binding interaction between SIRT3 and MPC2. SIRT3 deacetylated MPC2 at lysine K19/K27, mechanistically implicated in the podocyte injury in the process of DKD.
CONCLUSION: This study validated that hyperglycemia-induced SIRT3-mediated MPC2 acetylation contributes to mitochondrial dysfunction and cellular apoptosis.

Keywords:  Acetylation; Diabetic kidney disease; MPC2; Mitochondria; Podocytes; SIRT3

DOI:  https://doi.org/10.1016/j.cellsig.2025.112029
J Neurochem. 2025 Aug;169(8): e70163

MGlu5 Dependent Mitochondrial Translocation of PKCδ: A Mechanism Raising Astrocytic Oxidative Metabolism in Response to Extracellular Glutamate.

Kiavasch M N Farid, Rodrigo Lerchundi, Christine R Rose, Amin Derouiche.

  Synaptic activity imposes high demands of local energy production on astrocytes. However, the (an)aerobic pathways and fuel for generation of energy equivalents in astrocytes are still debated. Also, mechanisms to ensure rapid metabolic adaptation to bouts of neuronal activity have not been sufficiently explored. Here, we show a mechanism in astrocytes linking extracellular glutamate to upregulation of oxidative phosphorylation. We stimulated primary astrocytes with glutamate, and applied fluorescent immunocytochemistry with anti-protein kinase Cδ (PKCδ), anti-pyruvate dehydrogenase (PDH) and anti-phospho-PDH antibodies, and object oriented image analysis. Glutamate induces mitochondrial translocation of PKCδ and subsequent activation of the mitochondrial enzyme PDH-the point-of-no-return in the utilization of carbohydrates. Using the specific mGlu5 antagonist 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), the metabotropic glutamate receptor 5 (mGlu5) was identified as the key receptor inducing mitochondrial PKCδ translocation and PDH activation. We demonstrate by luminometric ATP assay and subtype-specific inhibitors of PKC and mGlu5 that the distinct initial drop in intracellular ATP following glutamate application is counteracted by the mGlu5/PKCδ-dependent mitochondrial activation. mGlu5 inhibition decreases ATP production also in astrocytes in the acute brain slice. Collectively, these findings reveal that astrocytes possess a potential for oxidative phosphorylation that can be stimulated by extracellular glutamate and the mGlu5/PKCδ/PDH axis, suggesting targets for pathologies involving excess glutamate. This also focuses the issue of activity-induced glia-neuronal metabolic interaction on perisynaptic energetics and the glia-synaptic microenvironment. Up-regulation of astrocytic metabolism via the mGlu5/PKCδ/PDH axis may affect only those perisynaptic astrocyte processes (PAPs) close to the active synapse(s), leaving other astrocyte domains and the whole cell unchanged.

Keywords:  glia‐synaptic interaction; neurometabolic coupling; pyruvate dehydrogenase; pyruvate dehydrogenase phosphatase; tripartite synapse

DOI:  https://doi.org/10.1111/jnc.70163
Mol Med Rep. 2025 Oct;pii: 271. [Epub ahead of print]32(4):

Role of mitochondrial Ca2+ in stroke: From molecular mechanism to treatment strategy (Review).

Yanlin Liu, Wenjie Jin, Huixin Zhou, Xiaomei Wang, Hongbin Ren, Xibing Yang, Kaitao Luo, Xiaobing Dou.

  Mitochondria serve a pivotal role in the pathological mechanisms of stroke, particularly in the regulation of intracellular calcium homeostasis. Stroke‑induced ischemia and reperfusion injury frequently result in disruptions of mitochondrial calcium ion (Ca2+) transport, characterized by Ca2+ overload. This imbalance directly impairs mitochondrial function and triggers neuronal death. Mitochondrial Ca2+ transport involves calcium influx, primarily mediated by the mitochondrial calcium uniporter (MCU) complex, and efflux, primarily through the sodium‑calcium exchanger (NCLX), making this mechanism a critical therapeutic target in stroke. The present review systematically explores the central role of mitochondrial Ca2+ transport in ischemia/reperfusion injury, with an in‑depth analysis of its pathological mechanisms in cellular energy metabolism, oxidative stress and apoptotic signaling pathways. Additionally, this review summarizes recent advancements in therapeutic strategies targeting mitochondrial Ca2+ transport, including MCU inhibitors, NCLX activators, antioxidant therapies and combination treatments. It also highlights the potential of Ca2+ signaling for early stroke diagnosis and reviews progress in dynamic monitoring technologies for mitochondrial Ca2+, such as fluorescence probes and super‑resolution microscopy. Despite significant progress in basic research, challenges remain in translating these findings into clinical applications. Future efforts should focus on elucidating the regulatory mechanisms of mitochondrial Ca2+, developing diagnostic tools and optimizing therapeutic interventions to improve stroke prognosis and enhance the quality of life of patients.

Keywords:  calcium homeostasis; diagnosis; dynamic monitoring; ischemia/reperfusion injury; mitochondrial calcium transport; stroke

DOI:  https://doi.org/10.3892/mmr.2025.13636
Mol Biol Cell. 2025 Jul 30. mbcE25060271

Rab14 promotes Parkin mediated mitophagy.

Samina Momtaz, Marco Padilla-Rodriguez, Paola Cruz Flores, Natalia Rulli, Nam Yong Lee, Jean M Wilson.

Mitochondrial degradation by mitophagy is essential to maintain cell metabolism; dysregulation can result in the accumulation of damaged mitochondria. While the Rab family of small GTPase proteins are involved with vesicular trafficking in the endocytic and biosynthetic pathways, Rab-GTPases also have a role in mitochondrial integrity. However, a role for Rab14, a trans-Golgi network (TGN)-endosomal Rab-GTPase in mitophagy has not been described. In cells knocked down for Rab14, mitochondria acquire an elongated morphology and increased levels of mitochondrial proteins, whereas overexpression of Rab14 decreased these proteins. Furthermore, mito-Keima assays show increased mitophagy upon Rab14 overexpression. Rab14-induced mitophagy is dependent on Parkin expression, as well as TBK1 and PI3K activity, placing it in the Parkin-dependent mitophagy pathway. 3D-reconstruction shows contact site formation between Rab14 and mitochondria, and inhibition of the TGN kinase PI(4)KIIIβ decreases Rab14-mitochondria contact sites and prevents Rab14-mediated mitophagy, suggesting that TGN-derived Rab14 vesicles mediate mitophagy. These results suggest that Rab14 promotes mitophagy and plays an essential role in modulating cellular metabolism. [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-06-0271
Cell Death Dis. 2025 Jul 29. 16(1): 574

PDK1-dependent metabolic reprogramming regulates stemness and tumorigenicity of osteosarcoma stem cells through ATF3.

Kazuya Tokumura, Kazuya Fukasawa, Jiro Ichikawa, Koki Sadamori, Manami Hiraiwa, Eiichi Hinoi.

Osteosarcoma stem cells (OSCs) are characterized by their self-renewal and multilineage differentiation abilities, contributing to osteosarcoma malignancy. The Warburg effect describes cancer cells' preference for glycolysis over mitochondrial oxidative phosphorylation (OXPHOS) for energy production. Unlike differentiated cancer cells, cancer stem cells exhibit unique and diverse metabolic properties depending on the context. This study investigated the metabolic reliance of OSCs and related genes through in silico analyses of clinical osteosarcoma specimens and in vitro and in vivo genetic and pharmacological analyses. Glycolysis and OXPHOS pathways were more active in OSCs than in non-OSCs at single-cell resolution. Pyruvate dehydrogenase kinase 1 (PDK1), a key enzyme balancing glycolysis and OXPHOS, was upregulated in OSCs and correlated with poor prognosis in patients with osteosarcoma. Genetic inhibition of PDK1 via RNA interference reduced OSC stemness, glycolysis, and heterotopic tumor formation. Pharmacological inhibition of PDK1 mirrored these genetic effects and repressed orthotopic tumor burden and pulmonary metastasis. Activating transcription factor 3 (ATF3) was identified through screening as a downstream factor of PDK1-regulated OSC properties. ATF3 overexpression reversed the stemness reduction caused by PDK1 deficiency through, at least in part, activating the TGF-β/Smad pathway without affecting the metabolic balance. ATF3 expression, glycolysis, and stemness were significantly induced by wild-type PDK1 overexpression but not by a kinase-dead PDK1 mutant in OSCs. Pharmacological inhibition of glycolysis counteracted the upregulation of ATF3 expression and increased stemness in OSCs by PDK1 overexpression. These findings indicate that PDK1 fine-tunes metabolic balance to govern OSC stemness and tumorigenicity through, at least in part, modulating ATF3/TGF-β/Smad pathway, suggesting a potential therapeutic approach for targeting OSCs in osteosarcoma.

DOI: https://doi.org/10.1038/s41419-025-07903-7
J Cell Biol. 2025 Sep 01. pii: e202411203. [Epub ahead of print]224(9):

STIM-IP3R crosstalk regulates migration of breast cancer cells.

Ruslana Militsin, Hadas Achildiev Cohen, Maya Hershfinkel, Ofek Levi, Stavit Drori, Adi Yifat Raz, Yuval Shaked, Raz Palty.

Calcium ions (Ca2+) are crucial second messengers involved in numerous processes including tumorigenesis and cancer cell migration. Previous studies have shown that the endoplasmic reticulum (ER) Ca2+ sensors, stromal interaction molecules STIM1 and STIM2, are key regulators of cancer cell migration. In this study, using breast cancer cells lacking one or both STIM isoforms we show that although STIM proteins are critical regulators of cell migration, they are dispensable for this cellular activity. The mechanism underlying this complex effect involves functional crosstalk between STIM proteins and inositol 1,4,5-trisphosphate receptors (IP3Rs). Our findings indicate that beyond their classical role in store-operated Ca2+ entry, STIM proteins shape the spatial dynamics of IP3R-mediated Ca2+ release. Our results suggest that following ER Ca2+ depletion, the activated STIM proteins shift the pattern of IP3R-mediated Ca2+ release from a localized signal, which promotes cell migration, to a more diffuse signal, which attenuates cell migration.

DOI: https://doi.org/10.1083/jcb.202411203
PLoS Biol. 2025 Jul 28. 23(7): e3003307

MEANtools integrates multi-omics data to identify metabolites and predict biosynthetic pathways.

Kumar Saurabh Singh, Hernando Suarez Duran, Elena Del Pup, Olga Zafra-Delgado, Saskia C M Van Wees, Justin J J van der Hooft, Marnix H Medema.

During evolution, plants have developed the ability to produce a vast array of specialized metabolites, which play crucial roles in helping plants adapt to different environmental niches. However, their biosynthetic pathways remain largely elusive. In the past decades, increasing numbers of plant biosynthetic pathways have been elucidated based on approaches utilizing genomics, transcriptomics, and metabolomics. These efforts, however, are limited by the fact that they typically adopt a target-based approach, requiring prior knowledge. Here, we present MEANtools, a systematic and unsupervised computational integrative omics workflow to predict candidate metabolic pathways de novo by leveraging knowledge of general reaction rules and metabolic structures stored in public databases. In our approach, possible connections between metabolites and transcripts that show correlated abundance across samples are identified using reaction rules linked to the transcript-encoded enzyme families. MEANtools thus assesses whether these reactions can connect transcript-correlated mass features within a candidate metabolic pathway. We validate MEANtools using a paired transcriptomic-metabolomic dataset recently generated to reconstruct the falcarindiol biosynthetic pathway in tomato. MEANtools correctly anticipated five out of seven steps of the characterized pathway and also identified other candidate pathways involved in specialized metabolism, which demonstrates its potential for hypothesis generation. Altogether, MEANtools represents a significant advancement to integrate multi-omics data for the elucidation of biochemical pathways in plants and beyond.

DOI: https://doi.org/10.1371/journal.pbio.3003307
Rev Neurosci. 2025 Jul 31.

From lactate to lactylation: potential targets for the treatment of neurodegenerative diseases.

Bingbing Wang, Shenghao Qian, Caizhen Shi, Li Dan, Tianyu Zhai, Can Zhang, Juan Shen, Yanling Yang, Lin Zhao.

  Traditionally, lactate is regarded as a byproduct of anaerobic metabolism. With the deepening of related research, the roles of lactate in cellular energy metabolism, signal transduction, and microenvironment regulation have attracted increasing attention. Against this research background, the discovery of a novel post-translational modification - lactylation modification - has further expanded its biological functions. In the context of the increasingly aging global population, neurodegenerative diseases (ND) have become a significant challenge threatening global public health. Studies have reported that lactate metabolic disorders are common metabolic characteristics in the occurrence and development of ND. In summary, this article focuses on reviewing lactate and lactylation in the brain and their roles in ND. It comprehensively outlines the process from lactate to lactylation, highlights the close connection between brain lactate metabolism and ND, and explores potential molecular mechanisms underlying disease development - providing new perspectives for understanding ND pathogenesis. Additionally, this review systematically summarizes potential therapeutic strategies for ND based on regulating lactate metabolism, aiming to offer innovative approaches for disease prevention, diagnosis, and treatment.

Keywords:  lactate; lactylation; neurodegenerative diseases (ND); signaling molecule; targeted therapy

DOI:  https://doi.org/10.1515/revneuro-2025-0068
Nat Rev Nephrol. 2025 Jul 31.

Endoplasmic reticulum-mediated organelle crosstalk in kidney disease.

Yu Ah Hong, Reiko Inagi.

The endoplasmic reticulum (ER) is a key organelle involved in a wide range of intracellular biological processes, including Ca2+ homeostasis; lipid metabolism; proteostasis through protein synthesis, folding and processing of secretory and transmembrane proteins; and signal transduction. The ER forms extensive physical interactions with various intracellular organelles through the membrane contact sites, enabling direct exchange of ions and lipids without vesicular transport. At mitochondria-associated membranes, ER-mitochondria communication governs calcium transfer, lipid synthesis, mitochondrial dynamics, the unfolded protein response and inflammation, all of which are essential for maintaining cellular homeostasis. The ER also interacts with the Golgi apparatus, endosomes and plasma membrane to facilitate transfer of calcium and lipids. Disruption of ER-organelle communication contributes to the development and progression of various kidney diseases, including diabetic kidney disease, acute kidney injury and polycystic kidney disease. Accordingly, ER-organelle communication has emerged as a promising therapeutic target. Pharmacological agents such as SGLT2 inhibitors, AMPK activators, mTOR inhibitors and RAAS blockers have been shown to restore ER-mitochondria communication and alleviate kidney injury in experimental models. Advancing our understanding of ER-organelle crosstalk may offer new mechanistic insights and contribute to the optimization of current treatment strategies for kidney disease.

DOI: https://doi.org/10.1038/s41581-025-00989-4
FASEB J. 2025 Aug 15. 39(15): e70882

PDE4D Regulates Mitochondrial Homeostasis and Adult Hippocampal Neurogenesis via the cAMP/CREB Signaling Pathway in Chronic Stress-Induced Depressive-Like Behavior.

Wei Zhao, Ziqi Wang, Xiaofei Chen, Shuang Zhao, Fangjiao Zong, Hanting Zhang.

  Phosphodiesterase 4D (PDE4D), a major enzyme responsible for cAMP degradation in the hippocampus, has been implicated in mood regulation. Although PDE4D inhibition exerts antidepressant effects, the underlying mechanisms remain poorly understood. Here, we explored the role of PDE4D in chronic stress-induced depressive-like behaviors, mitochondrial dysfunction, and impaired adult hippocampal neurogenesis (AHN). Using a chronic restraint stress (CRS) model, we found that PDE4D expression was significantly upregulated in the hippocampal dentate gyrus (DG) of CRS mice, leading to suppressed CREB signaling, mitochondrial dysfunction, and impaired AHN. PDE4D knockout (PDE4D-KO) restored mitochondrial quality by enhancing mitochondrial biogenesis, normalizing mitophagy, and improving oxidative phosphorylation (OXPHOS) via the nucleus and mitochondria cAMP/CREB signaling, ultimately promoting AHN and alleviating depression-like symptoms. These findings define PDE4D as a key regulator of mitochondrial homeostasis and AHN, suggesting that targeting PDE4D in the hippocampal DG may represent a novel treatment mechanism for depression.

Keywords:  adult hippocampal neurogenesis; chronic stress; depression; mitochondrion; pde4d

DOI:  https://doi.org/10.1096/fj.202501537R
Nat Commun. 2025 Jul 28. 16(1): 6923

Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure.

Andrew Roe, Catríona M Dowling, Cian D'Arcy, Daniel Alencar Rodrigues, Yu Wang, Matthew Hiller, Carl Keogh, Kate E R Hollinshead, Massimiliano Garre, Brenton Cavanagh, Kieran Wynne, Tianyan Liu, Zhixing Chen, Emma Kerr, Marie McIlroy, Jochen H M Prehn, Ingmar Schoen, Tríona Ní Chonghaile.

Fumarate hydratase (FH), a key node of mitochondrial metabolism, is also a tumour suppressor. Despite its prominent roles in tumourigenesis and inflammation, its regulation remains poorly understood. Herein, we show that histone deacetylase 6 (HDAC6) regulates FH activity. In triple-negative breast cancer cells, HDAC6 inhibition or knockdown results in alterations to mitochondrial cristae structure, as detected by live-cell super-resolution STED nanoscopy and electron microscopy, along with the release of mitochondrial DNA. Mass-spectrometry immunoprecipitation reveals multiple mitochondrial HDAC6-interactors, with FH emerging as a top hit. Super-resolution 3D-STORM shows HDAC6 interactions with FH in mitochondrial networks, which increases after perturbation of HDAC6 activity with BAS-2. Treatment with BAS-2 leads to fumarate accumulation by 13C glucose labelling, along with downstream succination of proteins and cell death. Together, these results identify HDAC6 inhibition as a regulator of endogenous FH activity in tumour cells, and highlight it as a promising candidate for indirectly targeting tumour metabolism.

DOI: https://doi.org/10.1038/s41467-025-61897-6
Cell Rep. 2025 Jul 29. pii: S2211-1247(25)00842-3. [Epub ahead of print]44(8): 116071

PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth.

Qingen Da, Yongfeng Cai, Qian Ma, Qiuhua Yang, Yapeng Cao, Yaqi Zhou, Dingwei Zhao, Zhiping Liu, Jiean Xu, Junming Quan, Liang Zhang, Rui Wang, Xuejun Jiang, Xiao Liu, Kunfu Ouyang, Zhen Han, Jikui Liu, Tao Wang, Chunxiang Zhang, Neal L Weintraub, David J R Fulton, Jun Zhao, Mei Hong, Zigang Li, Yuqing Huo.

  Aerobic glycolysis, termed the Warburg effect, is one of the aberrant metabolic pathways in highly proliferating cells. Glycolysis provides glycolytic metabolites to support the generation of biomass, such as nucleotides, amino acids, and lipids. Research on the direct interactions between glycolysis and other metabolic pathways is an emerging field that has garnered significant interest. Phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) activates glycolysis by synthesizing fructose-2,6-bisphosphate (F2,6BP), which allosterically activates the rate-limiting enzyme 6-phosphofructo-1-kinase (PFK-1). In this study, we found that PFKFB3 directly interacts with and regulates the phosphorylation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), the enzyme catalyzing the first three steps of de novo pyrimidine synthesis. PFKFB3 inactivation reduced de novo pyrimidine synthesis, RNA and DNA production, and cell proliferation. Thus, the glycolytic activator PFKFB3 bridges glycolysis with pyrimidine synthesis, unites both glucose metabolism and nucleic acid metabolism, and contributes to cell proliferation under pathological conditions.

Keywords:  CAD; CP: Metabolism; CP: Molecular biology; PFKFB3; Warburg effect; de novo pyrimidine synthesis; glycolysis; kinase activity

DOI:  https://doi.org/10.1016/j.celrep.2025.116071
Metabolomics. 2025 Jul 27. 21(4): 101

A diagnostic algorithm for inherited metabolic disorders using untargeted metabolomics.

Qian Gao, Adnan Khan, Mette Christensen, Xiaomin Zhou, Allan Lund, Sabine Weller Grønborg, Flemming Wibrand, Elsebet Østergaard, Thomas Moritz.

   INTRODUCTION: Untargeted metabolomics is a powerful tool for detecting perturbations in biological systems, offering significant potential for screening for rare inherited metabolic disorders (IMDs). However, the rarity and vast diversity of these diseases, results in limited availability of samples and incomplete metabolic pathway knowledge for each condition. Current diagnostic procedures rely heavily on manual interpretation, which is time-consuming, and data driven approaches are insufficient for small sample sizes.
OBJECTIVES: To develop a diagnostic algorithm for IMDs addressing the challenges posed by small sample sizes and continuously evolving datasets.
METHODS: 77 IMD patients (35 different IMDs) and 136 control samples were collected from Copenhagen University Hospital, Rigshospitalet. The metabolome was analyzed using liquid chromatography-mass spectrometry. An algorithm partially based on sparse hierarchical clustering was designed to generate IMD-specific metabolic signatures from metabolomics data, enabling comparison with undiagnosed patient samples to provide diagnostic predictions. An iterative improvement strategy was employed, where new data are continuously integrated to refine the IMD-specific signatures. The algorithm's performance was evaluated through both the current study and a case study using literature-derived data.
RESULTS: The algorithm demonstrated iterative improvement with each training round, correctly identifying the diagnosis within top 3 potential IMDs in 60% of samples (top 1 in 42%). The case study applied the method to literature-based data comprising 95 IMD samples (11 different IMDs) and 68 controls, yielding a correct diagnosis in 73.5% of cases.
CONCLUSION: These results demonstrate that the algorithm provides a flexible, data-driven framework for continuous improvement in IMD diagnosis, even with limited number of samples.

Keywords:  Diagnosis; IMD signature; Inherited metabolic disorders; Metabolomics; Unsupervised

DOI:  https://doi.org/10.1007/s11306-025-02302-7
Mol Med. 2025 Jul 25. 31(1): 266

Pyruvate kinase M2 activation maintains mitochondrial metabolism by regulating the interaction between HIF-1α and PGC-1α in diabetic kidney disease.

Jimin Park, Young Su Joo, Bo Young Nam, Gyuri Kim, Jung Tak Park, Tae-Hyun Yoo, Shin-Wook Kang, Seung Hyeok Han.

   BACKGROUND: Pyruvate kinase isoform M2 (PKM2) activation has been suggested as a potential protective mechanism against kidney injury by improving mitochondrial dysfunction and anaerobic glycolysis. However, the underlying molecular mechanisms are unclear. Herein, we have demonstrated that PKM2 activation alleviates HIF-1α-mediated suppression of PGC-1α in diabetic kidney disease (DKD) models.
METHODS: In animal DKD study, db/db mice were intraperitoneally injected with TEPP-46, a PKM2 activator. In vitro, primary cultured renal tubular epithelial cells (RTECs) from C57BL/6 mice were exposed to high glucose (HG) conditions with and without TEPP-46. The interaction between HIF-1α and PGC-1α was investigated using HIF-1α overexpression and suppression.
RESULTS: Our findings in db/db mice kidneys unveiled a reduced PKM2 activation, aberrant glycolysis, impaired fatty acid oxidation, and decreased mitochondrial mass, integrity, and function under diabetic conditions. These changes were accompanied by increased HIF-1α and decreased PGC-1α levels. Furthermore, diabetic kidney exhibited increased fibrosis and apoptosis markers. Notably, direct PKM2 activation by TEPP-46 treatment counteracted the perturbed energy metabolism, restored mitochondrial function, and reduced cell death. Similar effects were also observed in HG-treated RTECs upon TEPP-46 intervention. Mechanistically, our chromatin immunoprecipitation assay revealed that HIF-1α directly bound to the regulatory region of the Ppargc1a promoter, and this interaction was inversely dependent on PKM2 activation. Moreover, Hif1ɑ overexpression suppressed Ppargc1a and triggered aberrant energy metabolism, mitochondrial dysfunction, and apoptosis. These changes were reversed by HIF-1α suppression.
CONCLUSION: Our study highlights the role of PKM2 activation in restoring impaired mitochondrial metabolism and function by modulating HIF-1α and PGC-1α interactions in DKD.

Keywords:  Diabetic kidney disease; Mitochondrial metabolism; Pyruvate kinase M2

DOI:  https://doi.org/10.1186/s10020-025-01320-4
Cell Biosci. 2025 Jul 30. 15(1): 112

Filamentation of hCTPS1 with CTP.

Chen-Jun Guo, Xiaojie Bao, Ji-Long Liu.

  CTP synthase (CTPS) is a key enzyme in de novo CTP synthesis, playing a critical role in nucleotide metabolism and cellular proliferation. Human CTPS1 (hCTPS1), one of the two CTPS isoforms, is essential for immune responses and is highly expressed in proliferating cells, making it a promising therapeutic target for immune-related diseases and cancer. Despite its importance, the regulatory mechanisms governing hCTPS1 activity remain poorly understood. Here, we reveal that CTP, the product of CTPS, acts as a key regulator for hCTPS1 filamentation. Using cryo-electron microscopy (cryo-EM), we resolve the high-resolution structure of CTP-bound hCTPS1 filaments, uncovering the molecular details of CTP binding and its role in filament assembly. Importantly, we demonstrate that CTP generated from the enzymatic reaction does not trigger filament disassembly, suggesting a conserved regulatory pattern. Furthermore, by analyzing the binding modes of two distinct CTP-binding pockets, we provide evidence that this filamentation mechanism is evolutionarily conserved across species, particularly in eukaryotic CTPS. Our findings not only elucidate a novel regulatory mechanism of hCTPS1 activity but also deepen the understanding of how metabolic enzymes utilize filamentation as a conserved strategy for functional regulation. This study opens new avenues for targeting hCTPS1 in therapeutic interventions.

Keywords:  CTP synthase; Cryo-EM; Cytoophidium; Metabolic filament; Product feedback regulation

DOI:  https://doi.org/10.1186/s13578-025-01450-6