bims-celmim 2025-01-26 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2025–01–26
eleven papers selected by
Marc Segarra Mondejar

Metabolic interplays between the tumour and the host shape the tumour macroenvironment.
Impact of glycolysis enzymes and metabolites in regulating DNA damage repair in tumorigenesis and therapy.
Protocol for real-time assessment of energy metabolism in dissociated mouse retinal photoreceptors using a SeahorseXFe24 analyzer.
Tracing of Amino Acids Dynamics in Cell Lines Based on 18O Stable Isotope Labeling.
Succinate receptor 1 signaling mutually depends on subcellular localization and cellular metabolism.
Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.
GCTransNet: 3D mitochondrial instance segmentation based on Global Context Vision Transformers.
Arv1; a "Mover and Shaker" of Subcellular Lipids.
Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion.
ACOX1 activates autophagy via the ROS/mTOR pathway to suppress proliferation and migration of colorectal cancer.
Metabolism-driven chromatin dynamics: Molecular principles and technological advances.

Nat Rev Cancer. 2025 Jan 20.

Metabolic interplays between the tumour and the host shape the tumour macroenvironment.

Patricia Altea-Manzano, Amanda Decker-Farrell, Tobias Janowitz, Ayelet Erez.

Metabolic reprogramming of cancer cells and the tumour microenvironment are pivotal characteristics of cancers, and studying these processes offer insights and avenues for cancer diagnostics and therapeutics. Recent advancements have underscored the impact of host systemic features, termed macroenvironment, on facilitating cancer progression. During tumorigenesis, these inherent features of the host, such as germline genetics, immune profile and the metabolic status, influence how the body responds to cancer. In parallel, as cancer grows, it induces systemic effects beyond the primary tumour site and affects the macroenvironment, for example, through inflammation, the metabolic end-stage syndrome of cachexia, and metabolic dysregulation. Therefore, understanding the intricate metabolic interplay between the tumour and the host is a growing frontier in advancing cancer diagnosis and therapy. In this Review, we explore the specific contribution of the metabolic fitness of the host to cancer initiation, progression and response to therapy. We then delineate the complex metabolic crosstalk between the tumour, the microenvironment and the host, which promotes disease progression to metastasis and cachexia. The metabolic relationships among the host, cancer pathogenesis and the consequent responsive systemic manifestations during cancer progression provide new perspectives for mechanistic cancer therapy and improved management of patients with cancer.

DOI: https://doi.org/10.1038/s41568-024-00786-4
Cell Commun Signal. 2025 Jan 23. 23(1): 44

Impact of glycolysis enzymes and metabolites in regulating DNA damage repair in tumorigenesis and therapy.

Fengyao Sun, Wen Li, Ruihang Du, Mingchan Liu, Yi Cheng, Jianxing Ma, Siyuan Yan.

  Initially, it was believed that glycolysis and DNA damage repair (DDR) were two distinct biological processes that independently regulate tumor progression. The former metabolic reprogramming rapidly generates energy and generous intermediate metabolites, supporting the synthetic metabolism and proliferation of tumor cells. While the DDR plays a pivotal role in preserving genomic stability, thus resisting cellular senescence and cell death under both physiological and radio-chemotherapy conditions. Recently, an increasing number of studies have shown closely correlation between these two biological processes, and then promoting tumor progression. For instance, lactic acid, the product of glycolysis, maintains an acidic tumor microenvironment that not only fosters cell proliferation and invasion but also facilitates DDR by enhancing AKT activity. Here, we provide a comprehensive overview of the enzymes and metabolites involved in glycolysis, along with the primary methods for DDR. Meanwhile, this review explores existing knowledge of glycolysis enzymes and metabolites in regulating DDR. Moreover, considering the significant roles of glycolysis and DDR in tumor development and radio-chemotherapy resistance, the present review discusses effective direct or indirect therapeutic strategies targeted to glycolysis and DDR.

Keywords:  DNA damage repair; Genomic stability; Glycolysis; Resistance; Tumor

DOI:  https://doi.org/10.1186/s12964-025-02047-9
STAR Protoc. 2025 Jan 23. pii: S2666-1667(25)00001-2. [Epub ahead of print]6(1): 103595

Protocol for real-time assessment of energy metabolism in dissociated mouse retinal photoreceptors using a SeahorseXFe24 analyzer.

Maria Yera, Joshua J Wang, Sarah X Zhang.

  Defects in retinal metabolism have been linked to the onset and progression of various retinal diseases. Herein, we provide a protocol for measuring bioenergetics in dissociated mouse retinal photoreceptors. We outline detailed instructions for obtaining morphologically intact and viable photoreceptor cells from adult mice and preparing the cells for metabolic analysis using a SeahorseXFe24 analyzer. This protocol allows a real-time assessment of mitochondrial respiration and glycolysis in retinal photoreceptors in response to genetic modifications or pathological insults in mouse models.

Keywords:  Cell Biology; Metabolism; Neuroscience

DOI:  https://doi.org/10.1016/j.xpro.2025.103595
Anal Chem. 2025 Jan 23.

Tracing of Amino Acids Dynamics in Cell Lines Based on 18O Stable Isotope Labeling.

Cemil Can Eylem, İpek Baysal, Samiye Yabanoğlu Çiftçi, Emirhan Nemutlu.

Metabolite levels and turnover rates are necessary to understand metabolomic dynamics in a living organism fully. Amino acids can play distinct roles in various cellular processes, and their abnormal levels are associated with pathological conditions, including cancer. Therefore, their levels, especially turnover rates, may provide enormous information about a phenotype. 13C- or 13C,15N-labeled amino acids have also been commonly used to trace amino acid metabolism. This study presented a new methodology based on 18O labeling for amino acids that relied on monitoring mass isotopologues to calculate the turnover rates of amino acids. The method optimization studies were carried over for selective amino acid monitoring. This methodology provides a rapid, robust, and simple GC-MS method for analyzing the fluxes of amino acid metabolism. The developed method was applied to fetal human colon (FHC) and human colon carcinoma (Caco-2) cell lines to determine cancer-induced shifts in the turnover rates of amino acids. These results defined metabolic reprogramming in Caco-2 cells through increased glutamate and serine turnovers and sharply decreased turnovers of aspartate, threonine, and methionine, therefore pointing to some metabolic vulnerabilities in the metabolism of cancerous cells. The simple mechanism of the developed methodology, the availability of affordable 18O-enriched water, and the ease of application can open a new arena in fluxomics analysis.

DOI: https://doi.org/10.1021/acs.analchem.4c05015
FEBS J. 2025 Jan 21.

Succinate receptor 1 signaling mutually depends on subcellular localization and cellular metabolism.

Aenne-Dorothea Liebing, Philipp Rabe, Petra Krumbholz, Christian Zieschang, Franziska Bischof, Angela Schulz, Susan Billig, Claudia Birkemeyer, Thanigaimalai Pillaiyar, Mikel Garcia-Marcos, Robert Kraft, Claudia Stäubert.

  Succinate is a pivotal tricarboxylic acid cycle metabolite but also specifically activates the Gi- and Gq-coupled succinate receptor 1 (SUCNR1). Contradictory roles of succinate and succinate-SUCNR1 signaling include reports about its anti- or pro-inflammatory effects. The link between cellular metabolism and localization-dependent SUCNR1 signaling qualifies as a potential cause for the reported conflicts. To systematically address this connection, we used a diverse set of methods, including several bioluminescence resonance energy transfer-based biosensors, dynamic mass redistribution measurements, second messenger and kinase phosphorylation assays, calcium imaging, and metabolic analyses. Different cellular metabolic states were mimicked using glucose (Glc) or glutamine (Gln) as available energy substrates to provoke differential endogenous succinate (SUC) production. We show that SUCNR1 signaling, localization, and metabolism are mutually dependent, with SUCNR1 showing distinct spatial and energy substrate-dependent Gi and Gq protein activation. We found that Gln-consumption associated with a higher rate of oxidative phosphorylation causes increased extracellular SUC concentrations, accompanied by a higher rate of SUCNR1 internalization, reduced miniGq protein recruitment to the plasma membrane, and lower Ca2+ signals. In Glc, under basal conditions, SUCNR1 causes stronger Gq than Gi protein activation, while the opposite is true upon stimulation with an agonist. In addition, SUCNR1 specifically interacts with miniG proteins in endosomal compartments. In THP-1 cells, polarized to M2-like macrophages, endogenous SUCNR1-mediated Gi signaling stimulates glycolysis, while Gq signaling inhibits the glycolytic rate. Our results suggest that the metabolic context determines spatially dependent SUCNR1 signaling, which in turn modulates cellular energy homeostasis and mediates adaptations to changes in SUC concentrations.

Keywords:  SUCNR1; macrophages; metabolism; signal transduction; succinate

DOI:  https://doi.org/10.1111/febs.17407
Nat Cancer. 2025 Jan 17.

Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.

Jiaxin Liang, Tevis Vitale, Xixi Zhang, Thomas D Jackson, Deyang Yu, Mark Jedrychowski, Steve P Gygi, Hans R Widlund, Kai W Wucherpfennig, Pere Puigserver.

Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.

DOI: https://doi.org/10.1038/s43018-024-00895-x
J Struct Biol. 2025 Jan 20. pii: S1047-8477(25)00005-X. [Epub ahead of print] 108170

GCTransNet: 3D mitochondrial instance segmentation based on Global Context Vision Transformers.

Chaoyi Chen, Yidan Yan, Jingpeng Wu, Wen-Biao Gan.

  Mitochondria are double membrane-bound organelles essential for generating energy in eukaryotic cells. Mitochondria can be readily visualized in 3D using Volume Electron Microscopy (vEM), and accurate image segmentation is vital for quantitative analysis of mitochondrial morphology and function. To address the challenge of segmenting small mitochondrial compartments in vEM images, we propose an automated mitochondrial segmentation method called GCTransNet. This method employs grayscale migration technology to preprocess images, effectively reducing intensity distribution differences across EM images. By utilizing 3D Global Context Vision Transformers (GC-ViT) combined with global context self-attention modules and local self-attention modules, GCTransNet precisely models long-range and short-range spatial interactions. The long-range interactions enable the model to capture the global structural relationships within the mitochondrial segmentation network, while the short-range interactions refine local details and boundaries. In our approach, the encoder of the 3D U-Net network, a classical multi-scale learning architecture that retains high-resolution features through skip connections and combines multi-scale features for precise segmentation, is replaced by a 3D GC-ViT. The GC-ViT leverages shifted window-based self-attention, capturing long-range dependencies and offering improved segmentation accuracy compared to traditional U-Net encoders. In the MitoEM mitochondrial segmentation challenge, GCTransNet achieved state-of-the-art results, demonstrating its superiority in automated mitochondrial segmentation. The code and its documentation are publicly available at https://github.com/GanLab123/GCTransNet.

Keywords:  3D instance segmentation; Electron microscopy image; Mitochondrial morphology; Vision Transformer

DOI:  https://doi.org/10.1016/j.jsb.2025.108170
Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251314601

Arv1; a "Mover and Shaker" of Subcellular Lipids.

J Jose Corbalan, Karla K Frietze, Joseph Nickels, Stephen L Sturley.

  The composition of eukaryotic membranes reflects a varied but precise amalgam of lipids. The genetic underpinning of how such diversity is achieved or maintained is surprisingly obscure, despite its clear metabolic and pathophysiological impact. The Arv1 protein is represented in all eukaryotes and was initially identified in the model eukaryote Sacccharomyces cerevisiae as a candidate transporter of lipids from the endoplasmic reticulum. Human Arv1 has been shown to directly bind cholesterol and fatty acid affinity probes. Murine in vivo studies point to a role for ARV1 in regulating obesity, glucose tolerance, insulin sensitivity and brain function. Multiple human ARV1 variants have been associated with epileptic encephalopathy, cerebellar ataxia, and severe intellectual deficits. We hypothesize that Arv1 acts as an energy independent, lipid scramblase at the endoplasmic reticulum thereby modulating membrane lipid asymmetry and thus the trafficking of sterols and the substituents of glycosyl-phosphatidylinositol and sphingolipid biosynthesis.

Keywords:  cholesterol; encephalopathy; glycosyl-phosphatidylinositol; lipid flippase; sphingolipids

DOI:  https://doi.org/10.1177/25152564251314601
Sci Adv. 2025 Jan 24. 11(4): eadq7307

Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion.

Alessia Zotta, Juliana Toller-Kawahisa, Eva M Palsson-McDermott, Shane M O'Carroll, Órlaith C Henry, Emily A Day, Anne F McGettrick, Ross W Ward, Dylan G Ryan, Mark A Watson, Martin D Brand, Marah C Runtsch, Kathrin Maitz, Anna Lueger, Julia Kargl, Jan L Miljkovic, Ed C Lavelle, Luke A J O'Neill.

The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals. We have found that Suppressor of site IIIQo Electron Leak 1.2 (S3QEL 1.2), a specific inhibitor of reactive oxygen species (ROS) production from mitochondrial complex III, and myxothiazol, a complex III inhibitor, decrease IL-10 in lipopolysaccharide (LPS)-activated macrophages. IL-10 down-regulation is likely to be mediated by suppression of c-Fos, which is a subunit of activator protein 1 (AP1), a transcription factor required for IL-10 gene expression. S3QEL 1.2 impairs IL-10 production in vivo after LPS challenge and promotes the survival of mice bearing B16F10 melanoma by lowering tumor growth. Our data identify a link between complex III-dependent ROS generation and IL-10 production in macrophages, the targeting of which could have potential in boosting antitumor immunity.

DOI: https://doi.org/10.1126/sciadv.adq7307
Sci Rep. 2025 Jan 23. 15(1): 2992

ACOX1 activates autophagy via the ROS/mTOR pathway to suppress proliferation and migration of colorectal cancer.

Bo Shi, Junjie Chen, Haoran Guo, Xinyu Shi, Qingliang Tai, Guoliang Chen, Huihui Yao, Xiuwei Mi, Runze Zhong, Yang Lu, Yiyuan Zhao, Liang Sun, Diyuan Zhou, Yizhou Yao, Songbing He.

  Acyl-CoA oxidase 1 (ACOX1), a member of the acyl-coenzyme A oxidase family, is considered a crucial regulator whose dysregulation is implicated in the occurrence and progression of various cancers. This study aims to elucidate the impact of ACOX1 in CRC, shedding light on its potential as a therapeutic target. Through analysis of the GEO dataset, it was found that ACOX1 is significantly downregulated in colorectal cancer (CRC), and this lower expression level is associated with a worse prognosis. Additionally, in vitro as well as in vivo, ACOX1 overexpression dramatically reduced the proliferation and metastasis of CRC cells. Mass spectrometry revealed the crucial role of ACOX1 in fatty acid β-oxidation, as its overexpression led to a substantial increase in reactive oxygen species (ROS) derived from fatty acid β-oxidation. Further experiments demonstrated that ACOX1 overexpression, through modulation of fatty acid metabolism, increased ROS levels, reduced the phosphorylation activation of the key autophagy regulator mTOR, enhanced autophagy, and ultimately suppressed the growth and metastasis of CRC. In conclusions, ACOX1 expression is decreased in CRC. ACOX1 may regulate autophagy by reprogramming lipid metabolism to modulate the ROS/mTOR signaling pathway, consequently inhibiting the proliferation and migration of CRC.

Keywords:  ACOX1; Autophagy; Colorectal Cancer; ROS; mTOR

DOI:  https://doi.org/10.1038/s41598-025-87728-8
Mol Cell. 2025 Jan 16. pii: S1097-2765(24)01007-4. [Epub ahead of print]85(2): 262-275

Metabolism-driven chromatin dynamics: Molecular principles and technological advances.

Varun Sahu, Chao Lu.

  Cells integrate metabolic information into core molecular processes such as transcription to adapt to environmental changes. Chromatin, the physiological template of the eukaryotic genome, has emerged as a sensor and rheostat for fluctuating intracellular metabolites. In this review, we highlight the growing list of chromatin-associated metabolites that are derived from diverse sources. We discuss recent advances in our understanding of the mechanisms by which metabolic enzyme activities shape the chromatin structure and modifications, how specificity may emerge from their seemingly broad effects, and technologies that facilitate the study of epigenome-metabolome interplay. The recognition that metabolites are immanent components of the chromatin regulatory network has significant implications for the evolution, function, and therapeutic targeting of the epigenome.

Keywords:  chromatin; epigenome; histone acylation; histone methylation; metabolism; oncometabolite; transcription

DOI:  https://doi.org/10.1016/j.molcel.2024.12.012