bims-mibica 2025-12-14 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–12–14
thirteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

The sour regulation of metabolism: acidity challenges tumor cells while fueling their metabolic survival.
Three mammalian VDAC isoforms distinctly regulate mitochondrial function and proteome to maintain cell metabolism.
Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
Potent synergy of DHODH and SREBP inhibition in acute myeloid leukemia via disruption of cholesterol and lipid metabolism.
A step-by-step guide to performing cancer metabolism research using custom-made media.
An Alternative Metabolic Pathway of Glucose Oxidation Induced by Mitochondrial Complex I Inhibition: Serinogenesis and Folate Cycling.
CRTC2 Promotes AML Progression and Mediates Mitochondrially-Driven Venetoclax Resistance.
The ribosome-associated complex regulates cytosolic translation upon mitoprotein-induced stress.
Mitochondrial superoxide dismutase controls metabolic plasticity in pancreatic cancer.
Imaging mitochondrial membrane potential via concentration-dependent fluorescence lifetime changes.
Immunotherapy Inhibits Tumor Cholesterol Synthesis via the IFN-γ-ΙRF1-SREBF2 Axis.
Lypd6b depletion promotes CD8+ T cell-mediated anti-tumor immunity via metabolic reprogramming in colorectal cancer.
Elevated Lactate in AML Bone Marrow Contributes to Macrophage Polarization via GPR81 Signaling.

Cancer Res. 2025 Dec 11.

The sour regulation of metabolism: acidity challenges tumor cells while fueling their metabolic survival.

Bruna Martins Garcia, Patricia Altea-Manzano.

The tumor microenvironment imposes diverse metabolic challenges to cancer cells. Overcoming these challenges is essential for survival, proliferation, and dissemination. However, how cancer cells cope with the harsh environment and how the different coexisting stresses affect the tumor in vivo is unknown. Recently, Groessl, Kalis and colleagues published their findings in Science showing that acidosis outweighs all other stresses and plays a major role in the adaptation to them. Mechanistically, acidosis inhibits the ERK-DRP1 pathway, resulting in mitochondria elongation, which triggers a metabolic shift from glycolysis to oxidative phosphorylation. These findings highlight the plasticity of cancer cell mitochondria and refute the previous belief that cancer mitochondria are inherently dysfunctional. Indeed, inhibition of mitochondrial fusion or oxidative phosphorylation in acidic tumors is sufficient to promote cell death. Thus, enhancing respiration under acidosis comes to light as an essential metabolic adaptation to cancer survival and proliferation and targeting how cancer cells adapt to acidosis emerges as a new avenue for therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5633
J Biol Chem. 2025 Dec 05. pii: S0021-9258(25)02861-3. [Epub ahead of print] 111009

Three mammalian VDAC isoforms distinctly regulate mitochondrial function and proteome to maintain cell metabolism.

Megha Rajendran, William M Rosencrans, Nina A Bautista, Wendy Fitzgerald, Diana Huynh, Bethel G Beyene, Baiyi Quan, Jennifer D Petersen, Julie Hwang, Tsui-Fen Chou, Sergey M Bezrukov, Tatiana K Rostovtseva.

  The Voltage Dependent Anion Channel (VDAC) is the most ubiquitous protein in the mitochondrial outer membrane. This channel facilitates the flux of water-soluble metabolites and ions like calcium across the mitochondrial outer membrane. Beyond this canonical role, VDAC has been implicated, through interactions with protein partners, in several cellular processes such as apoptosis, calcium signaling, and lipid metabolism. There are three VDAC isoforms in mammalian cells, VDAC1, VDAC2, and VDAC3, with varying tissue-specific expression profiles. From a biophysical standpoint, all three isoforms conduct metabolites and ions with similar efficiency. However, isoform knockouts (KOs) in mice lead to distinct phenotypes, which may be due to differences in VDAC isoform interactions with partner proteins. To understand the functional role of each VDAC isoform within a single cell type, we created functional KOs of each isoform in HeLa cells and performed a comparative study of their metabolic activity and proteomics. We found that each isoform KO alters the proteome differently, with VDAC3 KO dramatically downregulating key members of the electron transport chain (ETC) while shifting the mitochondria into a glutamine-dependent state. Importantly, this unexpected dependence of mitochondrial function on the VDAC3 isoform is not compensated for by the more ubiquitously expressed VDAC1 and VDAC2 isoforms. In contrast, VDAC2 KO did not affect respiration but upregulated ETC components and decreased key enzymes in the glutamine metabolic pathway. VDAC1 KO specifically reduced glycolytic activity linked to decreased hexokinase localization to mitochondria. These results reveal non-redundant roles of VDAC isoforms in cancer cell metabolic adaptability.

Keywords:  CRISPR/Cas9 gene knockout; metabolic regulation; mitochondrial respiratory chain complex; proteomics; voltage-dependent anion channel

DOI:  https://doi.org/10.1016/j.jbc.2025.111009
Oncogenesis. 2025 Dec 08.

Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.

Melina C Mancini, Cameron P McCall, Robert C Noland, Wagner S Dantas, Timothy D Heden.

Mitochondrial metabolism is crucial for hepatocellular carcinoma (HCC) to thrive. Although phospholipids modulate mitochondrial metabolism, their impact on metabolism in HCC remains unknown. Here we report that the mitochondrial phospholipidome is unaltered in HCC mitochondria, suggesting HCC maintain their mitochondrial phospholipidome to enable efficient metabolism and promote thriftiness. Consistent with this, silencing phosphatidylserine decarboxylase (PISD), the inner mitochondrial membrane protein that generates mitochondrial phosphatidylethanolamine (PE), in HEPA1-6 cells impairs mitochondrial metabolism of fatty acid and glucose-derived substrates and reduces electron transport chain I and IV abundance. Moreover, PISD deficiency increased mitochondrial superoxide generation and altered mitochondria dynamics by augmenting mitochondrial fission, mitophagy, and mitochondrial extracellular efflux. Despite compensatory increases in anaerobic glycolysis and peroxisome fat oxidation, mitochondrial PE deficiency reduced DNA synthesis and cell proliferation, effects associated with reduced mTOR signaling and peptide levels. We conclude that targeting mitochondrial PE synthesis may be a viable therapy to slow HCC progression.

DOI: https://doi.org/10.1038/s41389-025-00593-y
Haematologica. 2025 Dec 11.

Potent synergy of DHODH and SREBP inhibition in acute myeloid leukemia via disruption of cholesterol and lipid metabolism.

Shanna M Hogeling, Dominique Sternadt, Nikita La Rose, Marjan Geugien, Diego Pereira-Martins, Fiona A J Van den Heuvel, Anna Kuchnio, Christine E Pietsch, Ulrike Philippar, Gerwin Huls, Jan Jacob Schuringa.

Acute myeloid leukemia (AML) remains difficult to cure, in part related to strong genetic and functional heterogeneity between and within individual patients. Metabolic reprogramming is emerging as an important feature of AML cells, allowing to explore alternative treatment strategies. Here, we describe a novel DHODH inhibitor, JNJ-74856665, that showed strong efficacy in a subset of AML samples. In a multi-omics approach, by combining label-free quantitative proteome data with drug sensitivity data in bone marrow stromal cocultures in a large cohort of primary AML patient samples we identified that sensitivity to DHODH inhibition (DHODHi) is linked to cholesterol and lipid metabolism. DHODHi resulted in an accumulation of cholesterol, mitochondrial ROS and lipid peroxidation. LC-MS/MS-based lipidomics studies revealed that DHODHi resulted in a strong increase in polyunsaturated fatty acids (PUFAs) and triglycerides (TGs), which are the primary lipid species stored in lipid droplets (LDs). We hypothesized that this might be the consequence of increased ROS and lipid peroxidation levels, prompting the cell to detoxify such toxic lipid species by storing them in LDs. Indeed, we could observed a marked increase in LD formation upon DHODHi. The transcriptional regulator SREBF2, known to control cholesterol and lipid metabolism, was upregulated in DHODHi sensitive AMLs, and a strong synergy was observed between combination of both DHODHi and the SREBP inhibitor dipyridamole. Our data indicate that combined DHODH and SREBP inhibition is of interest to explore further as a therapeutic target option in AML.

DOI: https://doi.org/10.3324/haematol.2025.287918
Life Sci Alliance. 2026 Feb;pii: e202503529. [Epub ahead of print]9(2):

A step-by-step guide to performing cancer metabolism research using custom-made media.

Sophie Seifert, Francisco Yanqui-Rivera, Tim Kühn, Lena Elise Høyland, Toman Borteçen, Bella Agranovich, Lara Elea Eckhardt, Martin Herdt, Alessa Henneberg, Verena Panitz, Faisal Hayat, Marie Migaud, Gernot Poschet, Ifat Abramovich, Eyal Gottlieb, Jeroen Krijgsveld, Mathias Ziegler, Mirja Tamara Prentzell, Christiane A Opitz.

The preparation of custom-made media offers precise control over nutrient composition, enabling detailed studies of cellular metabolism. We demonstrate how self-made media formulations enable diverse assay designs and readouts to assess cancer metabolism. Self-made media can be used in Seahorse assays to measure mitochondrial respiration under defined conditions. In nutrient deprivation experiments, amino acid or vitamin removal can uncover how cancer cells adapt to metabolic stress. Using labeled amino acids enables analysis of nascent protein synthesis and translational regulation, while stable-isotope tracing reveals metabolic fluxes through key pathways. This guide presents a suite of metabolic assays using custom-made media, covering experimental design, the selection of controls, sample preparation, data acquisition, and interpretation. The accompanying online media calculator "Media Minds" streamlines the creation of custom media formulations, ensuring accuracy and reproducibility.

DOI: https://doi.org/10.26508/lsa.202503529
Int J Mol Sci. 2025 Nov 24. pii: 11349. [Epub ahead of print]26(23):

An Alternative Metabolic Pathway of Glucose Oxidation Induced by Mitochondrial Complex I Inhibition: Serinogenesis and Folate Cycling.

Roman Abrosimov, Ankush Borlepawar, Parvana Hajieva, Bernd Moosmann.

  Inhibition of respiratory chain complex I (NADH dehydrogenase) is a widely encountered biochemical consequence of drug intoxication and a primary consequence of mtDNA mutations and other mitochondrial defects. In an organ-selective form, it is also deployed as antidiabetic pharmacological treatment. Complex I inhibition evokes a pronounced metabolic reprogramming of uncertain purposefulness, as in several cases, anabolism appears to be fostered in a state of bioenergetic shortage. A hallmark of complex I inhibition is the enhanced biosynthesis of serine, usually accompanied by an induction of folate-converting enzymes. Here, we have revisited the differential transcriptional induction of these metabolic pathways in three published models of selective complex I inhibition: MPP-treated neuronal cells, methionine-restricted rats, and patient fibroblasts harboring an NDUFS2 mutation. We find that in a coupled fashion, serinogenesis and circular folate cycling provide an unrecognized alternative pathway of complete glucose oxidation that is mostly dependent on NADP instead of the canonic NAD cofactor (NADP:NAD ≈ 2:1) and thus evades the shortage of oxidized NAD produced by complex I inhibition. In contrast, serine utilization for anabolic purposes and C1-folate provision for S-adenosyl-methionine production and transsulfuration cannot explain the observed transcriptional patterns, while C1-folate provision for purine biosynthesis did occur in some models, albeit not universally. We conclude that catabolic glucose oxidation to CO2, linked with NADPH production for indirect downstream respiration through fatty acid cycling, is the general purpose of the remarkably strong induction of serinogenesis after complex I inhibition.

Keywords:  NADPH-FADH2 axis; Parkinson’s disease; fatty acid cycling; futile cycle; glycolytic inhibition; metabolic reprogramming; metformin; mitochondrial disease; oxidative stress

DOI:  https://doi.org/10.3390/ijms262311349
FASEB J. 2025 Dec 15. 39(23): e71316

CRTC2 Promotes AML Progression and Mediates Mitochondrially-Driven Venetoclax Resistance.

Xiaomei Liang, Yilu Zheng, Bangxue Jiang, Yuling Huang, Jing Tang, Haimei Deng, Chenxing Zhang, Minyi Zhao, Dongjun Lin.

  Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the malignant proliferation of myeloid progenitor cells. Although the introduction of the B-cell lymphoma-2 (BCL-2) inhibitor Venetoclax (VEN) has significantly improved patient outcomes and established it as a first-line treatment, high rates of drug resistance and relapse remain major clinical challenges. We integrated RUNX3 chromatin immunoprecipitation sequencing (ChIP-seq) data with the GAPIA2 database to identify CRTC2 as a key candidate gene. Subsequently, we employed qRT-PCR to compare CRTC2 expression levels between donors and AML patients. The role of CRTC2 in apoptosis was further validated through knockdown and overexpression experiments in various cell lines. To investigate the impact of CRTC2 on AML progression, we established a cell line-derived xenograft (CDX) model. The proportion of human CD45-positive (hCD45+) cells in the bone marrow and liver was assessed, and histological examination was conducted using HE staining, along with peripheral blood smear analysis. In addressing VEN resistance, we analyzed CRTC2 expression patterns in clinical samples and explored the synergistic therapeutic effect of a CRTC2 inhibitor in combination with VEN. To further elucidate the underlying molecular mechanisms, we performed mitochondrial function assays and analyzed mitochondrial translation-related proteins. Clinical analyses have demonstrated that elevated expression levels of CRTC2, a downstream target of RUNX3, are significantly correlated with poor prognosis in patients with AML. Functional experiments have shown that CRTC2 plays a role in disease progression by modulating apoptosis in AML cells. The knockdown of CRTC2 was observed to delay disease progression in CDX mouse models. Additional investigations revealed a positive correlation between CRTC2 expression and resistance to VEN in AML cells, with CRTC2 inhibition synergistically enhancing VEN's cytotoxic effects. Mechanistic studies suggest that increased mitochondrial activity contributes to VEN resistance, thereby identifying a potential molecular target for overcoming drug resistance. CRTC2 is a key regulator in AML, with high expression levels promoting disease progression and resistance to VEN. Inhibiting CRTC2 reduces mitochondrial translation and energy reserves, increasing AML cell sensitivity to VEN. These results highlight CRTC2 as a promising therapeutic target and suggest a new strategy to overcome VEN resistance.

Keywords:  CRTC2; acute myeloid leukemia; drug resistance; mitochondrial translation

DOI:  https://doi.org/10.1096/fj.202503054R
FEBS J. 2025 Dec 07.

The ribosome-associated complex regulates cytosolic translation upon mitoprotein-induced stress.

Jiaxin Qian, Annika Nutz, Katja Hansen, Lea Bertgen, Mirita Franz-Wachtel, Boris Macek, Johannes M Herrmann, Doron Rapaport.

  The biogenesis of mitochondria relies on the import of newly synthesized precursor proteins from the cytosol. Tom70 is a mitochondrial surface receptor which recognizes precursors and serves as an interface between mitochondrial protein import and the cytosolic proteostasis network. Mitochondrial import defects trigger a complex stress response, in which compromised protein synthesis rates are a characteristic element. The molecular interplay that connects mitochondrial (dys)function to cytosolic translation rates in yeast cells is however poorly understood. Here, we show that the deletion of the two Tom70 paralogs of yeast (TOM70 and TOM71) leads to defects in mitochondrial biogenesis and slow cell growth. Surprisingly, upon heat stress, the deletion of ZUO1, a chaperone of the ribosome-associated complex (RAC), largely prevented the slow growth and the reduced translation rates in the tom70Δ/tom71Δ double deletion mutant. In contrast, the mitochondrial defects were not cured but even enhanced by ZUO1 deletion. Our study shows that Zuo1 is a critical component in the signaling pathway that mutes protein synthesis upon mitochondrial dysfunction. We propose a novel paradigm according to which RAC serves as a stress-controlled regulatory element of the cytosolic translation machinery.

Keywords:  Tom70; mitochondria; protein import; proteostasis; ribosome‐associated complex

DOI:  https://doi.org/10.1111/febs.70356
Cell Commun Signal. 2025 Dec 06. 23(1): 524

Mitochondrial superoxide dismutase controls metabolic plasticity in pancreatic cancer.

Sankaranarayanan Ramasubramanian, Rupert Öllinger, Carola Eberhagen, Hans Zischka, Roland M Schmid, Henrik Einwächter.

   BACKGROUND: The role of reactive oxygen species (ROS) in cancer is debated. One main antioxidant enzyme is mitochondrial superoxide dismutase (SOD2) which has been shown to influence tumor initiation and metastatic progression in several cancer types.
METHODS: To investigate the impact of Sod2 deletion on pancreatic cancer biology and metabolism, we used CRISPR/Cas9 gene editing to generate 3 independent Sod2-deficient cell lines from murine KrasG12D pancreatic cancer cell lines and analyzed them for proliferation, colony forming, mitochondrial respiration and RNA expression. In addition, mass spectrometry and isotope tracing were performed.
RESULTS: Proliferation and wound healing capacity were significantly impaired in Sod2 deficient cell lines. Myc levels were significantly elevated in Sod2-deficient cells, and mitochondrial respiration was consecutively increased. This resulted in increased tolerance to glucose deprivation. Mechanistically, we detected a significantly reduced activity of succinate dehydrogenase (SDH) in Sod2-deficient cells. This resulted in increased peroxynitrite formation which was the cause of increased Myc activation.
CONCLUSIONS: These findings reveal that Sod2 shapes cellular metabolism in pancreatic cancer through peroxynitrite formation and Myc activation.

Keywords:  Myc Proto-Oncogene Proteins; Pancreatic Neoplasms; Superoxide Dismutase (SOD2)

DOI:  https://doi.org/10.1186/s12964-025-02555-8
Nat Commun. 2025 Dec 12. 16(1): 11088

Imaging mitochondrial membrane potential via concentration-dependent fluorescence lifetime changes.

Dilizhatai Saimi, Luc Reymond, Tursunjan Aziz, Xuan Shen, Ziying Luo, Shuaibo Pi, Yitong Liu, Song Fu, Shuangjin Ding, Anming Meng, Liangyi Chen, Hui Jiang, Zhixing Chen.

Mitochondria are central to cellular metabolism. Various fluorescence tools have been developed for imaging the mitochondrial environment. Yet, new reporters and imaging methods for directly reading the mitochondrial status are needed for high spatial-temporal resolution imaging. Here, we introduce PK Mito Deep Red (PKMDR), a low-phototoxicity mitochondrial probe for time-lapse imaging, whose fluorescence lifetime serves as a sensitive indicator of mitochondrial membrane potential (Δψm). The positively charged PKMDR accumulates within mitochondria under a higher Δψm, leading to concentration-induced quenching and a measurable decrease in fluorescence lifetime. Since mitochondrial respiration primarily regulates Δψm, PKMDR's fluorescence lifetime effectively reports on the status of oxidative phosphorylation. Using PKMDR with fluorescence lifetime imaging microscopy (FLIM), we visualize heterogeneous Δψm across individual cells, organoids, and tissues over time. This method reliably reveals the heterogeneity between metabolically active peripheral mitochondria and relatively inactive perinuclear mitochondria in various cell types. Overall, PKMDR-FLIM is a robust tool for directly visualizing Δψm with high spatiotemporal resolution.

DOI: https://doi.org/10.1038/s41467-025-66042-x
Cancer Immunol Res. 2025 Dec 09.

Immunotherapy Inhibits Tumor Cholesterol Synthesis via the IFN-γ-ΙRF1-SREBF2 Axis.

Liping Xu, Xiaomin Zhang, Xiaowei Lai, Hongyuan Chen, Shuangye Liao, Mingzeng Chang, Xiaoqing Wu, Wen Rui, Juan Yang, Danyang Wang, Chengqi Gao, Ziqian Fang, Jianeng Zhang, Wende Li, Bo Li, Xiaojun Xia, Penghui Zhou.

Tumor cells employ metabolic mechanisms to limit antitumor immunity and promote resistance to immunotherapy. However, how immunotherapy modulates tumor metabolism remains unclear. Here, we demonstrated that anti-PD-1 treatment regulated cholesterol biosynthesis in cancer cells through the effector cytokine interferon IFN-γ. Mechanistically, IFN-γ-induced IRF1 transcriptionally suppresses the expression of SREBF2, a master regulator of cholesterol synthesis. Reduced cholesterol content inhibited tumor growth and sensitized tumor cells to statins, drugs lowering cholesterol. Overall, our study reveals that IFN-γ-mediated inhibition of cholesterol biosynthesis in tumor cells is an important antitumor mechanism of immunotherapy.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0242
Nat Commun. 2025 Dec 11.

Lypd6b depletion promotes CD8+ T cell-mediated anti-tumor immunity via metabolic reprogramming in colorectal cancer.

Ting Liu, Fanxin Zeng, Zuyin Li, Leirong Cheng, Xuanxuan Yan, Haiqiang Chen, Qin Liu, Xue Li, Zhao Li, Jiaheng Yao, Dan Xu, Zhinan Chen, Fengchao Wang, Jun Wang, Jinhua Zhang.

Lymphocyte antigen-plasminogen activator urokinase receptor domain-containing protein 6B (Lypd6b) is a newly identified molecule associated with neuromodulation. However, the role of Lypd6b in regulating the tumor microenvironment and its impact on CD8+ T cell-mediated antitumor immunity remain unknown. Here, we observe that Lypd6b expression is increased significantly in colorectal cancer (CRC) tumor tissues compared to normal tissues. Lypd6b is mainly expressed in CD8+ T cells in tumor tissues. Lypd6b knockout (Lypd6b-/-) mice are resistant to AOM/DSS-induced tumorigenesis. Furthermore, global deficiency or CD8+ cell deficiency of Lypd6b inhibits MC38 or CMT-93 tumor growth and promotes the infiltration of CD8+ T cells. Mechanistically, Lypd6b deficiency promotes activation and function of CD8+ T cells in anti-tumor response with increased glycolysis and reduced oxidative phosphorylation in a PI3K/mTOR/LDHA pathway-dependent manner. Notably, Lypd6b deficient CD8+ T cells have a more potent antitumor effect when combined with anti-PD1 antibody. Thus, Lypd6b as a negative regulator for T cell immunity promotes CRC development, providing a molecular target with therapeutic potential in CRC.

DOI: https://doi.org/10.1038/s41467-025-67344-w
Blood Adv. 2025 Dec 09. pii: bloodadvances.2025016400. [Epub ahead of print]

Elevated Lactate in AML Bone Marrow Contributes to Macrophage Polarization via GPR81 Signaling.

Celia A Soto, Maggie L Lesch, Jennifer L Becker, Azmeer Sharipol, Amal Khan, Xenia L Schafer, Zhewen Li, Amanda R Streeter, Michael W Becker, Joshua C Munger, Benjamin J Frisch.

Interactions between acute myeloid leukemia (AML) and the bone marrow microenvironment (BMME) are critical to leukemia progression and chemoresistance. In the solid tumor microenvironment, altered metabolite levels contribute to cancer progression. We performed a metabolomic analysis of AML patient bone marrow serum, revealing increased metabolites compared to age- and sex-matched controls. The most highly elevated metabolite in the AML BMME was lactate. Lactate signaling in solid tumors induces immunosuppressive tumor-associated macrophages and correlates with poor prognosis. This has not yet been studied in the leukemic BMME. Herein, we describe the role of lactate in the polarization of leukemia-associated macrophages (LAMs). Using a murine AML model of blast crisis chronic myelogenous leukemia (bcCML), we characterize the suppressive phenotype of LAMs by surface markers, transcriptomics, and cytokine profiling. Then, mice genetically lacking GPR81, the extracellular lactate receptor, were used to demonstrate GPR81 signaling as a mechanism of both the polarization of LAMs and the direct support of leukemia cells. Furthermore, elevated lactate diminished the function of hematopoietic progenitors and reduced stromal support for normal hematopoiesis. We report microenvironmental lactate as a mechanism of AML-induced immunosuppression and leukemic progression, thus identifying GPR81 signaling as an exciting and novel therapeutic target for treating this devastating disease.

DOI: https://doi.org/10.1182/bloodadvances.2025016400