bims-mibica 2025-03-30 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–03–30
twenty-two papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Fatty Acid Metabolism Provides an Essential Survival Signal in OxPhos and BCR DLBCL Cells.
BH3 mimetics augment cytotoxic T cell killing of acute myeloid leukemia via mitochondrial apoptotic mechanism.
H2S remodels mitochondrial ultrastructure and destabilizes respiratory supercomplexes.
MTFR1 phosphorylation-activated adaptive mitochondrial fusion is essential for colon cancer cell survival during glucose deprivation.
Function of intramitochondrial melatonin and its association with Warburg metabolism.
Low dose Taxol causes mitochondrial dysfunction in actively respiring cancer cells.
A human brain map of mitochondrial respiratory capacity and diversity.
A leigh syndrome mutation perturbs long-range energy coupling in respiratory complex I.
SOD2 is a regulator of proteasomal degradation promoting an adaptive cellular starvation response.
Clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cells.
LRPPRC confers enhanced oxidative phosphorylation metabolism in triple-negative breast cancer and represents a therapeutic target.
Lipid-metabolism-focused CRISPR screens identify enzymes of the mevalonate pathway as essential for prostate cancer growth.
AMP-activated protein kinase mediates adaptation of glioblastoma cells to conditions of the tumor microenvironment.
Dual-Modality Imaging Unveil Inner Mitochondrial Membrane Viscosity and Respiratory Dynamics in Mitophagy.
SLC3A2-Mediated Lysine Uptake by Cancer Cells Restricts T cell Activity in Hepatocellular Carcinoma.
Unclogging of the TOM complex under import stress.
Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
DHODH inhibition alters T cell metabolism limiting acute graft-versus-host disease while retaining graft-versus-leukemia response.
Targeting Mitophagy Using Isoliensinine as a Therapeutic Strategy for Renal Cell Carcinoma Treatment.
Concurrent inhibition of FLT3 and sphingosine kinase-1 triggers synergistic cytotoxicity in midostaurin resistant FLT3-ITD positive acute myeloid leukemia cells via blocking FLT3/STAT5A signaling to induce apoptosis.
SR-B1 deficiency suppresses progression in acute myeloid leukemia via ferroptosis and reverses resistance to venetoclax.
Targeting an AML-sustaining metabolic node.

Biomedicines. 2025 Mar 13. pii: 707. [Epub ahead of print]13(3):

Fatty Acid Metabolism Provides an Essential Survival Signal in OxPhos and BCR DLBCL Cells.

Aurélie Montagne, Konstantina Kotta, Karoline Kielbassa-Elkadi, Isabelle Martins, José Ángel Martinez-Climent, Guido Kroemer, Catherine Thieblemont, Véronique Baud.

  Backgroung/objectives: Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of malignant lymphoma and is a heterogeneous disease with various gene and chromosomal abnormalities. The development of novel therapeutic treatments has improved DLBCL prognosis, but patients with early relapse or refractory disease have a poor outcome (with a mortality of around 40%). Metabolic reprogramming is a hallmark of cancer cells. Fatty acid (FA) metabolism is frequently altered in cancer cells and recently emerged as a critical survival path for cancer cell survival. Methods: We first performed the metabolic characterization of an extended panel of DLBCL cell lines, including lipid droplet content. Then, we investigated the effect of drugs targeting FA metabolism on DLBCL cell survival. Further, we studied how the combination of drugs targeting FA and either mitochondrial metabolism or mTOR pathway impacts on DLBCL cell death. Results: Here, we reveal, using a large panel of DLBCL cell lines characterized by their metabolic status, that targeting of FA metabolism induces massive DLBCL cell death regardless of their OxPhos or BCR/glycolytic subtype. Further, FA drives resistance of DLBCL cell death induced by mitochondrial stress upon treatment with either metformin or L-asparaginase, two FDA-approved antimetabolic drugs. Interestingly, combining inhibition of FA metabolism with that of the mTOR oncogenic pathway strongly potentiates DLBCL cell death. Conclusion: Altogether, our data highlight the central role played by FA metabolism in DLBCL cell survival, independently of their metabolic subtype, and provide the framework for the use of drugs targeting this metabolic vulnerability to overcome resistance in DLBCL patients.

Keywords:  B-cell lymphoma; DLBCL; fatty acid; metabolism; mitochondrial stress; survival

DOI:  https://doi.org/10.3390/biomedicines13030707
Cell Death Discov. 2025 Mar 26. 11(1): 120

BH3 mimetics augment cytotoxic T cell killing of acute myeloid leukemia via mitochondrial apoptotic mechanism.

Kapil Saxena, Shao-Hsi Hung, Esther Ryu, Shailbala Singh, Qi Zhang Tatarata, Zhihong Zeng, Zhe Wang, Marina Y Konopleva, Cassian Yee.

Adoptive cell therapy (ACT) can address an unmet clinical need for patients with relapsed/refractory acute myeloid leukemia (AML), but its effect is often modest in the setting of high tumor burden. In this study, we postulated that strategies to lower the AML apoptotic threshold will augment T cell killing of AML cells. BH3 mimetics, such as venetoclax, are a clinically approved class of compounds that predispose cells to intrinsic apoptosis by inhibiting anti-apoptotic mitochondrial proteins. We explored the anti-leukemic efficacy of BH3 mimetics combined with WT1-specific CD8+ T cells on AML cell lines and primary samples from patients with a diverse array of disease characteristics to evaluate if lowering the cellular apoptotic threshold via inhibition of anti-apoptotic mitochondrial proteins can increase leukemic cell sensitivity to T cell therapy. We found that the combination approach of BH3 mimetic and CD8+ T cells led to significantly increased killing of established AML lines as well as of adverse-risk primary AML leukemic blast cells. In contrast to the hypothesis that enhanced killing would be due to combined activation of the intrinsic and extrinsic apoptotic pathways, our data suggests that CTL-mediated killing of AML cells was accomplished primarily through activation of the intrinsic/mitochondrial apoptotic pathway. This highly effective combinatorial activity due to convergence on the mitochondrial apoptotic pathway was conserved across multiple AML cell lines and primary samples, suggesting that mitochondrial priming may represent a novel mechanism of optimizing adoptive cell therapy for AML patients.

DOI: https://doi.org/10.1038/s41420-025-02375-2
J Biol Chem. 2025 Mar 20. pii: S0021-9258(25)00282-0. [Epub ahead of print] 108433

H2S remodels mitochondrial ultrastructure and destabilizes respiratory supercomplexes.

David A Hanna, Brandon Chen, Yatrik M Shah, Oleh Khalimonchuk, Brian Cunniff, Ruma Banerjee.

  Mitochondrial form and function are intimately interconnected, responding to cellular stresses and changes in energy demand. Hydrogen sulfide, a product of amino acid metabolism, has dual roles as an electron transport chain substrate and complex IV (CIV) inhibitor, leading to a reductive shift, which has pleiotropic metabolic consequences. Luminal sulfide concentration in colon is high due to microbial activity, and in this study, we demonstrate that chronic sulfide exposure of colonocyte-derived cells leads to lower Mic60 and Mic19 expression that is correlated with a profound loss of cristae and lower mitochondrial networking. Sulfide-induced depolarization of the inner mitochondrial membrane activates Oma1-dependent cleavage of Opa1 and is associated with a profound loss of CI and CIV activities associated with respirasomes. Our study reveals a potential role for sulfide as an endogenous modulator of mitochondrial dynamics and suggests that this regulation is corrupted in hereditary or acquired diseases associated with elevated sulfide.

Keywords:  Cristae; cristae; electron transport chain; hydrogen sulfide; mitochondrial dynamics; respirasome

DOI:  https://doi.org/10.1016/j.jbc.2025.108433
Neoplasia. 2025 Mar 22. pii: S1476-5586(25)00038-7. [Epub ahead of print]63 101159

MTFR1 phosphorylation-activated adaptive mitochondrial fusion is essential for colon cancer cell survival during glucose deprivation.

Nan Zhang, Lu Dong, Sifan Liu, Tingting Ning, Shengtao Zhu.

   BACKGROUND: Mitochondrial dynamics are essential for maintaining cellular function under metabolic stress. However, their role in colon cancer's response to glucose deprivation remains poorly understood.
METHODS: The role of the mitochondrial protein MTFR1 in colon cancer proliferation was evaluated using CCK-8 and colony formation assays. Mass spectrometry identified MTFR1-interacting proteins and phosphorylation sites. Mitochondrial morphology was examined with Mitotracker staining, and mitochondrial function was evaluated using MitoSOX, JC-1 staining, and the Seahorse cell mitochondrial stress test.
RESULTS: We observed that MTFR1 is highly expressed in colon cancer cells and interacts with NEK1 under glucose deprivation. This interaction induces phosphorylation of MTFR1 at serine 119, which promotes mitochondrial fusion and supports mitochondrial function. Consequently, enhanced oxidative phosphorylation improves cellular tolerance to glucose deprivation.
CONCLUSIONS: Our findings highlight the importance of MTFR1 in modulating mitochondrial dynamics and its potential impact on colon cancer cell survival under metabolic stress. These results suggest that MTFR1 serine 119 could be a key regulator of colon cancer cell metabolism and a potential therapeutic target for enhancing cancer cell response to metabolic challenges.

Keywords:  Colorectal cancer; Glucose deprivation; MTFR1; Mitochondrial fusion; NEK1

DOI:  https://doi.org/10.1016/j.neo.2025.101159
Cell Signal. 2025 Mar 21. pii: S0898-6568(25)00167-6. [Epub ahead of print]131 111754

Function of intramitochondrial melatonin and its association with Warburg metabolism.

Russel J Reiter, Ramaswamy Sharma, Yidong Bai, Luiz Gustavo de Almeida Chuffa, Doris Loh, Lihong Fan, Daniel P Cardinali.

  Warburg metabolism (aerobic glycolysis) is accompanied by high mitochondrial reactive oxygen species (ROS) generation from the electron transport chain; this is a "Hallmark of Cancer". The elevated ROS sustain the growth and proliferation of the cancer cells. Melatonin is a potent and functionally diverse free radical scavenger and antioxidant that is synthesized in the mitochondria of non-pathological cells and normally aids in keeping mitochondrial ROS levels low and in maintaining redox homeostasis. Because the glucose metabolite, pyruvate, does not enter mitochondria of Warburg metabolizing cells due to the inhibition of pyruvate dehydrogenase complex (PDH), acetyl coenzyme A production is diminished. Acetyl coenzyme A is a necessary co-substrate with serotonin for melatonin synthesis; thus, intramitochondrial melatonin levels become reduced in cancer cells. The hypothesis is that the depressed melatonin levels initiate aerobic glycolysis and allow the exaggerated ROS concentrations to go uncontested; the authors speculate that the elevated mtROS upregulates hypoxia inducible factor 1α (HIF-1α)/pyruvate dehydrogenase kinase (PDK) axis which inhibits PDH, thereby supporting cancer cell proliferation and stimulating cancer biomass. Exposing Warburg metabolizing cancer cells to melatonin elevates intramitochondrial melatonin, thereby reducing mtROS and concurrently interrupting aerobic glycolysis and inhibiting tumor cell proliferation. Mechanistically, higher mitochondrial melatonin levels by supplementation directly upregulates the sirtuin 3 (SIRT3)/FOXO/PDH axis, allowing pyruvate entry into mitochondria and enhancing intrinsic mitochondrial melatonin production as in non-pathological cells. Additionally, melatonin inhibits HIF1α, thereby decreasing PDK activity and disinhibiting PDH, so pyruvate enters mitochondria and is metabolized to acetyl coenzyme A, resulting in reversal of Warburg metabolism.

Keywords:  Acetyl coenzyme A; Antioxidant; Hypoxia inducible factor; Pyruvate dehydrogenase; Pyruvate metabolism; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.cellsig.2025.111754
J Biol Chem. 2025 Mar 25. pii: S0021-9258(25)00299-6. [Epub ahead of print] 108450

Low dose Taxol causes mitochondrial dysfunction in actively respiring cancer cells.

Rozhin Penjweini, Katie A Link, Shureed Qazi, Nikhil Mattu, Adam Zuchowski, Alexandra Vasta, Dan L Sackett, Jay R Knutson.

  Mitochondrial oxygen consumption, dynamics and morphology play roles in the occurrence, development and drug resistance of cancer; thus they are main targets for many anticancer drugs. Increased mitochondrial oxygen consumption and impaired oxygen delivery creates hypoxia, which influences the balance of metabolic co-factors for biogenesis, disease progression and response to therapeutics. We therefore investigated the effects of Taxol, a well-known anticancer drug, on mitochondrial respiration (principally via a measure of oxidative phosphorylation (OXPHOS) versus glycolysis), morphology and dynamics. The concomitant effects of Taxol on mitochondrial adenosine triphosphate (ATP) and reactive oxygen species (ROS) production, mitochondrial membrane potential, radical-induced formation of carbonyl groups, mitochondrial release of cytochrome c, as well as cell cycle were investigated. Cells used in this study include: A549 (non-small cell lung epithelial cancer cell line), A549-ρ0 (mitochondrial DNA-depleted derivative of A549), and BEAS-2B (a non-cancer cell line derived from normal bronchial epithelium), as well as PC3 (prostate cancer) and HepG2 (hepatocellular carcinoma); these cell lines are known to have disparate metabolic profiles. Using a multitude of fluorescence-based measurements, we show that Taxol, even at a low dose, still adversely effects mitochondria of actively respiring (aerobic) cancer cells. We find an increase in mitochondrial ROS and cytochrome c release, suppression of ATP production and OXPHOS, fragmentation of the mitochondrial network and disruption of mitochondria-microtubule linkage. We find these changes in oxidative, but not glycolytic, cancer cells. Non-cancer cells, which are oxidative, do not show these changes.

Keywords:  Low-dose Taxol; Mitochondrial metabolism; OXPHOS; morphology and dynamics

DOI:  https://doi.org/10.1016/j.jbc.2025.108450
Nature. 2025 Mar 26.

A human brain map of mitochondrial respiratory capacity and diversity.

Eugene V Mosharov, Ayelet M Rosenberg, Anna S Monzel, Corey A Osto, Linsey Stiles, Gorazd B Rosoklija, Andrew J Dwork, Snehal Bindra, Alex Junker, Ya Zhang, Masashi Fujita, Madeline B Mariani, Mihran Bakalian, David Sulzer, Philip L De Jager, Vilas Menon, Orian S Shirihai, J John Mann, Mark D Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard.

Mitochondrial oxidative phosphorylation (OXPHOS) powers brain activity1,2, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders3,4. To understand the basis of brain activity and behaviour, there is a need to define the molecular energetic landscape of the brain5-10. Here, to bridge the scale gap between cognitive neuroscience and cell biology, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3 × 3 × 3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes, including OXPHOS enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains diverse mitochondrial phenotypes driven by both topology and cell types. Compared with white matter, grey matter contains >50% more mitochondria. Moreover, the mitochondria in grey matter are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backwards linear regression model that integrates several neuroimaging modalities11 to generate a brain-wide map of mitochondrial distribution and specialization. This model predicted mitochondrial characteristics in an independent brain region of the same donor brain. This approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain function. This resource also relates to neuroimaging data and defines the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders. All data are available at http://humanmitobrainmap.bcblab.com .

DOI: https://doi.org/10.1038/s41586-025-08740-6
Chem Sci. 2025 Mar 21.

A leigh syndrome mutation perturbs long-range energy coupling in respiratory complex I.

Franziska Hoeser, Patricia Saura, Caroline Harter, Ville R I Kaila, Thorsten Friedrich.

Respiratory complex I is a central enzyme of cellular energy metabolism that couples electron transfer with proton translocation across a biological membrane. In doing so, it powers oxidative phosphorylation that drives energy consuming processes. Mutations in complex I lead to severe neurodegenerative diseases in humans. However, the biochemical consequences of these mutations remain largely unknown. Here, we use the Escherichia coli complex I as a model to biochemically characterize the F124LMT-ND5 mutation found in patients suffering from Leigh syndrome. We show that the mutation drastically perturbs proton translocation and electron transfer activities to the same extent, despite the remarkable 140 Å distance between the mutated position and the electron transfer domain. Our molecular dynamics simulations suggest that the disease-causing mutation induces conformational changes that hamper the propagation of an electric wave through an ion-paired network essential for proton translocation. Our findings imply that malfunction of the proton translocation domain is entirely transmitted to the electron transfer domain underlining the action-at-a-distance coupling in the proton-coupled electron transfer of respiratory complex I.

DOI: https://doi.org/10.1039/d4sc04036h
Cell Rep. 2025 Mar 24. pii: S2211-1247(25)00205-0. [Epub ahead of print]44(4): 115434

SOD2 is a regulator of proteasomal degradation promoting an adaptive cellular starvation response.

Nurul Khalida Ibrahim, Sabine Schreek, Buesra Cinar, Anna Sophie Stasche, Su Hyun Lee, Andre Zeug, Tim Dolgner, Julia Niessen, Evgeni Ponimaskin, Halyna Shcherbata, Beate Fehlhaber, Jean-Pierre Bourquin, Beat Bornhauser, Martin Stanulla, Andreas Pich, Alejandro Gutierrez, Laura Hinze.

  Adaptation to changes in amino acid availability is crucial for cellular homeostasis, which requires an intricate orchestration of involved pathways. Some cancer cells can maintain cellular fitness upon amino acid shortage, which has a poorly understood mechanistic basis. Leveraging a genome-wide CRISPR-Cas9 screen, we find that superoxide dismutase 2 (SOD2) has a previously unrecognized dismutase-independent function. We demonstrate that SOD2 regulates global proteasomal protein degradation and promotes cell survival under conditions of metabolic stress in malignant cells through the E3 ubiquitin ligases UBR1 and UBR2. Consequently, inhibition of SOD2-mediated protein degradation highly sensitizes different cancer entities, including patient-derived xenografts, to amino acid depletion, highlighting the pathophysiological relevance of our findings. Our study reveals that SOD2 is a regulator of proteasomal protein breakdown upon starvation, which serves as an independent catabolic source of amino acids, a mechanism co-opted by cancer cells to maintain cellular fitness.

Keywords:  CP: Cancer; CP: Molecular biology; SOD2; UBR1; UBR2; amino acid starvation; cancer; drug resistance; leukemia; protein degradation

DOI:  https://doi.org/10.1016/j.celrep.2025.115434
Genome Biol. 2025 Mar 26. 26(1): 70

Clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cells.

Xin Wang, Kun Wang, Weixing Zhang, Zhongjie Tang, Hao Zhang, Yuying Cheng, Da Zhou, Chao Zhang, Wen-Zhao Zhong, Qing Ma, Jin Xu, Zheng Hu.

   BACKGROUND: Mitochondrial DNA (mtDNA) variants hold promise as endogenous barcodes for tracking human cell lineages, but their efficacy as reliable lineage markers are hindered by the complex dynamics of mtDNA in somatic tissues.
RESULTS: Here, we use computational modeling and single-cell genomics to thoroughly interrogate the origin and clonal dynamics of mtDNA variants across various biological settings. Our findings reveal that the majority of mtDNA variants which are specifically present in a cell subpopulation, termed subpopulation-specific variants, are pre-existing heteroplasmies in the first cell instead of de novo somatic mutations during divisions. Moreover, subpopulation-specific variants demonstrate limited discriminatory power among different genuine lineages under weak clonal expansion; however, certain subpopulation-specific variants with consistently high frequencies among a subpopulation are capable of faithfully labeling cell lineages in scenarios of stringent clonal expansion, such as strongly expanded T cell populations in diseased conditions and clonal hematopoiesis in aged individuals. Inspired by our simulations, we introduce a lineage informative score, facilitating the identification of reliable mitochondrial lineage tracing markers across different modalities of single-cell genomic data.
CONCLUSIONS: Combining computational modeling and single-cell sequencing, our study reveals that the performance of mitochondrial lineage tracing is highly dependent on the extent of clonal expansion, which thus should be considered when applying mitochondrial lineage tracing.

Keywords:  Clonal dynamics; Lineage tracing; Single-cell genomics; mtDNA variants

DOI:  https://doi.org/10.1186/s13059-025-03540-7
J Transl Med. 2025 Mar 25. 23(1): 372

LRPPRC confers enhanced oxidative phosphorylation metabolism in triple-negative breast cancer and represents a therapeutic target.

Qiqi Xue, Wenxi Wang, Jie Liu, Dachi Wang, Tianyu Zhang, Tingting Shen, Xiangsheng Liu, Xiaojia Wang, Xiying Shao, Wei Zhou, Xiaohong Fang.

   BACKGROUND: Triple-negative breast cancer (TNBC) is a highly malignant tumor that requires effective therapeutic targets and drugs. Oxidative phosphorylation (OXPHOS) is a metabolic vulnerability of TNBC, but the molecular mechanism responsible for the enhanced OXPHOS remains unclear. The current strategies that target the electronic transfer function of OXPHOS cannot distinguish tumor cells from normal cells. Investigating the mechanism underlying OXPHOS regulation and developing corresponding therapy strategies for TNBC is of great significance.
METHODS: Immunohistochemistry and sequencing data reanalysis were used to investigate LRPPRC expression in TNBC. In vitro and in vivo assays were applied to investigate the roles of LRPPRC in TNBC progression. RT-qPCR, immunoblotting, and Seahorse XF assay were used to examine LRPPRC's functions in the expression of OXPHOS subunits and energy metabolism. In vitro and in vivo functional assays were used to test the therapeutic effect of gossypol acetate (GAA), a traditional gynecological drug, on LRPPRC suppression and OXPOHS inhibition.
RESULTS: LRPPRC was specifically overexpressed in TNBC. LRPPRC knockdown suppressed the proliferation, metastasis, and tumor formation of TNBC cells. LRPPRC enhanced OXPHOS metabolism by increasing the expression of OXPHOS complex subunits encoded by the mitochondrial genome. GAA inhibited OXPHOS metabolism by directly binding LRPPRC, causing LRPPRC degradation, and downregulating the expression of OXPHOS complex subunits encoded by the mitochondrial genome. GAA administration suppressed TNBC cell proliferation, metastasis in vitro, and tumor formation in vivo.
CONCLUSIONS: This work demonstrated a new regulatory pathway of TNBC to promote the expression of mitochondrial genes by upregulating the nuclear gene LRPPRC, resulting in increased OXPHOS. We also suggested a promising therapeutic target LRPPRC for TNBC, and its inhibitor, the traditional gynecological medicine GAA, presented significant antitumor activity.

Keywords:  Gossypol acetate; Oxidative phosphorylation; Triple-negative breast cancer

DOI:  https://doi.org/10.1186/s12967-024-05946-6
Cell Rep. 2025 Mar 26. pii: S2211-1247(25)00241-4. [Epub ahead of print]44(4): 115470

Lipid-metabolism-focused CRISPR screens identify enzymes of the mevalonate pathway as essential for prostate cancer growth.

Gio Fidelito, Izabela Todorovski, Leonie Cluse, Stephin J Vervoort, Renea A Taylor, Matthew J Watt.

  Dysregulated lipid metabolism plays an important role in prostate cancer, although the understanding of the essential regulatory processes in tumorigenesis is incomplete. We employ a CRISPR-Cas9 screen using a custom human lipid metabolism knockout library to identify essential genes for prostate cancer survival. Screening in three prostate cancer cell lines reveals 63 shared dependencies, with enrichment in terpenoid backbone synthesis and N-glycan biosynthesis. Independent knockout of key genes of the mevalonate pathway reduces cell proliferation. Further investigation focuses on NUS1, a subunit of cis-prenyltransferase required for dolichol synthesis. NUS1 knockout decreases tumor growth in vivo and viability in patient-derived xenograft (PDX)-derived organoids. Mechanistic studies reveal that loss of NUS1 promotes oxidative stress, lipid peroxidation and ferroptosis sensitivity, endoplasmic reticulum (ER) stress, and G1 cell-cycle arrest, and it dampens androgen receptor (AR) signaling, collectively leading to growth arrest. This study highlights the critical role of the mevalonate-dolichol-N-glycan biosynthesis pathway, particularly NUS1, in prostate cancer survival and growth.

Keywords:  CP: Cancer; CP: Metabolism; CRISPR screen; cancer metabolism; lipid metabolism; prostate cancer

DOI:  https://doi.org/10.1016/j.celrep.2025.115470
J Exp Clin Cancer Res. 2025 Mar 24. 44(1): 104

AMP-activated protein kinase mediates adaptation of glioblastoma cells to conditions of the tumor microenvironment.

Nadja I Lorenz, Benedikt Sauer, Hans Urban, Jan-Béla Weinem, Bhavesh S Parmar, Pia S Zeiner, Maja I Strecker, Dorothea Schulte, Michel Mittelbronn, Tijna Alekseeva, Lisa Sevenich, Patrick N Harter, Christian Münch, Joachim P Steinbach, Anna-Luisa Luger, Dieter Henrik Heiland, Michael W Ronellenfitsch.

  AMP-activated protein kinase (AMPK) is an energy sensor that regulates cellular metabolic activity. We hypothesized that in glioblastoma (GB), AMPK plays a pivotal role in balancing metabolism under conditions of the tumor microenvironment with fluctuating and often low nutrient and oxygen availability. Impairment of this network could thus interfere with tumor progression. AMPK activity was modulated genetically by CRISPR/Cas9-based double knockout (DKO) of the catalytic α1 and α2 subunits in human GB cells and effects were confirmed by pharmacological AMPK inhibition using BAY3827 and an inactive control compound in primary GB cell cultures. We found that metabolic adaptation of GB cells under energy stress conditions (hypoxia, glucose deprivation) was dependent on AMPK and accordingly that AMPK DKO cells were more vulnerable to glucose deprivation or inhibition of glycolysis and sensitized to hypoxia-induced cell death. This effect was rescued by reexpression of the AMPK α2 subunit. Similar results were observed using the selective pharmacological AMPK inhibitor BAY3827. Mitochondrial biogenesis was regulated AMPK-dependently with a reduced mitochondrial mass and mitochondrial membrane potential in AMPK DKO GB cells. In vivo, AMPK DKO GB cells showed impaired tumor growth and tumor formation in CAM assays as well as in an orthotopic glioma mouse model. Our study highlights the importance of AMPK for GB cell adaptation towards energy depletion and emphasizes the role of AMPK for tumor formation in vivo. Moreover, we identified mitochondria as central downstream effectors of AMPK signaling. The development of AMPK inhibitors could open opportunities for the treatment of hypoxic tumors.

Keywords:  AMP-activated protein kinase; AMPK; Glioblastoma; Hypoxia; Metabolic adaptation

DOI:  https://doi.org/10.1186/s13046-025-03346-2
Anal Chem. 2025 Mar 27.

Dual-Modality Imaging Unveil Inner Mitochondrial Membrane Viscosity and Respiratory Dynamics in Mitophagy.

Fei Peng, Xiangnan Ai, Bin Hao, Xiaoyu Bu, Zixuan Zhao, Linshuai Yang, Baoxiang Gao.

Mitophagy is a vital lysosome-dependent process that maintains mitochondrial integrity and cellular homeostasis, where respiration and inner mitochondrial membrane (IMM) viscosity play key roles. Despite its critical importance, achieving a high-resolution and dynamic visualization of respiration and IMM viscosity during mitophagy remains a significant challenge. In this study, we designed two innovative fluorescent probes: SiR-C8, a viscosity-sensitive rotor-type probe based on silicon-rhodamine, specifically targeting the IMM, and OR-ATP, a rhodamine-derived probe utilizing an intramolecular spirolactam structure to respond to mitochondrial ATP levels. Leveraging fluorescence intensity and lifetime dual-modality imaging, we successfully enabled the high-resolution, real-time monitoring of lysosome-dependent mitophagy. Remarkably, our results unveiled a progressive increase in IMM viscosity alongside a significant attenuation in mitochondrial respiration during mitophagy induced by starvation, carbonyl cyanide, m-chlorophenyl hydrazone (CCCP), and Oligomycin. Significantly, utilizing structured illumination microscopy super-resolution imaging, we have uncovered a novel mitochondrial quality control mechanism by which lysosomes selectively engulf locally damaged mitochondrial regions. This discovery provides novel insights into the intricate processes governing mitophagy and introduces an innovative platform for studying mitochondrial dynamics, dysfunction, and their implications for cellular homeostasis and pathology.

DOI: https://doi.org/10.1021/acs.analchem.5c00464
Cancer Res. 2025 Mar 24.

SLC3A2-Mediated Lysine Uptake by Cancer Cells Restricts T cell Activity in Hepatocellular Carcinoma.

Yating Chang, Naizhen Wang, Shaopeng Li, Jiaqi Zhang, Yipeng Rao, Zilong Xu, Lu Li, Hongning Wu, Jun Chen, Yanhua Lin, Xiaoxuan Huang, Pingguo Liu, Jun Zhang, Yueting Liao, Chaolong Lin, Chenghao Huang, Ningshao Xia.

Abnormal amino acid metabolism supports cancer cell proliferation, invasion, and immune evasion in hepatocellular carcinoma (HCC). Previous research exploring amino acid metabolism in HCC has primarily focused on how metabolic reprogramming impacts tumor cells. Here, we focused on the role of amino acid metabolism dysregulation in the crosstalk between HCC and T cells. HCC cells disrupted lysine uptake in T cells, leading to impaired T cell immunity. Lysine deprivation decreased STAT3 levels in T cells, inhibiting T cell proliferation and effector function and ultimately promoting tumor progression. Mechanistically, HCC cells outcompeted T cells for lysine by expressing high levels of the lysine transporter SLC3A2. Clinically, elevated SLC3A2 expression correlated with poor survival and was linked to dysregulated T cell functional gene signatures in HCC patients. Furthermore, the multikinase inhibitor lenvatinib induced a c-Myc-SLC3A2 regulatory axis that limited the efficacy of lenvatinib treatment. Lysine supplementation enhanced tumor sensitivity to combined treatment with lenvatinib and anti-PD-1 immunotherapy. These findings suggest that lysine supplementation is a potential therapeutic strategy for treating HCC and enhancing the sensitivity of HCC to tyrosine kinase inhibitors and immune checkpoint blockade.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3180
Biol Chem. 2025 Mar 28.

Unclogging of the TOM complex under import stress.

Joshua Jackson, Thomas Becker.

  Mitochondrial functions and biogenesis depend on the import of more than 1,000 proteins which are synthesized as precursor proteins on cytosolic ribosomes. Mitochondrial protein translocases sort the precursor proteins into the mitochondrial sub-compartments: outer and inner membrane, the intermembrane space and the matrix. The translocase of the outer mitochondrial membrane (TOM complex) constitutes the major import site for most of these precursor proteins. Defective protein translocases, premature folding of the precursor, or depletion of the membrane potential can cause clogging of the TOM channel by a precursor protein. This clogging impairs further protein import and leads to accumulation of precursor proteins in the cell that perturbates protein homeostasis, leading to proteotoxic stress in the cell. Therefore, unclogging of the translocon is critical for maintaining mitochondrial and cellular function. Ubiquitylation and AAA-ATPases play a central role in the extraction of the precursor proteins to deliver them to the proteasome for degradation. Here we summarize our understanding of the molecular mechanisms that remove such translocation-stalled precursor proteins from the translocation channel to regenerate the TOM complex for protein import.

Keywords:  AAA ATPases; TOM complex; mitochondria; protein import; quality control; ubiquitylation

DOI:  https://doi.org/10.1515/hsz-2025-0110
Nat Commun. 2025 Mar 21. 16(1): 2810

Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.

Donato D'Angelo, Víctor H Sánchez-Vázquez, Benjamín Cartes-Saavedra, Denis Vecellio Reane, Ryan R Cupo, Hilda Delgado de la Herran, Giorgia Ghirardo, James Shorter, Ron A Wevers, Saskia B Wortmann, Fabiana Perocchi, Rosario Rizzuto, Anna Raffaello, György Hajnóczky.

Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. Additionally, OPA1 decreases, and aggregation occurs, accompanied by mitochondrial fragmentation. Disease-associated mutations in the CLPB gene present in skin fibroblasts from patients also display mitochondrial calcium and structural changes. Thus, mtCU and fusion activity are dependent on CLPB, and their impairments might contribute to the disease caused by CLPB variants.

DOI: https://doi.org/10.1038/s41467-025-57641-9
J Immunol. 2025 Mar 22. pii: vkaf023. [Epub ahead of print]

DHODH inhibition alters T cell metabolism limiting acute graft-versus-host disease while retaining graft-versus-leukemia response.

Rathan Kumar, Kara M Braunreiter, Lotus Neidemire-Colley, Natalie Sell, Yandi Gao, Camryn Steere, Margot Weber, Dhruva Vanakeri, Eunice Choi, Hannah K Choe, Sandip Vibhute, Chad Bennett, Craig A Byersdorfer, Ola A Elgamal, Thomas E Goodwin, Erin K Hertlein, John C Byrd, Parvathi Ranganathan.

  Acute graft-versus-host disease (GVHD) is a donor T cell driven complication and the leading cause of non-relapse mortality in patients receiving an allogeneic hematopoietic cell transplantation (allo-HCT). Allogeneic donor T cells eradicate residual leukemia and prevent relapse via the graft-versus-leukemia (GVL) effect and are critical for responding against opportunistic infections post-transplant. Current regimens successful in preventing GVHD are broadly immunosuppressive and come at the cost of increased risk of relapse and/or infection. Therefore, there is an urgent need for new approaches that limit GVHD while retaining GVL responses. During GVHD, alloreactive T cells boost their energy production through oxidative phosphorylation (OXPHOS) and glycolysis, supporting heightened proliferation and pathogenicity against healthy host tissues. The enzyme dihydroorate dehydrogenase (DHODH), is essential for de novo pyrimidine biosynthesis and for maintaining mitochondrial membrane potential during OXPHOS. Having shown upregulation of DHODH messenger RNA and protein expression in activated human T cells, we evaluated DHODH inhibition, via a small molecule inhibitor HOSU-53, as a therapeutic approach for GVHD. Inhibiting DHODH significantly reduced oxidative metabolism in T cells both during and after activation, while selectively suppressing inflammatory cytokine production in de novo activated, but not previously activated, T cells. In a xenogeneic model, HOSU-53 treatment limited GVHD severity, decreased pathogenic Th1 and Th17 response, and preserved beneficial GVL effects. Altogether, we identify DHODH inhibition as an innovative treatment strategy in allo-HCT recipients to reduce GVHD severity and retain effective GVL response.

Keywords:  DHODH; GVHD; metabolism

DOI:  https://doi.org/10.1093/jimmun/vkaf023
Free Radic Biol Med. 2025 Mar 24. pii: S0891-5849(25)00187-X. [Epub ahead of print]

Targeting Mitophagy Using Isoliensinine as a Therapeutic Strategy for Renal Cell Carcinoma Treatment.

Ming-Ju Wu, Yu-Teng Chang, Tzu-Yi Chuang, Wang-Sheng Ko, Chih-Chiang Lu, Jeng-Jer Shieh.

  Renal cell carcinoma (RCC) is a formidable and lethal form of kidney cancer, necessitating the exploration of novel therapeutic options. Isoliensinine, an alkaloid derived from lotus seed embryos, has shown promising anti-cancer properties. However, its mechanistic actions and impact on mitochondrial dynamics remain poorly understood. This research has aimed to investigate the effects of isoliensinine on RCC, as well as its potential involvement in mitophagy and mitochondrial function. In vitro experiments utilizing RCC cell lines (786-O and ACHN) have demonstrated that isoliensinine treatment significantly reduced cell viability. Moreover, isoliensinine induced an increase in cellular and mitochondrial reactive oxygen species (ROS) levels, accompanied by reduced mitochondria membrane potential, indicating an influence on mitochondrial function. Furthermore, MitoTracker staining revealed distinct mitochondrial morphologies, with isoliensinine promoting mitochondrial fission, thus supporting its role in mitochondrial dynamics. Notably, isoliensinine led to a time-dependent upregulation of mitophagy-related proteins, indicative of mitophagy activation. Of particular interest, the addition of MitoTEMPO, a potent mitochondrial ROS scavenger, effectively reversed the isoliensinine-induced upregulation of mitophagy-related protein expression and mitochondrial ROS levels. These combined results provide novel insight into the impact of isoliensinine-induced mitophagy on mitochondrial dynamics in renal carcinoma cells. Overall, the findings from this study highlight isoliensinine as a promising candidate with significant potential for further investigation and eventual clinical application in RCC therapy. Moreover, the modulation of mitochondrial dynamics, mitophagy and ROS levels through the use of isoliensinine further adds to its appeal as a potential therapeutic agent.

Keywords:  Isoliensinine; Mitophagy; Reactive oxygen species; Renal cell carcinoma

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.03.037
J Chemother. 2025 Mar 21. 1-17

Concurrent inhibition of FLT3 and sphingosine kinase-1 triggers synergistic cytotoxicity in midostaurin resistant FLT3-ITD positive acute myeloid leukemia cells via blocking FLT3/STAT5A signaling to induce apoptosis.

Melisa Tecik, Aysun Adan.

  The FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations observed in acute myeloid leukemia (AML) which contributes to disease progression and unfavorable prognosis. Midostaurin, a small FLT3 inhibitor (FLT3I), is clinically approved. However, patients generally possess acquired resistance when midostaurin used alone. Shifting the balance in the sphingolipid rheostat toward anti-apoptotic sphingosine kinase-1 (SK-1) or glucosylceramide synthase (GCS) is related to therapy resistance in cancer, however, their role in midostaurin resistant FLT3-ITD positive AML has not been previously investigated. We generated midostaurin resistant MV4-11 and MOLM-13 cell lines which showed increased IC50 values compared to their sensitive partner cells. SK-1 is overexpressed in resistant cells while GCS remains unchanged. Subsequent pharmacological targeting of SK-1 in resistant cells decreased SK-1 protein level, inhibited cell proliferation and showed additive or synergistic effect on cell growth, as confirmed by the Chou-Talalay combination index, and induced G0/G1 arrest (PI staining by flow cytometry). Cotreatment (SKI-II plus midostaurin) triggered apoptosis via phosphatidylserine exposure (annexin V/PI double staining). Mechanistically, induction of the intrinsic pathway of apoptosis was confirmed as increased activating cleavages of caspase-3 and PARP and increased Bax/Bcl-2 ratios. Activating phosphorylations of FLT3 (at tyrosine residue 591) and STAT5A (at tyrosine residue 694) dramatically inhibited in resistant cells treated with the combination. In conclusion, midostaurin resistance could be reversed by dual SK-1 and FLT3 inhibition in midostaurin resistant AML cell lines, providing the first evidence of a novel treatment approach to re-sensitize FLT3-ITD positive AML.

Keywords:  FLT3-ITD AML; STAT5A; drug resistance; midostaurin; sphingosine kinase-1

DOI:  https://doi.org/10.1080/1120009X.2025.2478340
Free Radic Biol Med. 2025 Mar 21. pii: S0891-5849(25)00181-9. [Epub ahead of print]233 24-38

SR-B1 deficiency suppresses progression in acute myeloid leukemia via ferroptosis and reverses resistance to venetoclax.

Junfeng Shi, Yifeng Cheng, Lixue Wang, Wen Xing, Yudi Li, Xiulin Sun, Yunpeng Lv, Yichuan Zhang, Yanming Li, Wenhua Zhao.

  Increase of immature myeloid cells in the bone marrow drives the development of acute myeloid leukemia (AML). The study aimed to clarify the biological function and regulatory mechanism of scavenger receptor class B type 1 (SR-B1) in AML, mainly its effect on ferroptosis and the influences on leukemogenesis and resistance to venetoclax. In this study, we found that the SR-B1 deficiency directly reduced the invasion and promoted death of malignant cells in AML. Strikingly, SR-B1 deficiency could up-regulated the expression of ferroptosis-related proteins to facilitate the occurrence of ferroptosis in vivo, and could also down-regulated the expression of apoptosis related protein B-cell lymphoma-2 (BCL-2). And then, we confirmed SR-B1 inhibitor block lipid transport-1 (BLT-1) had a superior efficacy in AML cells and AML model mice. The study found that whether SR-B1 deficiency or BLT-1 treatment could cause iron deposition and the accumulation of lipid peroxides in vivo, thereby suppressing leukemogenesis through ferroptosis. Critically, we found that SR-B1 inhibitor BLT-1 could reverse drug-resistance of venetoclax to promote AML cells death via ferroptosis. Our finding identified that SR-B1 as a critical regulator of the proliferation in AML which could provide a promising therapeutic strategy against malignant myeloid leukemia cells and drug-resistance.

Keywords:  Acute myeloid leukemia; BLT-1; Drug-resistance; Ferroptosis; SR-B1; Venetoclax

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.03.031
Blood. 2025 Mar 27. 145(13): 1341-1343

Targeting an AML-sustaining metabolic node.

Sarada Achyutuni, Jian Xu.

DOI: https://doi.org/10.1182/blood.2024027768