bims-midysc 2025-04-13 papers

bims-midysc

Biomed News

on Mitochondria dysfunction in cancer

Issue of 2025–04–13
29 papers selected by
Papachristodoulou Lab, NJ State University at Rutgers

Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming.
Knockdown of POLG Mimics the Neuronal Pathology of Polymerase-γ Spectrum Disorders in Human Neurons.
Androgen Deprivation-Induced TET2 Activation Fuels Prostate Cancer Progression via Epigenetic Priming and Slow-Cycling Cancer Cells.
The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer.
Mitochondrial, metabolic and bioenergetic adaptations drive plasticity of colorectal cancer cells and shape their chemosensitivity.
Small molecules restore mutant mitochondrial DNA polymerase activity.
Galectin-8 drives ERK-dependent mitochondrial fragmentation, perinuclear relocation and mitophagy, with metabolic adaptations for cell proliferation.
FAO-fueled OXPHOS and NRF2-mediated stress resilience in MICs drive lymph node metastasis.
TP53 Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia.
Aging-associated mitochondrial decline accelerates skin aging and obesity.
Mitochondrial DNA released by senescent tumor cells enhances PMN-MDSC-driven immunosuppression through the cGAS-STING pathway.
Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.
Unraveling the nexus: Genomic instability and metabolism in cancer.
Mitochondrial dynamics at the intersection of macrophage polarization and metabolism.
Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism.
Mitochondria and cell death signalling.
DRP1, fission and apoptosis.
Inactivation of mitochondrial pyruvate dehydrogenase by singlet oxygen involves lipoic acid oxidation, side-chain modification and structural changes.
Metformin inhibits the progression of castration resistant prostate cancer by regulating PDE6D induced purine metabolic alternation and cGMP / PKG pathway activation.
Single-cell and spatial RNA sequencing identify divergent microenvironments and progression signatures in early- versus late-onset prostate cancer.
Cell Confluency Affects p53 Dynamics in Response to DNA Damage.
Organoid models of ovarian cancer: resolving immune mechanisms of metabolic reprogramming and drug resistance.
Protocol for dual metabolomics and proteomics using nanoflow liquid chromatography-tandem mass spectrometry.
Non-immune targeting of CXCR3 compromises mitochondrial function and suppresses tumor growth in glioblastoma.
The mitochondrial unfolded protein response inhibits pluripotency acquisition and mesenchymal-to-epithelial transition in somatic cell reprogramming.
Alternative start codon selection shapes mitochondrial function during evolution, homeostasis, and disease.
Construction and validation of a nomogram for identifying the patients at risk for rapid progression of advanced hormone-sensitive prostate cancer.
The role of lactate metabolism in retinoblastoma tumorigenesis and ferroptosis resistance.
Spatial multi-omics analysis of tumor-stroma boundary cell features for predicting breast cancer progression and therapy response.

J Exp Clin Cancer Res. 2025 Apr 07. 44(1): 114

Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming.

Su Jung Park, Claudia Cerella, Jin Mo Kang, Jinyoung Byun, David Kum, Barbora Orlikova-Boyer, Anne Lorant, Michael Schnekenburger, Ali Al-Mourabit, Christo Christov, Juyong Lee, Byung Woo Han, Marc Diederich.

   BACKGROUND: Acute myeloid leukemia (AML) is a highly aggressive cancer with a 5-year survival rate of less than 35%. It is characterized by significant drug resistance and abnormal energy metabolism. Mitochondrial dynamics and metabolism are crucial for AML cell survival. Mitochondrial fusion protein optic atrophy (OPA)1 is upregulated in AML patients with adverse mutations and correlates with poor prognosis.
METHOD: This study investigated targeting OPA1 with TMQ0153, a tetrahydrobenzimidazole derivative, to disrupt mitochondrial metabolism and dynamics as a novel therapeutic approach to overcome treatment resistance. Effects of TMQ0153 treatment on OPA1 and mitofusin (MFN)2 protein levels, mitochondrial morphology, and function in AML cells. In this study, we examined reactive oxygen species (ROS) production, oxidative phosphorylation (OXPHOS) inhibition, mitochondrial membrane potential (MMP) depolarization, and apoptosis. Additionally, metabolic profiling was conducted to analyze changes in metabolic pathways.
RESULTS: TMQ0153 treatment significantly reduced OPA1 and mitofusin (MFN)2 protein levels and disrupted the mitochondrial morphology and function in AML cells. This increases ROS production and inhibits OXPHOS, MMP depolarization, and caspase-dependent apoptosis. Metabolic reprogramming was observed, shifting from mitochondrial respiration to glycolysis and impaired respiratory chain activity. Profiling revealed reduced overall metabolism along with changes in the glutathione (GSH)/oxidized glutathione (GSSG) and NAD⁺/NADH redox ratios. TMQ0153 treatment reduces tumor volume and weight in MV4-11 xenografts in vivo. Combination therapies with TMQ0153 and other AML drugs significantly reduced the leukemic burden and prolonged survival in NOD scid gamma (NSG) mice xenografted with U937-luc and MOLM-14-luc cells.
CONCLUSION: TMQ0153 targets mitochondrial dynamics by inhibiting OPA1, inducing metabolic reprogramming, and triggering apoptosis in AML cells. It enhances the efficacy of existing AML therapies and provides a promising combination treatment approach that exploits mitochondrial vulnerability and metabolic reprogramming to improve treatment outcomes in AML.

Keywords:  Drug resistance; Glutathione; Glycolysis; Metabolic reprogramming; Monocytic myeloid leukemia; OXPHOS

DOI:  https://doi.org/10.1186/s13046-025-03372-0
Cells. 2025 Mar 22. pii: 480. [Epub ahead of print]14(7):

Knockdown of POLG Mimics the Neuronal Pathology of Polymerase-γ Spectrum Disorders in Human Neurons.

Çağla Çakmak Durmaz, Felix Langerscheidt, Imra Mantey, Xinyu Xia, Hans Zempel.

  Impaired function of Polymerase-γ (Pol-γ) results in impaired replication of the mitochondrial genome (mtDNA). Pathogenic mutations in the POLG gene cause dysfunctional Pol-γ and dysfunctional mitochondria and are associated with a spectrum of neurogenetic disorders referred to as POLG spectrum disorders (POLG-SDs), which are characterized by neurologic dysfunction and premature death. Pathomechanistic studies and human cell models of these diseases are scarce. SH-SY5Y cells (SHC) are an easy-to-handle and low-cost human-derived neuronal cell model commonly used in neuroscientific research. Here, we aimed to study the effect of reduced Pol-γ function using stable lentivirus-based shRNA-mediated knockdown of POLG in SHC, in both the proliferating cells and SHC-derived neurons. POLG knockdown resulted in approximately 50% reductions in POLG mRNA and protein levels in naïve SHC, mimicking the residual Pol-γ activity observed in patients with common pathogenic POLG mutations. Knockdown cells exhibited decreased mtDNA content, reduced levels of mitochondrial-encoded proteins, and altered mitochondrial morphology and distribution. Notably, while chemical induction of mtDNA depletion via ddC could be rescued by the mitochondrial biosynthesis stimulators AICAR, cilostazol and resveratrol (but not MitoQ and formoterol) in control cells, POLG-knockdown cells were resistant to mitochondrial biosynthesis-mediated induction of mtDNA increase, highlighting the specificity of the model, and pathomechanistically hinting towards inefficiency of mitochondrial stimulation without sufficient Pol-γ activity. In differentiated SHC-derived human neurons, POLG-knockdown cells showed impaired neuronal differentiation capacity, disrupted cytoskeletal organization, and abnormal perinuclear clustering of mitochondria. In sum, our model not only recapitulates key features of POLG-SDs such as impaired mtDNA content, which cannot be rescued by mitochondrial biosynthesis stimulation, but also reduced ATP production, perinuclear clustering of mitochondria and impaired neuronal differentiation. It also offers a simple, cost-effective and human (and, as such, disease-relevant) platform for investigating disease mechanisms, one with screening potential for therapeutic approaches for POLG-related mitochondrial dysfunction in human neurons.

Keywords:  Polymerase-γ; SH-SY5Y; mitochondria; mtDNA; neurogenetics; neuronal differentiation

DOI:  https://doi.org/10.3390/cells14070480
bioRxiv. 2025 Mar 29. pii: 2025.03.26.645495. [Epub ahead of print]

Androgen Deprivation-Induced TET2 Activation Fuels Prostate Cancer Progression via Epigenetic Priming and Slow-Cycling Cancer Cells.

Lin Li, Siyuan Cheng, Yaru Xu, Su Deng, Ping Mu, Xiuping Yu.

Advanced prostate cancer (PCa) frequently develops resistance to androgen deprivation therapy through various mechanisms including lineage plasticity. Slow-cycling cells (SCCs) have emerged as key players in adaptive responses to therapy, yet their role in PCa remains unclear. Through in silico analysis of single-cell RNA sequencing (scRNA-seq) data, we discovered that SCCs are enriched during pivotal stages of PCa progression, including the transition from androgen-dependent to castration-resistant states and the emergence of neuroendocrine PCa (NEPC). Using a tetracycline-inducible H2BeGFP reporter system, we confirmed SCC enrichment following androgen deprivation in both in vitro and in vivo models. Furthermore, we identified TET2 as a key regulator of SCCs, with its expression upregulated by androgen deprivation and positively correlated with SCC signature scores in PCa. Genome-wide 5-hydroxymethylcytosine (5hmC) profiling revealed increased hydroxymethylation after androgen deprivation, while TET2 knockdown reduced 5hmC levels at specific loci. Functional studies demonstrated that TET2 governs SCC maintenance, cell cycle progression, and DNA damage repair. Targeting TET2, either alone or in combination with an ATM inhibitor, significantly suppressed tumor growth, highlighting TET2 as a promising therapeutic target. Our study provides the first single-nucleotide resolution map of 5hmC dynamics in PCa, identifies a cell state driving epigenetic rewiring, and underscores the transformative potential of novel therapeutic strategies for advanced PCa.

DOI: https://doi.org/10.1101/2025.03.26.645495
J Bioenerg Biomembr. 2025 Apr 08.

The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer.

Thomas N Seyfried, Derek C Lee, Tomas Duraj, Nathan L Ta, Purna Mukherjee, Michael Kiebish, Gabriel Arismendi-Morillo, Christos Chinopoulos.

  Otto Warburg originally proposed that cancer arose from a two-step process. The first step involved a chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos), while the second step involved a protracted compensatory energy synthesis through lactic acid fermentation. His extensive findings showed that oxygen consumption was lower while lactate production was higher in cancerous tissues than in non-cancerous tissues. Warburg considered both oxygen consumption and extracellular lactate as accurate markers for ATP production through OxPhos and glycolysis, respectively. Warburg's hypothesis was challenged from findings showing that oxygen consumption remained high in some cancer cells despite the elevated production of lactate suggesting that OxPhos was largely unimpaired. New information indicates that neither oxygen consumption nor lactate production are accurate surrogates for quantification of ATP production in cancer cells. Warburg also did not know that a significant amount of ATP could come from glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis pathway with succinate produced as end product, thus confounding the linkage of oxygen consumption to the origin of ATP production within mitochondria. Moreover, new information shows that cytoplasmic lipid droplets and elevated aerobic lactic acid fermentation are both biomarkers for OxPhos insufficiency. Warburg's original hypothesis can now be linked to a more complete understanding of how OxPhos insufficiency underlies dysregulated cancer cell growth. These findings can also address several questionable assumptions regarding the origin of cancer thus allowing the field to advance with more effective therapeutic strategies for a less toxic metabolic management and prevention of cancer.

Keywords:  Cardiolipin; Lactate; Lipid droplets; Oxidative phosphorylation; Oxygen consumption; Somatic mutations; Substrate level phosphorylation; Succinate

DOI:  https://doi.org/10.1007/s10863-025-10059-w
Cell Death Dis. 2025 Apr 05. 16(1): 253

Mitochondrial, metabolic and bioenergetic adaptations drive plasticity of colorectal cancer cells and shape their chemosensitivity.

Nikita Markov, Sirina Sabirova, Gulnaz Sharapova, Marina Gomzikova, Anna Brichkina, Nick A Barlev, Marcel Egger, Albert Rizvanov, Hans-Uwe Simon.

The extent of mitochondrial heterogeneity and the presence of mitochondrial archetypes in cancer remain unknown. Mitochondria play a central role in the metabolic reprogramming that occurs in cancer cells. This process adjusts the activity of metabolic pathways to support growth, proliferation, and survival of cancer cells. Using a panel of colorectal cancer (CRC) cell lines, we revealed extensive differences in their mitochondrial composition, suggesting functional specialisation of these organelles. We differentiated bioenergetic and mitochondrial phenotypes, which point to different strategies used by CRC cells to maintain their sustainability. Moreover, the efficacy of various treatments targeting metabolic pathways was dependent on the respiration and glycolysis levels of cancer cells. Furthermore, we identified metabolites associated with both bioenergetic profiles and cell responses to treatments. The levels of these molecules can be used to predict the therapeutic efficacy of anti-cancer drugs and identify metabolic vulnerabilities of CRC. Our study indicates that the efficacy of CRC therapies is closely linked to mitochondrial status and cellular bioenergetics.

DOI: https://doi.org/10.1038/s41419-025-07596-y
Nature. 2025 Apr 09.

Small molecules restore mutant mitochondrial DNA polymerase activity.

Sebastian Valenzuela, Xuefeng Zhu, Bertil Macao, Mattias Stamgren, Carol Geukens, Paul S Charifson, Gunther Kern, Emily Hoberg, Louise Jenninger, Anja V Gruszczyk, Seoeun Lee, Katarina A S Johansson, Javier Miralles Fusté, Yonghong Shi, S Jordan Kerns, Laleh Arabanian, Gabriel Martinez Botella, Sofie Ekström, Jeremy Green, Andrew M Griffin, Carlos Pardo-Hernández, Thomas A Keating, Barbara Küppers-Munther, Nils-Göran Larsson, Cindy Phan, Viktor Posse, Juli E Jones, Xie Xie, Simon Giroux, Claes M Gustafsson, Maria Falkenberg.

Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits1. More than 300 mutations in POLG, the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists2. Here we report on the discovery and characterization of PZL-A, a first-in-class small-molecule activator of mtDNA synthesis that is capable of restoring function to the most common mutant variants of POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ in vitro and activates mtDNA synthesis in cells from paediatric patients with lethal POLG disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. Our work demonstrates that a small molecule can restore function to mutant DNA polymerases, offering a promising avenue for treating POLG disorders and other severe conditions linked to depletion of mtDNA.

DOI: https://doi.org/10.1038/s41586-025-08856-9
Eur J Cell Biol. 2025 Apr 04. pii: S0171-9335(25)00013-5. [Epub ahead of print]104(2): 151488

Galectin-8 drives ERK-dependent mitochondrial fragmentation, perinuclear relocation and mitophagy, with metabolic adaptations for cell proliferation.

Adely de la Peña, Claudio Retamal, Francisca Pérez-Molina, Nicole Díaz-Valdivia, Francisco Veloso-Bahamondes, Diego Tapia, Jorge Cancino, Felix Randow, Alfonso González, Claudia Oyanadel, Andrea Soza.

  Mitochondria adapt to the cell proliferative demands induced by growth factors through dynamic changes in morphology, distribution, and metabolic activity. Galectin-8 (Gal-8), a carbohydrate-binding protein that promotes cell proliferation by transactivating the EGFR-ERK signaling pathway, is overexpressed in several cancers. However, its impact on mitochondrial dynamics during cell proliferation remains unknown. Using MDCK and RPTEC kidney epithelial cells, we demonstrate that Gal-8 induces mitochondrial fragmentation and perinuclear redistribution. Additionally, mitochondria adopt donut-shaped morphologies, and live-cell imaging with two Keima-based reporters demonstrates Gal-8-induced mitophagy. ERK signaling inhibition abrogates all these Gal-8-induced mitochondrial changes and cell proliferation. Studies with established mutant versions of Gal-8 and CHO cells reveal that mitochondrial changes and proliferative response require interactions between the N-terminal carbohydrate recognition domain of Gal-8 and α-2,3-sialylated N-glycans at the cell surface. DRP1, a key regulator of mitochondrial fission, becomes phosphorylated in MDCK cells or overexpressed in RPTEC cells in an ERK-dependent manner, mediating mitochondrial fragmentation and perinuclear redistribution. Bafilomycin A abrogates Gal-8-induced cell proliferation, suggesting that mitophagy serves as an adaptation to cell proliferation demands. Functional analysis under Gal-8 stimulation shows that mitochondria maintain an active electron transport chain, partially uncoupled from ATP synthesis, and an increased membrane potential, indicative of healthy mitochondria. Meanwhile, the cells exhibit increased extracellular acidification rate and lactate production via aerobic glycolysis, a hallmark of an active proliferative state. Our findings integrate mitochondrial dynamics with metabolic adaptations during Gal-8-induced cell proliferation, with potential implications for physiology, disease, and therapeutic strategies.

Keywords:  Galectin-8; Glycosylation; Mitochondrial dynamics; Mitophagy; Proliferation

DOI:  https://doi.org/10.1016/j.ejcb.2025.151488
Proc Natl Acad Sci U S A. 2025 Apr 15. 122(15): e2411241122

FAO-fueled OXPHOS and NRF2-mediated stress resilience in MICs drive lymph node metastasis.

Shan-Shan Li, Baifeng Zhang, Cuicui Huang, Yuying Fu, Yuying Zhao, Lanqi Gong, Yanan Tan, Huali Wang, Wenqi Chen, Jie Luo, Yu Zhang, Stephanie Ma, Li Fu, Chenli Liu, Jiandong Huang, Huai-Qiang Ju, Anne Wing-Mui Lee, Xin-Yuan Guan.

  Metastasis is an inefficient process requiring cancer cells to adapt metabolically for survival and colonization in new environments. The contributions of tumor metabolic reprogramming to lymph node (LN) metastasis and its underlying mechanisms remain elusive. Through single-cell RNA sequencing, we identified rare metastasis-initiating cells (MICs) with stem-like properties that drive early LN metastasis. Integrated transcriptome, lipidomic, metabolomic, and functional analyses demonstrated that MICs depend on oxidative phosphorylation (OXPHOS) fueled by fatty acid oxidation (FAO) in the lipid-rich LN microenvironment. Mechanistically, the NRF2-SLC7A11 axis promotes glutathione synthesis to mitigate oxidative stress, thereby enhancing stress resistance and metastatic potential of MICs. Inhibition of NRF2-SLC7A11 reduced LN metastasis and sensitized tumors to cisplatin. Clinically, elevated NRF2-SLC7A11 expression was observed in tumors, with high expression correlating with LN metastasis, chemoresistance, and poor prognosis in esophageal squamous cell carcinoma (ESCC). These findings highlight the pivotal roles of FAO-fueled OXPHOS and NRF2 in LN metastasis and suggest targeting these pathways as a promising therapeutic strategy for metastatic ESCC.

Keywords:  NRF2; esophageal cancer; lymph node metastasis; metabolic reprogramming; oxidative phosphorylation

DOI:  https://doi.org/10.1073/pnas.2411241122
bioRxiv. 2025 Mar 27. pii: 2025.03.24.644993. [Epub ahead of print]

TP53 Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia.

Jeevitha D'Souza, Camille J Leung, Aishwarya C Ballapuram, Abigail S Lin, Alexa Rane Batingana, Adam J Lamble, Rhonda E Ries, Carolina E Morales, Charisa Cottonham, Pranav Gona, Li Fan, Xiaotu Ma, Kevin Shannon, Soheil Meshinchi, Benjamin S Braun, Benjamin J Huang.

Acute myeloid leukemia (AML) is a heterogeneous cancer that is associated with poor outcomes. Revumenib and other menin inhibitors have shown promising activity against AMLs with KMT2A -rearrangements or NPM1 mutations. However, mechanisms of de novo resistance have not yet been elucidated. We analyzed a panel of cell lines and generated an isogenic model to assess the impact of TP53 mutations on the response of AML cells to revumenib. TP53 mutations are associated with de novo resistance to revumenib, impaired induction of TP53 transcriptional targets, and deregulated expression of the BH3 proteins BCL-2 and MCL-1. The MCL-1 inhibitor MIK665, but not venetoclax, preferentially sensitized TP53 -mutant AML cells to revumenib. These data identify mutant TP53 as a potential biomarker for de novo resistance to revumenib, and provide a rationale to evaluate MCL-1 and menin inhibitor combinations in patients KMT2A -rearranged leukemias with TP53 mutations.

DOI: https://doi.org/10.1101/2025.03.24.644993
J Invest Dermatol. 2025 Apr 08. pii: S0022-202X(25)00395-1. [Epub ahead of print]

Aging-associated mitochondrial decline accelerates skin aging and obesity.

Shuji Yamamura, Haruki Horiguchi, Tsuyoshi Kadomatsu, Keishi Miyata, Daisuke Torigoe, Takehisa Suzuki, Michio Sato, Kimi Araki, Akira Suzuki, Satoshi Fukushima, Yuichi Oike.

  Skin tissue, which consists of epidermal, dermal, and hypodermal cells, plays an important role in biological defense and physical appearance. External and internal stresses occurring with aging disrupt skin homeostasis, promoting development of phenotypes associated with aging. While many studies of skin aging focus on the dermis, potential epidermal changes have largely remained uncharacterized. Here, we demonstrate that epidermal cells do not exhibit cellular senescence phenotypes with aging but instead show age-related decreases in mitochondrial number. We also found that mice lacking mitochondrial transcription factor A (TFAM) in epidermal cells exhibit delayed hair regrowth and impaired wound healing by middle age resembling changes seen in skin of aged mice. Furthermore, middle-aged epidermis-specific TFAM-deficient mice exhibited obesity, suggesting that impaired fatty acid metabolism in epidermal cells resulting from mitochondrial decline may lead to obesity. These findings overall suggest that mitochondrial decline occurs as a primary event in epidermal aging, and that anti-aging strategies to enhance activity or number of epidermal mitochondria could antagonize both skin-aging phenotypes and age-related metabolic disease.

Keywords:  aging; mitochondria; obesity

DOI:  https://doi.org/10.1016/j.jid.2025.03.028
Immunity. 2025 Apr 08. pii: S1074-7613(25)00124-4. [Epub ahead of print]58(4): 811-825.e7

Mitochondrial DNA released by senescent tumor cells enhances PMN-MDSC-driven immunosuppression through the cGAS-STING pathway.

Ping Lai, Lei Liu, Nicolò Bancaro, Martina Troiani, Bianca Calì, Yuxin Li, Jingjing Chen, Prafull Kumar Singh, Rydell Alvarez Arzola, Giuseppe Attanasio, Nicolò Pernigoni, Emiliano Pasquini, Simone Mosole, Andrea Rinaldi, Jacopo Sgrignani, Shi Qiu, Pan Song, Yingrui Li, Maria Andrea Desbats, Azucena Rendón Ángel, Ricardo Pereira Mestre, Andrea Cavalli, Lucio Barile, Johann de Bono, Andrea Alimonti.

  Mitochondrial dysfunction is a hallmark of cellular senescence. Here, we investigated whether senescent cells release mitochondrial (mt)DNA into the extracellular space and its impact on innate immunity. We found that both primary senescent cells and tumor cells undergoing therapy-induced senescence actively released mtDNA into the extracellular environment. mtDNA released by senescent cells was packaged within extracellular vesicles and selectively transferred to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment. Upon uptake, extracellular mtDNA enhanced the immunosuppressive activity of PMN-MDSCs via cGAS-STING-NF-κB signaling, thereby promoting tumor progression. While STING activation directly induced NF-κB signaling, it also activated PKR-like endoplasmic reticulum kinase (PERK), which further amplified NF-κB activity, in PMN-MDSCs. mtDNA release from senescent cells was mediated by voltage-dependent anion channels (VDACs), and pharmacological inhibition of VDAC reduced extracellular mtDNA levels, reversed PMN-MDSC-driven immunosuppression, and enhanced chemotherapy efficacy in prostate cancer mouse models. These findings suggest that targeting mtDNA release could reprogram the immunosuppressive tumor microenvironment, improving therapeutic outcomes for chemotherapy-treated patients.

Keywords:  DAMP; PMN-MDSCs; cGAS-STING pathway; immunosuppression; innate immunity; mtDNA; senescence; tumor microenvironment

DOI:  https://doi.org/10.1016/j.immuni.2025.03.005
Cell Death Dis. 2025 Apr 05. 16(1): 254

Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.

Ru Deng, Lingyi Fu, Haoyu Liang, Xixiong Ai, Fangyi Liu, Nai Li, Liyan Wu, Shuo Li, Xia Yang, Yansong Lin, Yuhua Huang, Jingping Yun.

Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment.

DOI: https://doi.org/10.1038/s41419-025-07510-6
Cell Rep. 2025 Apr 08. pii: S2211-1247(25)00311-0. [Epub ahead of print]44(4): 115540

Unraveling the nexus: Genomic instability and metabolism in cancer.

Vaibhavi Gujar, Haojian Li, Tanya T Paull, Carola A Neumann, Urbain Weyemi.

  The DNA-damage response (DDR) is a signaling network that enables cells to detect and repair genomic damage. Over the past three decades, inhibiting DDR has proven to be an effective cancer therapeutic strategy. Although cancer drugs targeting DDR have received approval for treating various cancers, tumor cells often develop resistance to these therapies, owing to their ability to undergo energetic metabolic reprogramming. Metabolic intermediates also influence tumor cells' ability to sense oxidative stress, leading to impaired redox metabolism, thus creating redox vulnerabilities. In this review, we summarize recent advances in understanding the crosstalk between DDR and metabolism. We discuss combination therapies that target DDR, metabolism, and redox vulnerabilities in cancer. We also outline potential obstacles in targeting metabolism and propose strategies to overcome these challenges.

Keywords:  CP: Cancer; DNA damage response; DNA repair; cancer therapy; metabolism; redox metabolism; therapy resistance

DOI:  https://doi.org/10.1016/j.celrep.2025.115540
Front Immunol. 2025 ;16 1520814

Mitochondrial dynamics at the intersection of macrophage polarization and metabolism.

Pan Li, Zhengbo Fan, Yanlan Huang, Liang Luo, Xiaoyan Wu.

  Macrophages are vital sentinels in innate immunity, and their functions cannot be performed without internal metabolic reprogramming. Mitochondrial dynamics, especially mitochondrial fusion and fission, contributes to the maintenance of mitochondrial homeostasis. The link between mitochondrial dynamics and macrophages in the past has focused on the immune function of macrophages. We innovatively summarize and propose a link between mitochondrial dynamics and macrophage metabolism. Among them, fusion-related FAM73b, MTCH2, SLP-2 (Stomatin-like protein 2), and mtSIRT, and fission-related Fis1 and MTP18 may be the link between mitochondrial dynamics and macrophage metabolism association. Furthermore, post-translational modifications (PTMs) of mtSIRT play prominent roles in mitochondrial dynamics-macrophage metabolism connection, such as deacetylates and hypersuccinylation. MicroRNAs such as miR-150, miR-15b, and miR-125b are also possible entry points. The metabolic reprogramming of macrophages through the regulation of mitochondrial dynamics helps improve their adaptability and resistance to adverse environments and provides therapeutic possibilities for various diseases.

Keywords:  fission; fusion; macrophage; metabolism; mitochondrial dynamics

DOI:  https://doi.org/10.3389/fimmu.2025.1520814
J Immunol. 2025 Apr 09. pii: vkaf034. [Epub ahead of print]

Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism.

KayLee K Steiner, Arissa C Young, Andrew R Patterson, Ayaka Sugiura, McLane J Watson, Samuel E J Preston, Anton Zhelonkin, Erin Q Jennings, Channing Chi, Darren R Heintzman, Andrew P Pahnke, Yasmine T Toudji, Zaid Hatem, Matthew Z Madden, Emily N Arner, Allison E Sewell, Allison K Blount, Richmond Okparaugo, Emilia Fallman, Evan S Krystofiak, Ryan D Sheldon, Katherine N Gibson-Corley, Kelsey Voss, Sara M Nowinski, Russell G Jones, Denis A Mogilenko, Jeffrey C Rathmell.

  Imbalanced effector and regulatory CD4+ T cell subsets drive many inflammatory diseases. These T cell subsets rely on distinct metabolic programs, modulation of which differentially affects T cell fate and function. Lipid metabolism is fundamental yet remains poorly understood across CD4+ T cell subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid metabolism genes and pathways essential for T cell functions. These screens established mitochondrial fatty acid synthesis genes Mecr, Mcat, and Oxsm as key metabolic regulators. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Mecrfl/fl; Cd4cre mice had normal naïve CD4+ and CD8+ T cell numbers, demonstrating that MECR is not essential in homeostatic conditions. However, effector and memory T cells were reduced in Mecr knockout and MECR-deficient CD4+ T cells and proliferated, differentiated, and survived less well than control T cells. Interestingly, T cells ultimately showed signs of mitochondrial stress and dysfunction in the absence of MECR. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced tricarboxylic acid intermediates, and accumulated intracellular iron, which appeared to contribute to increased cell death and sensitivity to ferroptosis. Importantly, MECR-deficient T cells exhibited fitness disadvantages and were less effective at driving disease in an in vivo model of inflammatory bowel disease. Thus, MECR-mediated metabolism broadly supports CD4+ T cell proliferation and survival in vivo. These findings may also provide insight to the immunological state of MECR- and other mitochondrial fatty acid synthesis-deficient patients.

Keywords:  CD4+ T cells; MECR; lipid metabolism; mtFAS

DOI:  https://doi.org/10.1093/jimmun/vkaf034
Curr Opin Cell Biol. 2025 Apr 10. pii: S0955-0674(25)00048-1. [Epub ahead of print]94 102510

Mitochondria and cell death signalling.

Ella Hall-Younger, Stephen Wg Tait.

Mitochondria are essential organelles in the life and death of a cell. During apoptosis, mitochondrial outer membrane permeabilisation (MOMP) engages caspase activation and cell death. Under nonlethal apoptotic stress, some mitochondria undergo permeabilisation, termed minority MOMP. Nonlethal apoptotic signalling impacts processes including genome stability, senescence and innate immunity. Recent studies have shown that upon MOMP, mitochondria and consequent signalling can trigger inflammation. We discuss how this occurs, and how mitochondrial inflammation might be targeted to increase tumour immunogenicity. Finally, we highlight how mitochondria contribute to other types of cell death including pyroptosis and ferroptosis. Collectively, these studies reveal critical new insights into how mitochondria regulate cell death, highlighting that mitochondrial signals engaged under nonlethal apoptotic stress have wide-ranging biological functions.

DOI: https://doi.org/10.1016/j.ceb.2025.102510
Cell Death Discov. 2025 Apr 07. 11(1): 150

DRP1, fission and apoptosis.

Nan Wang, Xinwai Wang, Beiwu Lan, Yufei Gao, Yuanyuan Cai.

Mitochondrial fission is a critical physiological process in eukaryotic cells, participating in various vital activities such as mitosis, mitochondria quality control, and mitophagy. Recent studies have revealed a tight connection between mitochondrial fission and the mitochondrial metabolism, as well as apoptosis, which involves multiple cellular events and interactions between organelles. As a pivotal molecule in the process of mitochondrial fission, the function of DRP1 is regulated at multiple levels, including transcription, post-translational modifications. This review follows the guidelines for Human Gene Nomenclature and will focus on DRP1, discussing its activity regulation, its role in mitochondrial fission, and the relationship between mitochondrial fission and apoptosis.

DOI: https://doi.org/10.1038/s41420-025-02458-0
Free Radic Biol Med. 2025 Apr 07. pii: S0891-5849(25)00221-7. [Epub ahead of print]

Inactivation of mitochondrial pyruvate dehydrogenase by singlet oxygen involves lipoic acid oxidation, side-chain modification and structural changes.

Qing Gao, Per Hägglund, Luke F Gamon, Michael J Davies.

  The multi-subunit pyruvate dehydrogenase complex (PDC) plays a crucial role in glucose oxidation as it determines whether pyruvate is used for mitochondrial oxidative phosphorylation or is converted to lactate for aerobic glycolysis. PDC contains three lipoic acid groups, covalently attached at lysine residues to give lipoyllysine, which are responsible for acyl group transfer and critical to complex activity. We have recently reported that both free lipoic acid, and lipoyllysine in alpha-keto glutarate dehydrogenase, are highly susceptible to singlet oxygen (1O2)-induced oxidation. We therefore hypothesized that PDC activity and structure would be influenced by 1O2 (generated using Rose Bengal and light) via modification of the lipoyllysines and other residues. PDC activity was decreased by photooxidation, with this being dependent on light exposure, O2, the presence of Rose Bengal, and D2O consistent with 1O2-mediated reactions. These changes were modulated by pre-illumination addition of free lipoic acid and lipoamide. Activity loss occurred concurrently with lipoyllysine and sidechain modification (determined by mass spectrometry) and protein aggregation (detected by SDS-PAGE). Peptide mass mapping provided evidence for modification at 42 residues (Met, Trp, His and Tyr; with modification extents of 20-50%) and each of the lipoyllysine sites (6-20% modification). Structure modelling indicated the modifications occur across all 4 subunit types, and occur in functional domains or at multimer interfaces, consistent with damage at multiple sites contributing to the overall loss of activity. These data indicate that PDC activity and structure are susceptible to 1O2-induced damage with potential effects on cellular pathways of glucose metabolism.

Keywords:  Pyruvate dehydrogenase complex; crosslinking; glucose metabolism; lipoic acid; lipoyllysine; mitochondria; photooxidation; protein oxidation; singlet oxygen; tricarboxylic acid cycle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.011
Cancer Lett. 2025 Apr 09. pii: S0304-3835(25)00260-5. [Epub ahead of print] 217694

Metformin inhibits the progression of castration resistant prostate cancer by regulating PDE6D induced purine metabolic alternation and cGMP / PKG pathway activation.

Shanghua Cai, Yulin Deng, Zhihao Zou, Weicheng Tian, Zhenfeng Tang, Jinchuang Li, Zeheng Tan, Zhenjie Wu, Zhaodong Han, Biyan Wen, Yuanfa Feng, Ren Liu, Xuejin Zhu, Yongding Wu, Haiyin Xiao, Huichan He, Jianheng Ye, Weide Zhong.

  The castration-resistant prostate cancer (CRPC) remains an incurable disease. Metformin has demonstrated a potential therapeutic effect on CRPC. However, the poor clinical performance of metformin against cancer may be due to its clinical dose being much lower than the anticancer concentration used in pre-clinical experiments. The challenge is to determine a way to enhance sensitivity to metformin at an appropriate concentration on CRPC. In this study, a mouse model of low-dose metformin treatment for CRPC cells were established. Metabolomic-seq and transcriptomic-seq was used to investigate changes in CRPC xenografts. We discovered that low-dose metformin inhibits the progression of CRPC by regulating PDE6D, which induces alterations in purine metabolism and activates the cGMP/PKG pathway. Furthermore, we found that cells with high expression of PDE6D were more resistant to metformin. When combined with the PDE6D inhibitor TMX-4100, the inhibitory effect on tumors was enhanced, and TMX-4100 demonstrated favorable biosafety in animal models. In conclusion, we found that low-dose metformin inhibits the progression of CRPC by regulating PDE6D-induced alterations in purine metabolism and activating the cGMP/PKG pathway. Moreover, patients with high PDE6D expression may exhibit greater resistance to metformin. Combining metformin with TMX-4100 could further improve the inhibitory effects on tumors.

Keywords:  Apoptosis; CRPC; PDE6D; Precision medicine; Therapy sensitization

DOI:  https://doi.org/10.1016/j.canlet.2025.217694
Nat Aging. 2025 Apr 10.

Single-cell and spatial RNA sequencing identify divergent microenvironments and progression signatures in early- versus late-onset prostate cancer.

Yifei Cheng, Bingxin Liu, Junyi Xin, Xiaobin Wu, Wenchao Li, Jinwei Shang, Jiajin Wu, Zhengdong Zhang, Bin Xu, Mulong Du, Gong Cheng, Meilin Wang.

The clinical and pathological outcomes differ between early-onset (diagnosed in men ≤55 years of age) and late-onset prostate cancer, potentially attributed to the changes in hormone levels and immune activities associated with aging. Exploring the heterogeneity therein holds potential for developing age-specific precision interventions. Here, through single-cell and spatial transcriptomic analyses of prostate cancer tissues, we identified that an androgen response-related transcriptional meta-program (AR-MP) might underlie the age-related heterogeneity of tumor cells and microenvironment. APOE+ tumor-associated macrophages infiltrated AR-MP-activated tumor cells in early-onset prostate cancer, potentially facilitating tumor progression and immunosuppression. By contrast, inflammatory cancer-associated fibroblasts in late-onset prostate cancer correlated with downregulation of AR-MP of tumor cells and increased epithelial-to-mesenchymal transition and pre-existing castration resistance, which may also be linked to smoking. This study provides potential insights for tailoring precision treatments by age groups, emphasizing interventions that include targeting AR and tumor-associated macrophages in young patients but anchoring epithelial-to-mesenchymal transition and inflammatory cancer-associated fibroblasts in old counterparts.

DOI: https://doi.org/10.1038/s43587-025-00842-0
Mol Biol Cell. 2025 Apr 09. mbcE24090394

Cell Confluency Affects p53 Dynamics in Response to DNA Damage.

Alina Simerzin, Emily E Ackerman, Kotaro Fujimaki, Rainer H Kohler, Yoshiko Iwamoto, Mathias S Heltberg, Ashwini Jambhekar, Ralph Weissleder, Galit Lahav.

The tumor suppressor protein p53 plays a key role in the cellular response to DNA damage. In response to DNA double strand breaks (DSB), cultured cells exhibit oscillations of p53 levels, which impact gene expression and cell fate. The dynamics of p53 in-vivo have only been studied in fixed tissues or using reporters for p53's transcriptional activity. Here we established breast tumors expressing a fluorescent reporter for p53 levels and employed intravital imaging to quantify its dynamics in response to DSB in-vivo. Our findings revealed large heterogeneity among individual cells, with most cells exhibiting a single prolonged pulse. We then tested how p53 dynamics might change under high cell confluency, one factor that differs between cell culture and tissues. We revealed that highly confluent cultured breast cancer cells also show one broad p53 pulse instead of oscillations. Through mathematical modeling, sensitivity analysis and live cell imaging we identified low levels of the phosphatase Wip1, a transcriptional target and negative regulator of p53, as a key contributor to these dynamics. Since high cell confluency better reflects the microenvironment of tissues, the impact of cell confluency on p53 dynamics may have important consequences for cancerous tissues responding to DNA damage inducing therapies.

DOI: https://doi.org/10.1091/mbc.E24-09-0394
Front Immunol. 2025 ;16 1573686

Organoid models of ovarian cancer: resolving immune mechanisms of metabolic reprogramming and drug resistance.

Lanyue Zhang, Jiangnan Zhao, Chunyu Su, Jianxi Wu, Lai Jiang, Hao Chi, Qin Wang.

  Metabolic reprogramming is a hallmark of ovarian cancer, enabling tumor progression, immune evasion and drug resistance. The tumor microenvironment (TME) further shapes metabolic adaptations, enabling cancer cells to withstand hypoxia and nutrient deprivation. While organoid models provide a physiologically relevant platform for studying these processes, they still lack immune and vascular components, limiting their ability to fully recapitulate tumor metabolism and drug responses. In this study, we investigated the key metabolic mechanisms involved in ovarian cancer progression, focusing on glycolysis, lipid metabolism and amino acid metabolism. We integrated metabolomic analyses and drug sensitivity assays to explore metabolic-TME interactions using patient-derived, adult stem cell-derived and iPSC-derived organ tissues. Among these, we found that glycolysis, lipid metabolism and amino acid metabolism play a central role in tumor progression and chemotherapy resistance. We identified methylglyoxal (MGO)-mediated BRCA2 dysfunction as a driver of immune escape, a role for sphingolipid signaling in tumor proliferation and a role for kynurenine metabolism in CD8+ T cell suppression. In addition, PI3K/AKT/mTOR and Wnt/β-catenin pathways promote chemoresistance through metabolic adaptation. By elucidating the link between metabolic reprogramming and immune evasion, this study identifies key metabolic vulnerabilities and potential drug targets in ovarian cancer. Our findings support the development of metabolically targeted therapies and increase the utility of organoid-based precision medicine models.

Keywords:  drug resistance; immune escape; metabolic reprogramming; molecular mechanisms; organoid; ovarian cancer; personalized therapy

DOI:  https://doi.org/10.3389/fimmu.2025.1573686
STAR Protoc. 2025 Apr 05. pii: S2666-1667(25)00151-0. [Epub ahead of print]6(2): 103745

Protocol for dual metabolomics and proteomics using nanoflow liquid chromatography-tandem mass spectrometry.

Weiwei Lin, Fatemeh Mousavi, Benjamin C Blum, Christian F Heckendorf, Matthew Lawton, Noah Lampl, Ryan Hekman, Mark McComb, Andrew Emili.

  Nanoflow liquid chromatography-tandem mass spectrometry (nLC-MS) benefits untargeted metabolomics by enhancing sensitivity and integrating proteomics for the same sample. Here, we present a protocol to enable nLC-MS for dual metabolomics and proteomics. We describe steps for solid-phase micro-extraction (SPME)-assisted metabolite cleaning and enrichment, which avoids capillary column blockage. We then detail nLC-MS data acquisition and analysis. This protocol has been applied in diverse specimens including biofluids, cell lines, and tissues. For complete details on the use and execution of this protocol, please refer to Lin et al.1.

Keywords:  Bioinformatics; Mass Spectrometry; Metabolomics; Proteomics; Systems biology

DOI:  https://doi.org/10.1016/j.xpro.2025.103745
Cell Death Discov. 2025 Apr 04. 11(1): 143

Non-immune targeting of CXCR3 compromises mitochondrial function and suppresses tumor growth in glioblastoma.

Travis Yui Hei Chan, Bo Chen, Wanjun Tang, Henry Hei Chan, Yogesh K H Wong, Ethan C L Wong, Junbo Liao, Anson Cho-Kiu Ng, Jenny Sum Yee Wong, Gilberto Ka-Kit Leung, Karrie M Kiang.

The chemokine receptor CXCR3 is traditionally recognized for its role in immune cell trafficking. However, emerging evidence suggests that its functions may extend beyond the immune system, particularly in cancer, where its roles remain to be elucidated. In this study, we demonstrated that CXCR3 expression correlates with glioblastoma (GBM) grading, with CXCR3-A isoform being associated with poorer patient prognosis compared to CXCR3-B. Ablation of both CXCR3 isoforms significantly impaired GBM cell proliferation, migration, and tumor growth both in vitro and in immunodeficient mice. To elucidate the mechanistic role of CXCR3, we conducted transcriptomic profiling of tumor xenografts, revealing that CXCR3 depletion would disrupt mitochondrial homeostasis. This was further supported by our findings that CXCR3 would localize to the mitochondrial membrane, and that inhibition of CXCR3 would lead to mitochondrial depolarization and increased reactive oxygen species production. Notably, activation of phosphorylated-STAT3 rescued cell viability in CXCR3-depleted cells, suggesting that CXCR3 may modulate mitochondrial function through a STAT3-dependent mechanism, consistent with the known functional role of STAT3 in maintaining mitochondrial redox balance. Furthermore, treatment with the selective CXCR3 antagonist AMG487 reduced tumor growth and disrupted mitochondrial function in vitro, in vivo, and in patient-derived GBM stem cells. Our findings reveal CXCR3 as a previously unrecognized regulator of mitochondrial function in cancer cells, positioning the CXCR3-mitochondrial signaling axis as a promising therapeutic target for GBM. Chemokine receptors are well-established mediators of inflammatory responses, emerging evidence suggests that these receptors may play roles beyond the immune system. In this study, we have demonstrated that CXCR3 would localize to the mitochondrial membrane and exert a previously unrecognized function in regulating cancer metabolism and mitochondrial function. Figure created using BioRender ( https://biorender.com ).

DOI: https://doi.org/10.1038/s41420-025-02449-1
Nat Metab. 2025 Apr 09.

The mitochondrial unfolded protein response inhibits pluripotency acquisition and mesenchymal-to-epithelial transition in somatic cell reprogramming.

Zhongfu Ying, Yanmin Xin, Zihuang Liu, Tianxin Tan, Yile Huang, Yingzhe Ding, Xuejun Hong, Qiuzhi Li, Chong Li, Jingyi Guo, Gaoshen Liu, Qi Meng, Shihe Zhou, Wenxin Li, Yao Yao, Ge Xiang, Linpeng Li, Yi Wu, Yang Liu, Miaohui Mu, Zifeng Ruan, Wenxi Liang, Junwei Wang, Yaofeng Wang, Baojian Liao, Yang Liu, Wuming Wang, Gang Lu, Dajiang Qin, Duanqing Pei, Wai-Yee Chan, Xingguo Liu.

The mitochondrial unfolded protein response (UPRmt), a mitochondria-to-nucleus retrograde pathway that promotes the maintenance of mitochondrial function in response to stress, plays an important role in promoting lifespan extension in Caenorhabditis elegans1,2. However, its role in mammals, including its contributions to development or cell fate decisions, remains largely unexplored. Here, we show that transient UPRmt activation occurs during somatic reprogramming in mouse embryonic fibroblasts. We observe a c-Myc-dependent, transient decrease in mitochondrial proteolysis, accompanied by UPRmt activation at the early phase of pluripotency acquisition. UPRmt impedes the mesenchymal-to-epithelial transition (MET) through c-Jun, thereby inhibiting pluripotency acquisition. Mechanistically, c-Jun enhances the expression of acetyl-CoA metabolic enzymes and reduces acetyl-CoA levels, thereby affecting levels of H3K9Ac, linking mitochondrial signalling to the epigenetic state of the cell and cell fate decisions. c-Jun also decreases the occupancy of H3K9Ac at MET genes, further inhibiting MET. Our findings reveal the crucial role of mitochondrial UPR-modulated MET in pluripotent stem cell plasticity. Additionally, we demonstrate that the UPRmt promotes cancer cell migration and invasion by enhancing epithelial-to-mesenchymal transition (EMT). Given the crucial role of EMT in tumour metastasis3,4, our findings on the connection between the UPRmt and EMT have important pathological implications and reveal potential targets for tumour treatment.

DOI: https://doi.org/10.1038/s42255-025-01261-6
bioRxiv. 2025 Mar 27. pii: 2025.03.27.645657. [Epub ahead of print]

Alternative start codon selection shapes mitochondrial function during evolution, homeostasis, and disease.

Jimmy Ly, Yi Fei Tao, Matteo Di Bernardo, Ekaterina Khalizeva, Christopher J Giuliano, Sebastian Lourido, Mark D Fleming, Iain M Cheeseman.

Mitochondrial endosymbiosis was a pivotal event in eukaryotic evolution, requiring core proteins to adapt to function both within the mitochondria and in the host cell. Here, we systematically profile the localization of protein isoforms generated by alternate start codon selection during translation. We identify hundreds of pairs of differentially-localized protein isoforms, many of which affect mitochondrial targeting and are essential for mitochondrial function. The emergence of dual-localized mitochondrial protein isoforms coincides with mitochondrial acquisition during early eukaryotic evolution. We further reveal that eukaryotes use diverse mechanisms-such as leaky ribosome scanning, alternative transcription, and paralog duplication-to maintain the production of dual-localized isoforms. Finally, we identify multiple isoforms that are specifically dysregulated by rare disease patient mutations and demonstrate how these mutations can help explain unique clinical presentations. Together, our findings illuminate the evolutionary and pathological relevance of alternative translation initiation, offering new insights into the molecular underpinnings of mitochondrial biology.

DOI: https://doi.org/10.1101/2025.03.27.645657
BMC Cancer. 2025 Apr 08. 25(1): 634

Construction and validation of a nomogram for identifying the patients at risk for rapid progression of advanced hormone-sensitive prostate cancer.

Xiaolong Xu, Weiyu Fei, Mingshuang Wu, Yi He, Bo Yang, Cuicui Lv.

   BACKGROUND: This study aimed to evaluate the prognostic significance of lactate dehydrogenase (LDH) and fasting triglyceride-glucose (TyG) index in advanced hormone-sensitive prostate cancer (HSPC) patients, with the ultimate goal of developing and validating a nomogram for predicting castration-resistant prostate cancer (CRPC) free survival.
MATERIALS AND METHODS: The follow-up data of 207 CRPC patients who had androgen deprivation therapy as their initial and only treatment before progression were retrospectively reviewed. To assess prognostic variables, univariate and multivariate Cox regression analyses were performed. The concordance index (C-index), calibration curves, receiver operating characteristic (ROC) curves, and decision curve analyses (DCA) were utilized to construct and test a novel nomogram model.
RESULTS: TyG index, LDH, M stage and Gleason sum were determined to be independent prognostic markers and were combined to create a nomogram. This nomogram worked well in the tailored prediction of CRPC development at the sixth, twelve, eighteen, and twenty-fourth months. The C-indexes for the training and validation sets were 0.798 and 0.790, respectively. The ROC curves, calibration plots, and DCA all indicated good discrimination and prediction performance. Furthermore, the nomogram had a higher prognostic ability than the M stage and the Gleason sum. The nomogram-related risk score classified the patient population into two groups with significant progression differences.
CONCLUSIONS: The created nomogram could help identify patients at high risk for rapid progression of advanced HSPC, allowing for the formulation of tailored therapy regimens and follow-up methods in a timely manner.

Keywords:  Fasting triglyceride-glucose; Hormone-sensitive prostate cancer; Lactate dehydrogenase; Nomogram

DOI:  https://doi.org/10.1186/s12885-025-14035-w
Tissue Cell. 2025 Apr 01. pii: S0040-8166(25)00173-9. [Epub ahead of print]95 102893

The role of lactate metabolism in retinoblastoma tumorigenesis and ferroptosis resistance.

Zhihui Zhang, Junjie Tang, Yaoming Liu, Yinghao Wang, Jinmiao Li, Yang Gao, Chao Cheng, Shicai Su, Shuxia Chen, Siming Ai, Ping Zhang, Rong Lu.

  The Warburg effect, a hallmark of cancer, describes the preference of cancer cells for glucose metabolism via aerobic glycolysis, leading to substantial lactate accumulation. However, the role of lactate metabolism in retinoblastoma, the primary intraocular malignancy in children, remains unclear. This study aimed to elucidate the gene expression profiles associated with lactate metabolism in retinoblastoma and their impact on tumorigenesis and ferroptosis resistance. The involvement of metabolic characteristics in retinoblastoma was analyzed by comparing single-cell RNA sequencing transcriptome profiles from normal retina tissues and retinoblastoma tissues from patient samples. The effects of lactate on retinoblastoma cell line viability and its mechanisms were examined both in vitro and in vivo. Single-cell RNA sequencing analysis revealed enhanced glycolysis in retinoblastoma cells and significant differences in lactate metabolism-related gene expression among various retinoblastoma cell types. Retinoblastoma cell lines with moderate lactate levels exhibited increased viability and resistance to ferroptosis induced by ferroptosis inducers. Additionally, lactate promoted the upregulation of monocarboxylate transporter 1 (MCT1), which facilitated lactate transport, in a dose-dependent manner in retinoblastoma cell lines. Knocking down MCT1 reduced both viability and ferroptosis resistance of retinoblastoma cell lines in a lactate-rich environment. In vivo, disrupting lactate transport through MCT1 inhibition suppressed retinoblastoma tumorigenesis and invasion in a mouse xenograft model, and this effect was reversed by the ferroptosis inhibitor liproxstatin-1. These findings highlighted the crucial role of lactate metabolism in retinoblastoma tumorigenesis and resistance to ferroptosis.

Keywords:  Ferroptosis; Lactate metabolism; Monocarboxylate transporter 1; Retinoblastoma

DOI:  https://doi.org/10.1016/j.tice.2025.102893
Front Cell Dev Biol. 2025 ;13 1570696

Spatial multi-omics analysis of tumor-stroma boundary cell features for predicting breast cancer progression and therapy response.

Yuanyuan Wu, Youyang Shi, Zhanyang Luo, Xiqiu Zhou, Yonghao Chen, Xiaoyun Song, Sheng Liu.

   Background: The tumor boundary of breast cancer represents a highly heterogeneous region. In this area, the interactions between malignant and non-malignant cells influence tumor progression, immune evasion, and drug resistance. However, the spatial transcriptional profile of the tumor boundary and its role in the prognosis and treatment response of breast cancer remain unclear.
Method: Utilizing the Cottrazm algorithm, we reconstructed the intricate boundaries and identified differentially expressed genes (DEGs) associated with these regions. Cell-cell co-positioning analysis was conducted using SpaCET, which revealed key interactions between tumor-associated macrophage (TAMs) and cancer-associated fibroblasts (CAFs). Additionally, Lasso regression analysis was employed to develop a malignant body signature (MBS), which was subsequently validated using the TCGA dataset for prognosis prediction and treatment response assessment.
Results: Our research indicates that the tumor boundary is characterized by a rich reconstruction of the extracellular matrix (ECM), immunomodulatory regulation, and the epithelial-to-mesenchymal transition (EMT), underscoring its significance in tumor progression. Spatial colocalization analysis reveals a significant interaction between CAFs and M2-like tumor-associated macrophage (TAM), which contributes to immune exclusion and drug resistance. The MBS score effectively stratifies patients into high-risk groups, with survival outcomes for patients exhibiting high MBS scores being significantly poorer. Furthermore, drug sensitivity analysis demonstrates that high-MB tumors had poor response to chemotherapy strategies, highlighting the role of the tumor boundary in modulating therapeutic efficacy.
Conclusion: Collectively, we investigate the spatial transcription group and bulk data to elucidate the characteristics of tumor boundary molecules in breast cancer. The CAF-M2 phenotype emerges as a critical determinant of immunosuppression and drug resistance, suggesting that targeting this interaction may improve treatment responses. Furthermore, the MBS serves as a novel prognostic tool and offers potential strategies for guiding personalized treatment approaches in breast cancer.

Keywords:  CAF-M2 interaction; breast cancer; prognostic model; spatial transcriptomics; therapy resistance; tumor boundary

DOI:  https://doi.org/10.3389/fcell.2025.1570696