bims-midysc 2025-02-02 papers

bims-midysc

Biomed News

on Mitochondria dysfunction in cancer

Issue of 2025–02–02
28 papers selected by
Papachristodoulou Lab

Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival.
FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.
Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.
PRPS activity tunes redox homeostasis in Myc-driven lymphoma.
Fluorescence lifetime imaging microscopy for metabolic analysis of LDHB inhibition in triple negative breast cancer.
VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis.
Targeting pancreatic cancer glutamine dependency confers vulnerability to GPX4-dependent ferroptosis.
'Dark proteins' hiding in our cells could hold clues to cancer and other diseases.
piR-26441 inhibits mitochondrial oxidative phosphorylation and tumorigenesis in ovarian cancer through m6A modification by interacting with YTHDC1.
The curious case of mitochondrial sirtuin in rewiring breast cancer metabolism: Mr Hyde or Dr Jekyll?
Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.
Lactoferrin conjugated radicicol nanoparticles enhanced drug delivery and cytotoxicity in prostate cancer cells.
Protocol to identify small-molecule inhibitors against cancer drug resistance.
Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth.
ECM-mimicking hydrogel models of human adipose tissue identify deregulated lipid metabolism in the prostate cancer-adipocyte crosstalk under antiandrogen therapy.
The Homeobox Transcription Factor NKX3.1 Displays an Oncogenic Role in Castration-Resistant Prostate Cancer Cells.
The histone modification regulator, SIN3, plays a role in the cellular response to changes in glycolytic flux.
PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response.
Mitochondrial DNA alterations in precision oncology: Emerging roles in diagnostics and therapeutics.
Correcting a pathogenic mitochondrial DNA mutation by base editing in mice.
Mitochondrial dysfunction-driven AMPK-p53 axis activation underpins the anti-hepatocellular carcinoma effects of sulfane sulfur.
Oncogenic competence: balancing mutations, cellular state, and microenvironment.
Identification of intraductal-to-invasive spatial transitions in prostate cancer: proposal for a new unifying model on intraductal carcinogenesis.
Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
Mitochondrial base editing: from principle, optimization to application.
AR-V7 condensates drive androgen-independent transcription in castration resistant prostate cancer.
The roles of mitochondria in global and local intracellular calcium signalling.
Optical metabolic imaging identifies metabolic shifts and mitochondria heterogeneity in POLG mutator macrophages.

Cell Commun Signal. 2025 Jan 25. 23(1): 47

Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival.

Monika Komza, Jesminara Khatun, Jesse D Gelles, Andrew P Trotta, Ioana Abraham-Enachescu, Juan Henao, Ahmed Elsaadi, Andriana G Kotini, Cara Clementelli, JoAnn Arandela, Sebastian El Ghaity-Beckley, Agneesh Barua, Yiyang Chen, Mirela Berisa, Bridget K Marcellino, Eirini P Papapetrou, Masha V Poyurovsky, Jerry Edward Chipuk.

  One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.

Keywords:  Adaptations; Bioenergetics; Cancer; Chemotherapy; Glucose; Leukemia; Metabolism; Mitochondria; Oncogenes; Stem cells

DOI:  https://doi.org/10.1186/s12964-025-02044-y
J Cell Biol. 2025 Mar 03. pii: e202311082. [Epub ahead of print]224(3):

FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.

Alva G Sainz, Gladys R Rojas, Alexandra G Moyzis, Matthew P Donnelly, Kailash C Mangalhara, Melissa A Johnson, Pau B Esparza-Moltó, Kym J Grae, Reuben J Shaw, Gerald S Shadel.

Mitochondrial retrograde signaling (MRS) pathways relay the functional status of mitochondria to elicit homeostatic or adaptive changes in nuclear gene expression. Budding yeast have "intergenomic signaling" pathways that sense the amount of mitochondrial DNA (mtDNA) independently of oxidative phosphorylation (OXPHOS), the primary function of genes encoded by mtDNA. However, MRS pathways that sense the amount of mtDNA in mammalian cells remain poorly understood. We found that mtDNA-depleted IMR90 cells can sustain OXPHOS for a significant amount of time, providing a robust model system to interrogate human intergenomic signaling. We identified FAM43A, a largely uncharacterized protein, as a CHK2-dependent early responder to mtDNA depletion. Depletion of FAM43A activates a mitochondrial biogenesis program, resulting in an increase in mitochondrial mass and mtDNA copy number via CHK2-mediated upregulation of the p53R2 form of ribonucleotide reductase. We propose that FAM43A performs a checkpoint-like function to limit mitochondrial biogenesis and turnover under conditions of mtDNA depletion or replication stress.

DOI: https://doi.org/10.1083/jcb.202311082
Nat Cell Biol. 2025 Jan 24.

Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.

DOI: https://doi.org/10.1038/s41556-024-01603-8
bioRxiv. 2025 Jan 13. pii: 2025.01.08.632009. [Epub ahead of print]

PRPS activity tunes redox homeostasis in Myc-driven lymphoma.

Austin C MacMillan, Bibek Karki, Juechen Yang, Karmela R Gertz, Samantha Zumwalde, Maria F Czyzyk-Krzeska, Jarek Meller, John T Cunningham.

Myc hyperactivation coordinately regulates numerous metabolic processes to drive lymphomagenesis. Here, we elucidate the temporal and functional relationships between the medley of pathways, factors, and mechanisms that cooperate to control redox homeostasis in Myc-overexpressing B cell lymphomas. We find that Myc overexpression rapidly stimulates the oxidative pentose phosphate pathway (oxPPP), nucleotide synthesis, and mitochondrial respiration, which collectively steers cellular equilibrium to a more oxidative state. We identify Myc-dependent hyperactivation of the phosphoribosyl pyrophosphate synthetase (PRPS) enzyme as a primary regulator of redox status in lymphoma cells. Mechanistically, we show that genetic inactivation of the PRPS2 isozyme, but not PRPS1, in Myc-driven lymphoma cells leads to elevated NADPH levels and reductive stress-mediated death. Employing a pharmacological screen, we demonstrate how targeting PRPS1 or PRPS2 elicits opposing sensitivity or resistance, respectively, to chemotherapeutic agents affecting the thioredoxin and glutathione network, thus providing a therapeutic blueprint for treating Myc-driven lymphomas.

DOI: https://doi.org/10.1101/2025.01.08.632009
bioRxiv. 2025 Jan 18. pii: 2025.01.13.632864. [Epub ahead of print]

Fluorescence lifetime imaging microscopy for metabolic analysis of LDHB inhibition in triple negative breast cancer.

A Galloway, B Ter Hofstede, Alex J Walsh.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with no targeted treatments currently available. TNBC cells participate in metabolic symbiosis, a process that optimizes tumor growth by balancing metabolic processes between glycolysis and oxidative phosphorylation through increased activity by the enzyme lactate dehydrogenase B (LDHB). Metabolic symbiosis allows oxidative cancer cells to function at a similar rate as glycolytic cancer cells, increasing overall metabolic activity and proliferation. Here, fluorescence lifetime imaging microscopy (FLIM) is used to analyze the metabolism of TNBC cells with inhibition of LDHB using a multiphoton microscope to measure the fluorescent lifetimes of two metabolic coenzymes, NAD(P)H and FAD. LDHB is inhibited via an indole derivative known as AXKO-0046 in varying concentrations. Understanding how TNBC cell metabolism changes due to LDHB inhibition will provide further insight into metabolic symbiosis and potential new TNBC treatment options.

DOI: https://doi.org/10.1101/2025.01.13.632864
Nat Commun. 2025 Jan 29. 16(1): 1160

VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis.

Juan Yang, Xiao Lu, Jing-Lan Hao, Lan Li, Yong-Tong Ruan, Xue-Ni An, Qi-Lai Huang, Xiao-Ming Dong, Ping Gao.

Ferroptosis is a form of iron-dependent programmed cell death, which is distinct from apoptosis, necrosis, and autophagy. Mitochondria play a critical role in initiating and amplifying ferroptosis in cancer cells. Voltage-Dependent Anion Channel 1 (VDAC1) embedded in the mitochondrial outer membrane, exerts roles in regulation of ferroptosis. However, the mechanisms of VDAC1 oligomerization in regulating ferroptosis are not well elucidated. Here, we identify that a VDAC1 binding protein V-Set and Transmembrane Domain Containing 2 Like (VSTM2L), mainly localized to mitochondria, is positively associated with prostate cancer (PCa) progression, and a key regulator of ferroptosis. Moreover, VSTM2L knockdown in PCa cells enhances the sensitivity of RSL3-induced ferroptosis. Mechanistically, VSTM2L forms complex with VDAC1 and hexokinase 2 (HK2), enhancing their binding affinity and preventing VDAC1 oligomerization, thereby inhibiting ferroptosis and maintaining mitochondria homeostasis in vitro and in vivo. Collectively, our findings reveal a pivotal role for mitochondria-localized VSTM2L in driving ferroptosis resistance and highlight its potential as a ferroptosis-inducing therapeutic target for the treatment of PCa.

DOI: https://doi.org/10.1038/s41467-025-56494-6
Cell Rep Med. 2025 Jan 27. pii: S2666-3791(25)00001-1. [Epub ahead of print] 101928

Targeting pancreatic cancer glutamine dependency confers vulnerability to GPX4-dependent ferroptosis.

Xuqing Shen, Yueyue Chen, Yingying Tang, Ping Lu, Mingzhu Liu, Tiebo Mao, Yawen Weng, Feier Yu, Yimei Liu, Yujie Tang, Liwei Wang, Ningning Niu, Jing Xue.

  Pancreatic ductal adenocarcinoma (PDAC) relies heavily on glutamine (Gln) utilization to meet its metabolic and biosynthetic needs. How epigenetic regulators contribute to the metabolic flexibility and PDAC's response and adaptation to Gln scarcity in the tumor milieu remains largely unknown. Here, we elucidate that prolonged Gln restriction or treatment with the Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), leads to growth inhibition and ferroptosis program activation in PDAC. A CRISPR-Cas9 screen identifies an epigenetic regulator, Paxip1, which promotes H3K4me3 upregulation and Hmox1 transcription upon DON treatment. Additionally, ferroptosis-related repressors (e.g., Slc7a11 and Gpx4) are increased as an adaptive response, thereby predisposing PDAC cells to ferroptosis upon Gln deprivation. Moreover, DON sensitizes PDAC cells to GPX4 inhibitor-induced ferroptosis, both in vitro and in patient-derived xenografts (PDXs). Taken together, our findings reveal that targeting Gln dependency confers susceptibility to GPX4-dependent ferroptosis via epigenetic remodeling and provides a combination strategy for PDAC therapy.

Keywords:  PDAC; combination therapy; epigenetic remodeling; ferroptosis; pancreatic ductal adenocarcinoma; prolonged glutamine starvation

DOI:  https://doi.org/10.1016/j.xcrm.2025.101928
Nature. 2025 Jan;637(8048): 1038-1040

'Dark proteins' hiding in our cells could hold clues to cancer and other diseases.

Ewen Callaway.



Keywords:  Genetics; Genomics; Proteomics

DOI:  https://doi.org/10.1038/d41586-025-00217-w
Cell Death Dis. 2025 Jan 18. 16(1): 25

piR-26441 inhibits mitochondrial oxidative phosphorylation and tumorigenesis in ovarian cancer through m6A modification by interacting with YTHDC1.

Jing Yuan, Bu-Min Xie, Yu-Meng Ji, Hai-Juan Bao, Jie-Lin Wang, Jia-Chen Cheng, Xiang-Chun Huang, Yang Zhao, Shuo Chen.

Ovarian cancer (OC) is a heterogeneous cancer. In contrast to other tumor cells, which rely primarily on aerobic glycolysis (Warburg effect) as their energy source, oxidative phosphorylation (OXPHOS) is also one of its major metabolic modes. Piwi-interacting RNAs (piRNAs) play a regulatory function in various biological processes in tumor cells. However, the role and mechanisms of piRNAs in OC and mitochondrial OXPHOS remain to be elucidated. Here, we found that piR-26441 was aberrantly downregulated in OC, and its overexpression suppressed the malignant features of OC cells and tumor growth in a xenograft model. Moreover, overexpression of piR-26441 significantly reduced mitochondrial OXPHOS levels in OC cells. Furthermore, piR-26441 directly binds to and upregulates the expression of YTHDC1 in OC cells. piR-26441 also increased m6A levels, thereby interacting with YTHDC1 to destabilize the mRNA of TSFM. The resultant TSFM loss reduced mitochondrial complex I activity and mitochondrial OXPHOS, leading to mitochondrial dysfunction in OC cells, increased reactive oxygen species levels, and thus, DNA damage and apoptosis in OC cells, thereby inhibiting OC progression. Additionally, ago-piR-26441 suppressed tumor growth and mitochondrial metabolism in the patient-derived organoid model. Altogether, piR-26441 could inhibit OC cell growth via the YTHDC1/TSFM signaling axis, underscoring its significant importance in the context of OC, as well as offering potential as a therapeutic target.

DOI: https://doi.org/10.1038/s41419-025-07340-6
Biochim Biophys Acta Mol Basis Dis. 2025 Jan 27. pii: S0925-4439(25)00036-5. [Epub ahead of print]1871(3): 167691

The curious case of mitochondrial sirtuin in rewiring breast cancer metabolism: Mr Hyde or Dr Jekyll?

Jesline Shaji Tharayil, Amoolya Kandettu, Sanjiban Chakrabarty.

  Mammalian sirtuins are class III histone deacetylases involved in the regulation of multiple biological processes including senescence, DNA repair, apoptosis, proliferation, caloric restriction, and metabolism. Among the mammalian sirtuins, SIRT3, SIRT4, and SIRT5 are localized in the mitochondria and collectively termed the mitochondrial sirtuins. Mitochondrial sirtuins are NAD+-dependent deacetylases that play a central role in cellular metabolism and function as epigenetic regulators by performing post-translational modification of cellular proteins. Several studies have identified the role of mitochondrial sirtuins in age-related pathologies and the rewiring of cancer metabolism. Mitochondrial sirtuins regulate cellular functions by contributing to post-translational modifications, including deacetylation, ADP-ribosylation, demalonylation, and desuccinylation of diverse cellular proteins to maintain cellular homeostasis. Here, we review and discuss the structure and function of the mitochondrial sirtuins and their role as metabolic regulators in breast cancer. Altered breast cancer metabolism may promote tumor progression and has been an essential target for therapy. Further, we discuss the potential role of targeting mitochondrial sirtuin and its impact on breast cancer progression using sirtuin inhibitors and activators as anticancer agents.

Keywords:  Breast cancer; Glutamine; Glycolysis; Mitochondrial sirtuins; Oxidative phosphorylation; ROS

DOI:  https://doi.org/10.1016/j.bbadis.2025.167691
Cell Death Dis. 2025 Jan 25. 16(1): 40

Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.

Lohans Pedrera, Laura Prieto Clemente, Alina Dahlhaus, Sara Lotfipour Nasudivar, Sofya Tishina, Daniel Olmo González, Jenny Stroh, Fatma Isil Yapici, Randhwaj Pratap Singh, Nils Grotehans, Thomas Langer, Ana J García-Sáez, Silvia von Karstedt.

Constitutive mitochondrial dynamics ensure quality control and metabolic fitness of cells, and their dysregulation has been implicated in various human diseases. The large GTPase Dynamin-related protein 1 (Drp1) is intimately involved in mediating constitutive mitochondrial fission and has been implicated in mitochondrial cell death pathways. During ferroptosis, a recently identified type of regulated necrosis driven by excessive lipid peroxidation, mitochondrial fragmentation has been observed. Yet, how this is regulated and whether it is involved in ferroptotic cell death has remained unexplored. Here, we provide evidence that Drp1 is activated upon experimental induction of ferroptosis and promotes cell death execution and mitochondrial fragmentation. Using time-lapse microscopy, we found that ferroptosis induced mitochondrial fragmentation and loss of mitochondrial membrane potential, but not mitochondrial outer membrane permeabilization. Importantly, Drp1 accelerated ferroptotic cell death kinetics. Notably, this function was mediated by the regulation of mitochondrial dynamics, as overexpression of Mitofusin 2 phenocopied the effect of Drp1 deficiency in delaying ferroptosis cell death kinetics. Mechanistically, we found that Drp1 is phosphorylated and activated after induction of ferroptosis and that it translocates to mitochondria. Further activation at mitochondria through the phosphatase PGAM5 promoted ferroptotic cell death. Remarkably, Drp1 depletion delayed mitochondrial and plasma membrane lipid peroxidation. These data provide evidence for a functional role of Drp1 activation and mitochondrial fragmentation in the acceleration of ferroptotic cell death, with important implications for targeting mitochondrial dynamics in diseases associated with ferroptosis.

DOI: https://doi.org/10.1038/s41419-024-07312-2
Eur J Pharmacol. 2025 Jan 25. pii: S0014-2999(25)00053-6. [Epub ahead of print] 177300

Lactoferrin conjugated radicicol nanoparticles enhanced drug delivery and cytotoxicity in prostate cancer cells.

Zeinab Kooshan, Srilakshmi Srinivasan, Taskeen Iqbal Janjua, Amirali Popat, Jyotsna Batra.

  Pyruvate dehydrogenase kinase-1 (PDK1) plays a crucial role in cancer cell metabolism by regulating the glycolytic pathway. Although, inhibitors targeting PDK1 have been effective in inhibiting glycolysis in multiple cancers, their lack of selectivity leading to off-target effects limit their therapeutic benefit. Herein, we investigated the inhibitory potential of six PDK1 inhibitors on cellular proliferation, migration, and invasion of androgen-sensitive LNCaP and androgen-negative PC-3 prostate cancer cells. Of the six PDK1 inhibitors, radicicol and dicumarol significantly inhibited cellular proliferation and exhibited lower metabolic activity in both LNCaP and PC-3 metastatic prostate cancer cells. Radicicol was highly effective at lower concentration. Moreover, radicicol significantly inhibited migration and invasion in PC-3 cells. We then developed a lactoferrin nanoparticle (LF-NP) encapsulated with Radicicol (Ra-LF-NP), using a rotary evaporation method. Spheroid assays confirmed the higher inhibitory potential of Ra-LF-NP with a reduction in spheroid area by 80%, and invasiveness compared to radicicol alone. Lactoferrin receptors are overexpressed on the surface of many cancer cells, including prostate cancer. Conjugating radicicol with lactoferrin nanoparticles, potentially enhanced the specific uptake of the drug by prostate cancer cells while minimizing the off-target effects on healthy cells. This targeted therapy approach could lead to improved treatment outcomes and reduced side effects. Our study demonstrated the potential of radicicol delivery by lactoferrin-conjugated nanoparticle as an efficient drug delivery strategy for prostate cancer treatment.

Keywords:  Prostate cancer; chemotherapy; inhibitor; lactoferrin; nanoparticle; pyruvate dehydrogenase kinase-1

DOI:  https://doi.org/10.1016/j.ejphar.2025.177300
STAR Protoc. 2025 Jan 30. pii: S2666-1667(25)00011-5. [Epub ahead of print]6(1): 103605

Protocol to identify small-molecule inhibitors against cancer drug resistance.

Juan Wei, She-Yu Zhang, Xue-Yuan Zhou, Yong Wei, Hao-Ran Jia, Qin Wu, Weihong Tan.

  Drug resistance has emerged as a critical challenge in clinical cancer treatment. Here, we present a high-throughput screening protocol to identify therapeutic small-molecule inhibitors against drug-resistant cancer cells. We detail the steps for constructing drug-resistant cell models, executing the chemical screening process, and performing data analysis and validation. This protocol facilitates the rapid identification of therapeutic strategies for different types of drug-resistant cancers and aids in studying mechanisms. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.

Keywords:  cancer; cell-based assays; high-throughput screening

DOI:  https://doi.org/10.1016/j.xpro.2025.103605
Nat Commun. 2025 Jan 30. 16(1): 1191

Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth.

Yanhan Jia, Sheng Wang, Sylvia Urban, Judith M Müller, Manuela Sum, Qing Wang, Helena Bauer, Uwe Schulte, Heike Rampelt, Nikolaus Pfanner, Katrin M Schüle, Axel Imhof, Ignasi Forné, Christopher Berlin, August Sigle, Christian Gratzke, Holger Greschik, Eric Metzger, Roland Schüle.

Prostate cancer (PCa) growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). In this study, we identify lysine methyltransferase (KMT)9 as a regulator of PDC activity. KMT9 is localized in mitochondria of PCa cells, but not in mitochondria of other tumor cell types. Mitochondrial KMT9 regulates PDC activity by monomethylation of its subunit dihydrolipoamide transacetylase (DLAT) at lysine 596. Depletion of KMT9 compromises PDC activity, de novo lipogenesis, and PCa cell proliferation, both in vitro and in a PCa mouse model. Finally, in human patients, levels of mitochondrial KMT9 and DLAT K596me1 correlate with Gleason grade. Together, we present a mechanism of PDC regulation and an example of a histone methyltransferase with nuclear and mitochondrial functions. The dependency of PCa cells on mitochondrial KMT9 allows to develop therapeutic strategies to selectively fight PCa.

DOI: https://doi.org/10.1038/s41467-025-56492-8
Mater Today Bio. 2025 Feb;30 101424

ECM-mimicking hydrogel models of human adipose tissue identify deregulated lipid metabolism in the prostate cancer-adipocyte crosstalk under antiandrogen therapy.

Agathe Bessot, Joan Röhl, Maria Emmerich, Anton Klotz, Akhilandeshwari Ravichandran, Christoph Meinert, David Waugh, Jacqui McGovern, Jenni Gunter, Nathalie Bock.

  Antiandrogen therapies are effectively used to treat advanced prostate cancer, but eventually cancer adaptation drives unresolved metastatic castration-resistant prostate cancer (mCRPC). Adipose tissue influences metabolic reprogramming in cancer and was proposed as a contributor to therapy resistance. Using extracellular matrix (ECM)-mimicking hydrogel coculture models of human adipocytes and prostate cancer cells, we show that adipocytes from subcutaneous or bone marrow fat have dissimilar responses under the antiandrogen Enzalutamide. We demonstrate that androgen receptor (AR)-dependent cancer cells (LNCaP) are more influenced by human adipocytes than AR-independent cells (C4-2B), with altered lipid metabolism and adipokine secretion. This response changes under Enzalutamide, with increased AR expression and adipogenic and lipogenic genes in cancer cells and decreased lipid content and gene dysregulation associated with insulin resistance in adipocytes. This is in line with the metabolic syndrome that men with mCRPC under Enzalutamide experience. The all-human, all-3D, models presented here provide a significant advance to dissect the role of fat in therapy response for mCRPC.

Keywords:  Adipose models; Androgen receptor; Bone marrow adipocytes; C4-2B cells; Enzalutamide; LNCaP cells; Lipids; Metabolism; Prostate cancer; SGBS cells; Seahorse assay

DOI:  https://doi.org/10.1016/j.mtbio.2024.101424
Cancers (Basel). 2025 Jan 18. pii: 306. [Epub ahead of print]17(2):

The Homeobox Transcription Factor NKX3.1 Displays an Oncogenic Role in Castration-Resistant Prostate Cancer Cells.

Audris Budreika, John T Phoenix, Raymond J Kostlan, Carleen D Deegan, Marina G Ferrari, Kristen S Young, Sean W Fanning, Steven Kregel.

   BACKGROUND/OBJECTIVES: Prostate cancer (PCa) is the second leading cause of cancer-related death in men. The increase in incidence rates of more advanced and aggressive forms of the disease year-to-year fuels urgency to find new therapeutic interventions and bolster already established ones. PCa is a uniquely targetable disease in that it is fueled by male hormones (androgens) that drive tumorigenesis via the androgen receptor or AR. Current standard-of-care therapies directly target AR and its aberrant signaling axis but resistance to these therapies commonly arises, and the mechanisms behind the onset of therapy-resistance are still elusive. Research has shown that even with resistant disease, AR remains the main driver of growth and survival of PCa, and AR target genes and cofactors may help mediate resistance to therapy. Here, we focused on a homeobox transcription factor that exhibits a close relationship with AR-NKX3.1. Though NKX3.1 is traditionally thought of as a tumor suppressor, it has been previously reported to promote cancer cell survival by cooperating with AR. The role of NKX3.1 as a tumor suppressor perhaps in early-stage disease also contradicts its profile as a diagnostic biomarker for advanced prostate cancer.
METHODS: We investigated the physical interaction between NKX3.1 and AR, a modulated NKX3.1 expression in prostate cancer cells via overexpression and knockdown and assayed subsequent viability and downstream target gene expression.
RESULTS: We find that the expression of NKX3.1 is maintained in advanced PCa, and it is often elevated because of aberrant AR activity. Transient knockdown experiments across various PCa cell line models reveal NKX3.1 expression is necessary for survival. Similarly, stable overexpression of NKX3.1 in PCa cell lines reveals an androgen insensitive phenotype, suggesting NKX3.1 is sufficient to promote growth in the absence of an AR ligand.
CONCLUSIONS: Our work provides new insight into NKX3.1's oncogenic influence on PCa and the molecular interplay of these transcription factors in models of late-stage prostate cancer.

Keywords:  NKX3.1; androgen receptor; castration resistance; enzalutamide; prostate cancer; therapy resistance

DOI:  https://doi.org/10.3390/cancers17020306
bioRxiv. 2025 Jan 15. pii: 2025.01.15.633193. [Epub ahead of print]

The histone modification regulator, SIN3, plays a role in the cellular response to changes in glycolytic flux.

Imad Soukar, Anindita Mitra, Linh Vo, Melanie Rofoo, Miriam L Greenberg, Lori A Pile.

Epigenetic regulation and metabolism are connected. Epigenetic regulators, like the SIN3 complex, affect the expression of a wide range of genes, including those encoding metabolic enzymes essential for central carbon metabolism. The idea that epigenetic modifiers can sense and respond to metabolic flux by regulating gene expression has long been proposed. In support of this cross-talk, we provide data linking SIN3 regulatory action on a subset of metabolic genes with the cellular response to changes in metabolic flux. Furthermore, we show that loss of SIN3 is linked to decreases in mitochondrial respiration and the cellular response to mitochondrial and glycolytic stress. Data presented here provide evidence that SIN3 is important for the cellular response to metabolic flux change.

DOI: https://doi.org/10.1101/2025.01.15.633193
Elife. 2025 Jan 29. pii: RP102852. [Epub ahead of print]13

PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response.

Ling Cheng, Ian Meliala, Yidi Kong, Jingyuan Chen, Christopher G Proud, Mikael Björklund.

  Mitochondrial dysfunction is involved in numerous diseases and the aging process. The integrated stress response (ISR) serves as a critical adaptation mechanism to a variety of stresses, including those originating from mitochondria. By utilizing mass spectrometry-based cellular thermal shift assay (MS-CETSA), we uncovered that phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitory protein (RKIP), is thermally stabilized by stresses which induce mitochondrial ISR. Depletion of PEBP1 impaired mitochondrial ISR activation by reducing eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and subsequent ISR gene expression, which was independent of PEBP1's role in inhibiting the RAF/MEK/ERK pathway. Consistently, overexpression of PEBP1 potentiated ISR activation by heme-regulated inhibitor (HRI) kinase, the principal eIF2α kinase in the mitochondrial ISR pathway. Real-time interaction analysis using luminescence complementation in live cells revealed an interaction between PEBP1 and eIF2α, which was disrupted by eIF2α S51 phosphorylation. These findings suggest a role for PEBP1 in amplifying mitochondrial stress signals, thereby facilitating an effective cellular response to mitochondrial dysfunction. Therefore, PEBP1 may be a potential therapeutic target for diseases associated with mitochondrial dysfunction.

Keywords:  PEBP1; cell biology; human; integrated stress response; mitochondrial dysfunction

DOI:  https://doi.org/10.7554/eLife.102852
Clinics (Sao Paulo). 2025 Jan 29. pii: S1807-5932(24)00247-3. [Epub ahead of print]80 100570

Mitochondrial DNA alterations in precision oncology: Emerging roles in diagnostics and therapeutics.

Alexis Germán Murillo Carrasco, Roger Chammas, Tatiane Katsue Furuya.

  Mitochondria are dynamic organelles essential for vital cellular functions, including ATP production, apoptosis regulation, and calcium homeostasis. Increasing research has highlighted the significance of mitochondrial DNA (mtDNA) content and alterations in the development and progression of various diseases, including cancer. The high mutation rate and vulnerability of mtDNA to damage make these alterations valuable biomarkers for cancer diagnosis, monitoring disease progression, detecting metastasis, and predicting treatment resistance across different tumor types. This review explores the emerging roles of mtDNA alterations in precision oncology, emphasizing their potential in theranostics. The authors explore the mechanisms by which mtDNA mutations contribute to tumorigenesis and therapy resistance, the impact of heteroplasmy in cancer biology, and the integration of mtDNA-based diagnostics with current therapeutic strategies. Additionally, the authors highlight the experimental tools and models currently used to investigate mtDNA alterations in cancer, including advanced sequencing technologies and animal models.

Keywords:  Biomarkers; Cancer; Mitochondrial genome; Mutations; Precision oncology

DOI:  https://doi.org/10.1016/j.clinsp.2024.100570
Sci Transl Med. 2025 Jan 29. 17(783): eadr0792

Correcting a pathogenic mitochondrial DNA mutation by base editing in mice.

Jose D Barrera-Paez, Sandra R Bacman, Till Balla, Derek Van Booven, Durga P Gannamedi, James B Stewart, Beverly Mok, David R Liu, David B Lombard, Anthony J Griswold, Danny D Nedialkova, Carlos T Moraes.

Primary mitochondrial disorders are most often caused by deleterious mutations in the mitochondrial DNA (mtDNA). Here, we used a mitochondrial DddA-derived cytosine base editor (DdCBE) to introduce a compensatory edit in a mouse model that carries the pathological mutation in the mitochondrial transfer RNA (tRNA) alanine (mt-tRNAAla) gene. Because the original m.5024C→T mutation (G→A in the mt-tRNAAla) destabilizes the mt-tRNAAla aminoacyl stem, we designed a compensatory m.5081G→A edit (C→T in the mt-tRNAAla) that could restore the secondary structure of the tRNAAla aminoacyl stem. For this, the DdCBE gene construct was initially tested in an m.5024C→T mutant cell line. The reduced mt-tRNAAla amounts in these cells were increased after editing up to 78% of the mtDNA. Then, DdCBE was packaged in recombinant adeno-associated virus 9 (AAV9) and intravenously administered by retro-orbital injections into mice. Expression of the transduced DdCBE was observed in the heart and skeletal muscle. Total mt-tRNAAla amounts were restored in heart and muscle by the m.5081G→A edit in a dose-dependent manner. Lactate amounts, which were increased in the heart, were also decreased in treated mice. However, the highest dose tested of AAV9-DdCBE also induced severe adverse effects in vivo because of the extensive mtDNA off-target editing that it generated. These results show that although DdCBE is a promising gene therapy tool for mitochondrial disorders, the doses of the therapeutic constructs must be carefully monitored to avoid deleterious off-target editing.

DOI: https://doi.org/10.1126/scitranslmed.adr0792
Sci Rep. 2025 Jan 29. 15(1): 3708

Mitochondrial dysfunction-driven AMPK-p53 axis activation underpins the anti-hepatocellular carcinoma effects of sulfane sulfur.

Xue Zheng, Yuhua Luo, Rui Huo, Yiwen Wang, Youbang Chen, Mianrong Chen, Qi Zhao, Kexin Li, Hanyi Zhang, Xiaotong Li, Xiang Li, Hui Zhang, Zaopeng He, Li Huang, Chun-Tao Yang.

  Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, notoriously refractory to conventional chemotherapy. Historically, sulfane sulfur-based compounds have been explored for the treatment of HCC, but their efficacy has been underwhelming. We recently reported a novel sulfane sulfur donor, PSCP, which exhibited improved chemical stability and structural malleability. This study aimed to investigate the effects of PSCP on HCC and elucidate the underlying mechanisms. We utilized bioinformatics algorithms for clustering, function enrichment, feature screening and survival analysis on proteomic data from the Cancer Proteome Atlas (CPTAC) and transcriptomic data from the Cancer Genome Atlas (TCGA). The impact of PSCP on HCC was assessed in vitro and in vivo, focusing on the expression and activity of p53 and AMP-activated protein kinase (AMPK), as well as mitochondrial function. The molecular target of PSCP was identified using Autodock, and binding interactions were visually analyzed. Sulfur metabolism was found to be reprogrammed in HCC, with downregulation of sulfur-related pathways correlating with poor patient prognosis. PSCP treatment significantly inhibited HCC tumor growth in an allograft model, reduced cell viability and proliferation, and induced apoptosis. PSCP potently increased p53 expression and induced AMPK phosphorylation in SNU398 HCC cells. AMPK suppression diminished PSCP-induced p53 upregulation. PSCP also impaired mitochondrial function by inhibiting mitochondrial respiratory complex I, with Ndus3 likely being the target of PSCP's action. Supplementation with ATP significantly countered PSCP-induced SNU398 cell injury. Our findings suggest that the reprogramming of sulfur-related metabolic pathways is pivotal in HCC. PSCP presents as a promising therapeutic strategy by activating the AMPK-p53 signaling axis.

Keywords:  AMPK; Hepatocellular carcinoma; Metabolic reprogramming; Mitochondrial complex; Sulfane sulfur; p53

DOI:  https://doi.org/10.1038/s41598-024-83530-0
Trends Cancer. 2025 Jan 28. pii: S2405-8033(25)00004-4. [Epub ahead of print]

Oncogenic competence: balancing mutations, cellular state, and microenvironment.

Lisa Pavinato, Arianna Baggiolini.

  Cancer development is driven by mutations, yet tumor-causing mutations only lead to tumor formation within specific cellular contexts. The reasons why certain mutations trigger malignant transformation in some contexts but not others remain often unclear. Both intrinsic and extrinsic factors play a key role in driving carcinogenesis by leading the cells toward a state of 'oncogenic competence'. This state is shaped by the transcriptional and epigenetic programs that define a specific cell in time and space. These programs arise from the interplay between genetic mutations, cellular lineage, differentiation state, and microenvironment. A deeper understanding of oncogenic competence is essential to uncover the mechanisms behind tumor initiation and, ultimately, advance the development of novel targeted therapies for cancer treatment and prevention.

Keywords:  cellular lineage; differentiation state; microenvironment; mutations; oncogenic competence

DOI:  https://doi.org/10.1016/j.trecan.2025.01.002
Histopathology. 2025 Jan 30.

Identification of intraductal-to-invasive spatial transitions in prostate cancer: proposal for a new unifying model on intraductal carcinogenesis.

Lucia L Rijstenberg, Hridya Harikumar, Esther I Verhoef, Thierry P P van den Bosch, Roselyne Choiniere, Martin E van Royen, Geert J L H van Leenders.

   AIMS: Intraductal carcinoma (IDC) is an independent pathological parameter for adverse prostate cancer (PCa) outcome. Although most IDC are believed to originate from retrograde spread of established PCa, rare IDC cases may represent precursor lesions. The actual transition areas between intraductal and invasive cancer, however, have not yet been identified. Our objective was to identify intraductal-invasive PCa transitions using 2- and 3-dimensional microscopy.
METHODS AND RESULTS: Seventy-five samples from 46 radical prostatectomies with PCa were immunohistochemically stained for basal cell keratins. In 35 samples, atypical glands that were indistinguishable from invasive adenocarcinoma (IAC) had focal 34BE12-positive basal cells. These IAC-like glands were present adjacent to IDC and prostatic intra-epithelial neoplasia (PIN) in 21 of 45 (46.7%) and 16 of 58 (27.6%) cases, respectively. Whole-mount confocal imaging of immunofluorescent Ker5/18 double-stained and cleared 1-mm-thick intact tissues revealed spatial continuity between IDC, IAC-like glands and IAC with a gradual loss of basal cells. In 24 of 35 (68.6%) samples more than one IAC-like focus (median 3.0) was present.
CONCLUSIONS: We identified areas of spatial transition between PIN, IDC and IAC, characterised by remnant basal cells in IAC-like glands. Based on the coexistence of IDC and PIN, the gradual loss of basal cells in IAC-like glands and IAC-like glands' multifocality, we propose a novel hypothesis on intraductal carcinogenesis, which we term 'repetitive invasion, precursor progression' (RIPP).

Keywords:  IDC; PTEN; basal cell; intraductal; prostate cancer; three‐dimensional; transition

DOI:  https://doi.org/10.1111/his.15414
Trends Endocrinol Metab. 2025 Jan 28. pii: S1043-2760(25)00003-7. [Epub ahead of print]

Subcellular mitochondrial heterogeneity enables opposing metabolic demands.

Brandon Chen, Yatrik M Shah, Costas A Lyssiotis.

  Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox demands within the same cell. They demonstrate that subcellular mitochondrial heterogeneity enables metabolic compartmentalization to permit concurrent oxidative ATP production and reductive proline biosynthesis.

Keywords:  metabolic compartmentalization; mitochondria dynamics; mitochondrial ultrastructure; organelle communication; proline metabolism

DOI:  https://doi.org/10.1016/j.tem.2025.01.003
Cell Biosci. 2025 Jan 24. 15(1): 9

Mitochondrial base editing: from principle, optimization to application.

Jinling Tang, Kunzhao Du.

  In recent years, mitochondrial DNA (mtDNA) base editing systems have emerged as bioengineering tools. DddA-derived cytosine base editors (DdCBEs) have been developed to specifically induce C-to-T conversion in mtDNA by the fusion of sequence-programmable transcription activator-like effector nucleases (TALENs) or zinc-finger nucleases (ZFNs), and split deaminase derived from interbacterial toxins. Similar to DdCBEs, mtDNA adenine base editors have been developed with the ability to introduce targeted A-to-G conversions into human mtDNA. In this review, we summarize the principles of mtDNA base-editing systems and elaborate on the evolution of different platforms of mtDNA base editors, including their deaminase replacement, engineering of DddAtox variants, structure optimization and editing outcomes. Finally, we highlight their applications in animal models and human embroys and discuss the future developmental direction and challenges of mtDNA base editors.

Keywords:  DdCBEs; Genetic engineering; Mitochondrial DNA; TALENs; mtDNA base editing

DOI:  https://doi.org/10.1186/s13578-025-01351-8
bioRxiv. 2025 Jan 13. pii: 2025.01.08.631986. [Epub ahead of print]

AR-V7 condensates drive androgen-independent transcription in castration resistant prostate cancer.

Shabnam Massah, Nicholas Pinette, Jane Foo, Sumanjit Datta, Maria Guo, Robert Bell, Anne Haegert, Tahsin Emirhan Tekoglu, Mailyn Terrado, Stanislav Volik, Stephane Le Bihan, Jennifer M Bui, Nathan A Lack, Martin E Gleave, Suhn K Rhie, Colin C Collins, Jörg Gsponer, Nada Lallous.

Biomolecular condensates organize cellular environments and regulate key processes such as transcription. We previously showed that full-length androgen receptor (AR-FL), a major oncogenic driver in prostate cancer (PCa), forms nuclear condensates upon androgen stimulation in androgen-sensitive PCa cells. Disrupting these condensates impairs AR-FL transcriptional activity, highlighting their functional importance. However, resistance to androgen deprivation therapy often leads to castration-resistant prostate cancer (CRPC), driven by constitutively active splice variants like AR variant 7 (AR-V7). The mechanisms underlying AR-V7's role in CRPC remain unclear. In this study, we characterized the condensate-forming ability of AR-V7 and compared its phase behavior with AR-FL across a spectrum of PCa models and in vitro conditions. Our findings indicate that cellular context can influence AR-V7's condensate-forming capacity. Unlike AR-FL, AR-V7 spontaneously forms condensates in the absence of androgen stimulation and functions independently of AR-FL in CRPC models. However, AR-V7 requires a higher concentration to form condensates, both in cellular contexts and in vitro . We further reveal that AR-V7 drives transcription via both condensate-dependent and condensate-independent mechanisms. Using an AR-V7 mutant incapable of forming condensates, while retaining nuclear localization and DNA-binding ability, we reveal that the condensate-dependent regime activates part of the oncogenic KRAS pathway in CRPC models. Genes under this condensate-dependent regime were found to harbor significantly higher numbers of AR-binding sites and exhibited boosted expression in response to AR-V7. These findings uncover a previously unrecognized role of AR-V7 condensate formation in driving oncogenic transcriptional programs and shed light on its unique contribution to CRPC progression.
Highlights: AR-V7 condensates form independently of both androgens and AR-FL in CRPC models.AR-V7 mediates condensate-dependent and independent transcriptionCondensate-dependent transcription enables boosted expression of oncogenic KRAS genesCondensate-dependent genes exhibit an exponential increase in expression, with a higher number of AR binding sites potentially playing a key role in their reliance on condensate formation.

DOI: https://doi.org/10.1101/2025.01.08.631986
Nat Rev Mol Cell Biol. 2025 Jan 27.

The roles of mitochondria in global and local intracellular calcium signalling.

Benjamín Cartes-Saavedra, Arijita Ghosh, György Hajnóczky.

Activation of Ca2+ channels in Ca2+ stores in organelles and the plasma membrane generates cytoplasmic calcium ([Ca2+]c) signals that control almost every aspect of cell function, including metabolism, vesicle fusion and contraction. Mitochondria have a high capacity for Ca2+ uptake and chelation, alongside efficient Ca2+ release mechanisms. Still, mitochondria do not store Ca2+ in a prolonged manner under physiological conditions and lack the capacity to generate global [Ca2+]c signals. However, mitochondria take up Ca2+ at high local [Ca2+]c signals that originate from neighbouring organelles, and also during sustained global elevations of [Ca2+]c. Accumulated Ca2+ in the mitochondria stimulates oxidative metabolism and upon return to the cytoplasm, can produce spatially confined rises in [Ca2+]c to exert control over processes that are sensitive to Ca2+. Thus, the mitochondrial handling of [Ca2+]c is of physiological relevance. Furthermore, dysregulation of mitochondrial Ca2+ handling can contribute to debilitating diseases. We discuss the mechanisms and relevance of mitochondria in local and global calcium signals.

DOI: https://doi.org/10.1038/s41580-024-00820-1
bioRxiv. 2025 Jan 15. pii: 2025.01.13.632822. [Epub ahead of print]

Optical metabolic imaging identifies metabolic shifts and mitochondria heterogeneity in POLG mutator macrophages.

Linghao Hu, A Phillip West, Alex J Walsh.

The polymerase gamma (POLG) gene mutation is associated with mitochondria and metabolism disorders, resulting in heterogeneous responses to immunological activation and posing challenges for mitochondrial disease therapy. Optical metabolic imaging captures the autofluorescent signal of two coenzymes, NADH and FAD, and offers a label-free approach to detect cellular metabolic phenotypes, track mitochondria morphology, and quantify metabolic heterogeneity. In this study, fluorescence lifetime imaging (FLIM) of NAD(P)H and FAD revealed that POLG mutator macrophages exhibit a decreased NAD(P)H lifetime, and optical redox ratio compared to the wild-type macrophages, indicating an increased dependence on glycolysis. FLIM revealed that both wild-type and POLG mutator macrophages switch to a decreased NAD(P)H τ 1 , and τ m after immune stimulation by Lipopolysaccharides (LPS). Furthermore, a bimodality index of subpopulation analysis identified heterogenous populations of POLG mutator macrophage responses under immune challenge by LPS. Moreover, to quantify the mitochondria variations in POLG mutator macrophages, a customized thresholding image processing pipeline was developed to segment mitochondria regions within each cell from the NADH image, allowing for the feature analysis of mitochondria clusters. Consequently, the wild-type macrophages exhibited a higher percentage of mitochondria-containing pixels and longer lengths of connected mitochondria, as compared with POLG mutated macrophages. Altogether, these results illustrate the potential of optical metabolic imaging for non-invasive detection and quantification of cellular metabolism, metabolic heterogeneity within cell populations, and intra-cellular mitochondria morphology differences in POLG mutator macrophages. Optical metabolic imaging will be valuable for studying POLG-mutation diseases and evaluating efficacy of potential therapies.

DOI: https://doi.org/10.1101/2025.01.13.632822