bims-mibica 2025-05-25 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–05–25
23 papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.
De novo serine biosynthesis is protective in mitochondrial disease.
Adenine nucleotide translocase 2 silencing promotes metabolic reprogramming in P19 embryonal carcinoma stem cells.
Mechanistic insights into Bcs1-mediated mitochondrial membrane translocation of the folded Rieske protein.
Mitochondrial fission factor drives an actionable metabolic vulnerability in multiple myeloma.
MTFP1 is a mitophagy receptor that operates in PINK1/PRKN-dependent mitophagy and promotes oral cancer cell survival.
A lncRNA-mediated metabolic rewiring of cell senescence.
S-adenosylmethionine metabolism shapes CD8+ T cell functions in colorectal cancer.
Mapping of Functional Metabolic Phenotypes in Acute Myeloid Leukemia.
Stepwise ATP translocation into the endoplasmic reticulum by human SLC35B1.
Silencing mitochondrial gene expression in living cells.
GPT2 mediates metabolic alterations in platinum-resistant ovarian cancer cells.
Unexpected Discovery of a Novel Triphenylphosphonium Alkylalcohol That Triggers Cancer Cell Death via Mitophagy and Ferroptosis.
Unravelling cysteine-deficiency-associated rapid weight loss.
Nanoinducer-mediated mitochondria-selective degradation enhances T cell immunotherapy against multiple cancers.
Dual Ribosome Profiling reveals metabolic limitations of cancer and stromal cells in the tumor microenvironment.
Image-guided targeting of mitochondrial metabolism sensitizes pediatric malignant rhabdoid tumors to low-dose radiotherapy.
Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure.
Recharacterization of the Tumor Suppressive Mechanism of RSL3 Identifies the Selenoproteome as a Druggable Pathway in Colorectal Cancer.
Antioxidant capacity of the iron-sulfur cluster assembly protein IscU2 is mediated by aspartate metabolism to promote tumor survival.
Targeting lipid metabolism in acute myeloid leukemia: biological insights and therapeutic opportunities.
Mitochondrial SLC25A10 promotes prostate cancer progression by inhibiting ferritinophagy.
Targeting mitochondrial ClpP: structural insights and therapeutic potential of ClpP agonists in cancer therapy.

Cancer Metab. 2025 May 19. 13(1): 22

Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.

Ayşegül Erdem, Séléna Kaye, Francesco Caligiore, Manuel Johanns, Fleur Leguay, Jan Jacob Schuringa, Keisuke Ito, Guido Bommer, Nick van Gastel.

   BACKGROUND: Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA), a key glycolytic enzyme converting pyruvate to lactate coupled with the recycling of NAD+.
METHODS: We compared the glycolytic activity of primary AML patient samples to protein levels of metabolic enzymes involved in central carbon metabolism including glycolysis, glutaminolysis and the tricarboxylic acid cycle. To evaluate the therapeutic potential of targeting glycolysis in AML, we treated AML primary patient samples and cell lines with pharmacological inhibitors of LDHA and monitored cell viability. Glycolytic activity and mitochondrial oxygen consumption were analyzed in AML patient samples and cell lines post-LDHA inhibition. Perturbations in global metabolite levels and redox balance upon LDHA inhibition in AML cells were determined by mass spectrometry, and ROS levels were measured by flow cytometry.
RESULTS: Among metabolic enzymes, we found that LDHA protein levels had the strongest positive correlation with glycolysis in AML patient cells. Blocking LDHA activity resulted in a strong growth inhibition and cell death induction in AML cell lines and primary patient samples, while healthy hematopoietic stem and progenitor cells remained unaffected. Investigation of the underlying mechanisms showed that LDHA inhibition reduces glycolytic activity, lowers levels of glycolytic intermediates, decreases the cellular NAD+ pool, boosts OXPHOS activity and increases ROS levels. This increase in ROS levels was however not linked to the observed AML cell death. Instead, we found that LDHA is essential to maintain a correct NAD+/NADH ratio in AML cells. Continuous intracellular NAD+ supplementation via overexpression of water-forming NADH oxidase from Lactobacillus brevis in AML cells effectively increased viable cell counts and prevented cell death upon LDHA inhibition.
CONCLUSIONS: Collectively, our results demonstrate that AML cells critically depend on LDHA to maintain an adequate NAD+/NADH balance in support of their abnormal glycolytic activity and biosynthetic demands, which cannot be compensated for by other cellular NAD+ recycling systems. These findings also highlight LDHA inhibition as a promising metabolic strategy to eradicate leukemic cells.

Keywords:  Acute myeloid leukemia; Cancer metabolism; Glycolysis; Lactate dehydrogenase A; NAD+ ; Redox balance

DOI:  https://doi.org/10.1186/s40170-025-00392-4
Cell Rep. 2025 May 15. pii: S2211-1247(25)00481-4. [Epub ahead of print]44(5): 115710

De novo serine biosynthesis is protective in mitochondrial disease.

Christopher B Jackson, Anastasiia Marmyleva, Geoffray Monteuuis, Ryan Awadhpersad, Takayuki Mito, Nicola Zamboni, Takashi Tatsuta, Amy E Vincent, Liya Wang, Nahid A Khan, Thomas Langer, Christopher J Carroll, Anu Suomalainen.

  The importance of serine as a metabolic regulator is well known for tumors and is also gaining attention in degenerative diseases. Recent data indicate that de novo serine biosynthesis is an integral component of the metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-driven de novo serine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles, and enhanced the mitochondrial integrated stress response (ISRmt) in vivo in skeletal muscle and in cultured cells. Our evidence indicates that de novo serine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activating de novo serine synthesis may protect against mitochondrial failure in skeletal muscle.

Keywords:  CP: Metabolism; de novo serine synthesis; mitochondrial disease; mitochondrial integrated stress response; mitochondrial translation; tissue specificity; treatment

DOI:  https://doi.org/10.1016/j.celrep.2025.115710
Biochim Biophys Acta Mol Basis Dis. 2025 May 15. pii: S0925-4439(25)00250-9. [Epub ahead of print]1871(6): 167902

Adenine nucleotide translocase 2 silencing promotes metabolic reprogramming in P19 embryonal carcinoma stem cells.

Gabriela L Oliveira, Jaromir Novak, Zuzana Nahacka, Petra Brisudova, Sandra I Mota, Jiri Neuzil, Paulo J Oliveira, Ricardo Marques.

  Although controversial, cancer stem cells (CSCs) are thought to be one tumor component, being characterized by their strong self-renewal and survival properties. Cancer cells, CSCs included, are thought to rely mostly on glycolysis, even in the presence of oxygen, which confers them adaptive advantages. Adenine nucleotide translocator 2 (ANT2), responsible for the exchange of ADP and ATP in the mitochondrial inner membrane, has been correlated with a higher glycolytic metabolism and is known to be overexpressed in cancer cells. Using P19 embryonal carcinoma stem cells, we inhibited ANT2 translation by using siRNA. ANT2 protein levels were shown to be overexpressed in P19 undifferentiated cells (P19SCs) when compared to their differentiated counterparts (P19dCs). Furthermore, we showed here that the OXPHOS machinery and mitochondrial membrane potential are compromised after ANT2 depletion, leading to a metabolic adaptation towards a less oxidative phenotype. Interestingly, hexokinase II levels were downregulated, which was also accompanied by decreased cell growth, and reduced ability to form spheroids. Our findings underscore ANT2 as a key regulator of metabolic remodeling and cell survival of cancer stem-like cells, suggesting its potential as a therapeutic target for controlling CSC-driven tumor progression.

Keywords:  ANT2; Hexokinase II; Metabolism; Mitochondria; Spheroids; cancer stem cells

DOI:  https://doi.org/10.1016/j.bbadis.2025.167902
EMBO J. 2025 May 23.

Mechanistic insights into Bcs1-mediated mitochondrial membrane translocation of the folded Rieske protein.

Cristian Rosales-Hernandez, Matthias Thoms, Otto Berninghausen, Thomas Becker, Roland Beckmann.

  A functional mitochondrial respiratory chain requires coordinated and tightly regulated assembly of mitochondrial- and nuclear-encoded subunits. For bc1 complex (complex III) assembly, the iron-sulfur protein Rip1 must first be imported into the mitochondrial matrix to fold and acquire its 2Fe-2S cluster, then translocated and inserted into the inner mitochondrial membrane (IM). This translocation of folded Rip1 is accomplished by Bcs1, an unusual heptameric AAA ATPase that couples ATP hydrolysis to translocation. However, the molecular and mechanistic details of Bcs1-mediated Rip1 translocation have remained elusive. Here, we provide structural and biochemical evidence on how Bcs1 alternates between conformational states to translocate Rip1 across the IM. Using cryo-electron microscopy (cryo-EM), we identified substrate-bound pre-translocation and pre-release states, revealing how electrostatic interactions promote Rip1 binding to Bcs1. An ATP-induced conformational switch of the Bcs1 heptamer facilitates Rip1 translocation between two distinct aqueous vestibules-one exposed to the matrix, the other to the intermembrane space-in an airlock-like mechanism. This would minimize disruption of the IM permeability barrier, which could otherwise lead to proton leakage and compromised mitochondrial energy conversion.

Keywords:  Bcs1; Cryo-EM; Folded Protein Translocation; Mitochondria; Rieske

DOI:  https://doi.org/10.1038/s44318-025-00459-4
Haematologica. 2025 May 22.

Mitochondrial fission factor drives an actionable metabolic vulnerability in multiple myeloma.

Maria Eugenia Gallo Cantafio, Ilenia Valentino, Roberta Torcasio, Ludovica Ganino, Claudia Veneziano, Pierpaolo Murfone, Maria Mesuraca, Ida Perrotta, Federico Tallarigo, Valter Agosti, Carmela De Marco, Teresa Pasqua, Cesarina Giallongo, Anna Rita Cappello, Marco Fiorillo, Massimo Gentile, Daniele Tibullo, Giuseppe Viglietto, Antonino Neri, Nicola Amodio.

Proliferating multiple myeloma (MM) cells in the bone marrow fluctuate across various metabolic states to resist cancer treatments. Herein, we investigate how mitochondrial dynamics, which controls mitochondrial fitness via coordinated fission and fusion events, shapes MM cell metabolism impacting growth, survival and drug sensitivity. We identify MFF (Mitochondrial Fission Factor), a pivotal driver of mitochondrial fragmentation, as being highly expressed in MM plasma cells bearing cytogenetic abnormalities predicting poor clinical outcome. In preclinical models, MFF selective inhibition via multiple RNAbased strategies (shRNAs, siRNAs or LNA gapmeR ASOs) reduces MM cell growth both in vitro and in vivo, enabling adaptive metabolic responses consistent with the induction of glycolysis and the inhibition of lactate-mediated OXPHOS. We also demonstrate that lactate supplementation, as well as clinically relevant drugs promoting lactate accumulation, such as AZD3965 and Syrosingopine, trigger MFF-dependent metabolic changes, enhancing the sensitivity of MM cells to strategies targeting mitochondrial fission. Finally, we highlight a novel lactate-MFF axis involved in proteasome inhibitor resistance, and show that combining AZD3965 or Syrosingopine with bortezomib results in synergistic anti-MM activity along with MFF down-regulation. Collectively, these data point to MFF-dependent mitochondrial fragmentation as a key metabolic hallmark of MM, providing a framework for the development of novel therapeutic strategies targeting mitochondrial dynamics and harnessing the metabolic plasticity of malignant plasma cells.

DOI: https://doi.org/10.3324/haematol.2025.287526
Autophagy Rep. 2023 ;2(1): 2267882

MTFP1 is a mitophagy receptor that operates in PINK1/PRKN-dependent mitophagy and promotes oral cancer cell survival.

Debasna P Panigrahi, Sujit K Bhutia.

  MTFP1 (mitochondrial fission process 1), an inner mitochondrial membrane protein, plays a crucial role in mitochondrial fission to maintain mitochondrial morphology. Our study found that MTFP1 contains a LIR (LC3-interacting region) to interact with MAP1LC3B (microtubule-associated protein 1 light chain 3 beta) and serves as a mitophagy receptor to eliminate damaged mitochondria. Interestingly, mutation of MTFP1 LIR motif (MTFP1mLIR) inhibits this interaction, decreasing mitophagy in oral cancer cells. Moreover, knockdown of PRKN (parkin RBR E3 ubiquitin protein ligase) or PINK1 (PTEN-induced kinase 1) abolished mitophagy in MTFP1-overexpressing oral cancer cells. In this setting, we observed that MTFP1mLIR-expressing cells display a decrease in TOMM20 (translocase of outer mitochondrial membrane 20) levels without affecting those of COX4 (cytochrome c oxidase subunit 4). In contrast, loss of PRKN or PINK1 caused inhibition of both TOMM20 and COX4 degradation in MTFP1mLIR-expressing cells exposed to cellular stress, suggesting that PRKN may activate the rupture of outer mitochondrial membrane in MTFP1-overexpressing cells for effective mitophagy. We also observed that MTFP1 is beneficial to oral cancer cell survival exposed to anticancer drugs, such as cisplatin, through mitophagy, since inhibition of MTFP1-dependent mitophagy induced cell death. Thus, targeting MTFP1-associated mitophagy could represent a strategy for oral cancer therapy. Abbreviations: BBC3/PUMA, BCL2 binding component 3; BCL2L13, BCL2 like 13; BINIP3L, BCL2 interacting protein 3 like; BNIP3, BCL2 interacting protein 3; CCCP, Carbonyl cyanide m-chlorophenylhydrazone; COX4, cytochrome c oxidase subunit 4; DNM1L, dynamin 1 like;FKBP8, FKBP prolyl isomerase 8; FIS1, fission, mitochondrial 1; FUNDC1, FUN14 domain containing 1; LIR, LC3 interacting region; MTFP1, mitochondrial fission process 1; PHB2, prohibitin 2; PI3K, Phosphatidylinositol 3-kinase; PRKN, Parkin RBR E3 ubiquitin protein ligase; PINK1, PTEN induced kinase 1; TOMM20, translocase of outer mitochondrial membrane 20.

Keywords:  Apoptosis; MTFP1; Mitochondrial fission; Mitophagy; PRKN

DOI:  https://doi.org/10.1080/27694127.2023.2267882
Cell Rep. 2025 May 21. pii: S2211-1247(25)00518-2. [Epub ahead of print]44(6): 115747

A lncRNA-mediated metabolic rewiring of cell senescence.

Elena Grossi, Francesco P Marchese, Jovanna González, Enrique Goñi, José Miguel Fernández-Justel, Alicia Amadoz, Nicolás Herranz, Leonor Puchades-Carrasco, Marta Montes, Maite Huarte.

  Despite not proliferating, senescent cells remain metabolically active to maintain the senescence program. However, the mechanisms behind this metabolic reprogramming are not well understood. We identify senescence-induced long noncoding RNA (sin-lncRNA), a previously uncharacterized long noncoding RNA (lncRNA), a key player in this response. While strongly activated in senescence by C/EBPβ, sin-lncRNA loss reinforces the senescence program by altering oxidative phosphorylation and rewiring mitochondrial metabolism. By interacting with dihydrolipoamide S-succinyltransferase (DLST), it facilitates its mitochondrial localization. Depletion of sin-lncRNA causes DLST nuclear translocation, leading to transcriptional changes in oxidative phosphorylation (OXPHOS) genes. While not expressed in highly proliferative cancer cells, it is strongly induced upon cisplatin-induced senescence. Depletion of sin-lncRNA in ovarian cancer cells reduces oxygen consumption and increases extracellular acidification, sensitizing cells to cisplatin treatment. Altogether, these results indicate that sin-lncRNA is specifically induced in senescence to maintain metabolic homeostasis, unveiling an RNA-dependent metabolic rewiring specific to senescent cells.

Keywords:  CP: Metabolism; CP: Molecular biology; RNA-binding proteins; lncRNA; metabolism; senescence; therapy resistance

DOI:  https://doi.org/10.1016/j.celrep.2025.115747
Cancer Metab. 2025 May 19. 13(1): 23

S-adenosylmethionine metabolism shapes CD8+ T cell functions in colorectal cancer.

Xiaohua Yang, Tianzhang Kou, Hongmiao Wang, Ji Zhu, Zheng-Jiang Zhu, Yuping Cai.

  Metabolite nutrients within the tumor microenvironment shape both tumor progression and immune cell functionality. It remains elusive how the metabolic interaction between T cells and tumor cells results in different anti-cancer immunotherapeutic responses. Here, we use untargeted metabolomics to investigate the metabolic heterogeneity in patients with colorectal cancer (CRC). Our analysis reveals enhanced S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism in microsatellite stable (MSS) CRC, a subtype known for its resistance to immunotherapy. Functional studies reveal that SAM and SAH enhance the initial activation and effector functions of CD8+ T cells. Instead, cancer cells outcompete CD8+ T cells for SAM and SAH availability to impair T cell survival. In vivo, SAM supplementation promotes T cell proliferation and reduces exhaustion of the tumor-infiltrating CD8+ T cells, thus suppressing tumor growth in tumor-bearing mice. This study uncovers the metabolic crosstalk between T cells and tumor cells, which drives the development of tumors resistant to immunotherapy.

Keywords:  CD8+ T cell function; Metabolite nutrients; Metabolomics; Microsatellite stable colorectal cancer; S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism

DOI:  https://doi.org/10.1186/s40170-025-00394-2
Cancer Med. 2025 May;14(10): e70950

Mapping of Functional Metabolic Phenotypes in Acute Myeloid Leukemia.

Sissel Dyrstad, Kimberley Joanne Hatfield, Endre Stigen, Marte Karen Brattås, Karl Johan Tronstad, Håkon Reikvam.

   BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis, particularly in older patients. AML is highly heterogeneous, influenced by various chromosomal, genetic, and epigenetic alterations.
METHODS: This study investigated the metabolic profiles of primary AML cells from 46 patients, focusing on mitochondrial respiration and glycolysis. We hypothesized that the metabolic profiles would reflect distinct disease characteristics. Using Seahorse technology, we measured the oxygen consumption rate (OCR) for mitochondrial respiration and the extracellular acidification rate (ECAR) for glycolysis.
RESULTS: Our results showed significant variability in metabolic activity, with some samples relying more on glycolysis than mitochondrial respiration. Mature AML cells (FAB M4/M5, CD34 negative) exhibited increased rates of both mitochondrial respiration and glycolysis, indicating distinct metabolic adaptations. Higher glycolytic activity was observed in patients with adverse cytogenetic abnormalities. However, no clear associations were found between metabolic profiles and mutations in FLT3 or NPM1.
CONCLUSION: These findings highlight the role of metabolic variability in AML and suggest that targeting specific metabolic pathways could offer therapeutic opportunities, particularly for subgroups like FAB M4/M5 with unique metabolic features. Further studies are needed to refine these therapeutic strategies for clinical application.

Keywords:  acute myeloid leukemias; glycolysis; metabolic phenotypes; metabolism

DOI:  https://doi.org/10.1002/cam4.70950
Nature. 2025 May 21.

Stepwise ATP translocation into the endoplasmic reticulum by human SLC35B1.

Ashutosh Gulati, Do-Hwan Ahn, Albert Suades, Yurie Hult, Gernot Wolf, So Iwata, Giulio Superti-Furga, Norimichi Nomura, David Drew.

ATP generated in the mitochondria is exported by an ADP/ATP carrier of the SLC25 family1. The endoplasmic reticulum (ER) cannot synthesize ATP but must import cytoplasmic ATP to energize protein folding, quality control and trafficking2,3. It was recently proposed that a member of the nucleotide sugar transporter family, termed SLC35B1 (also known as AXER), is not a nucleotide sugar transporter but a long-sought-after ER importer of ATP4. Here we report that human SLC35B1 does not bind nucleotide sugars but indeed executes strict ATP/ADP exchange with uptake kinetics consistent with the import of ATP into crude ER microsomes. A CRISPR-Cas9 cell-line knockout demonstrated that SLC35B1 clusters with the most essential SLC transporters for cell growth, consistent with its proposed physiological function. We have further determined seven cryogenic electron microscopy structures of human SLC35B1 in complex with an Fv fragment and either bound to an ATP analogue or ADP in all major conformations of the transport cycle. We observed that nucleotides were vertically repositioned up to approximately 6.5 Å during translocation while retaining key interactions with a flexible substrate-binding site. We conclude that SLC35B1 operates by a stepwise ATP translocation mechanism, which is a previously undescribed model for substrate translocation by an SLC transporter.

DOI: https://doi.org/10.1038/s41586-025-09069-w
Science. 2025 May 22. eadr3498

Silencing mitochondrial gene expression in living cells.

Luis Daniel Cruz-Zaragoza, Drishan Dahal, Mats Koschel, Angela Boshnakovska, Aiturgan Zheenbekova, Mehmet Yilmaz, Marcel Morgenstern, Jan-Niklas Dohrke, Julian Bender, Anusha Valpadashi, Kristine A Henningfeld, Silke Oeljeklaus, Laura Sophie Kremer, Mirjam Breuer, Oliver Urbach, Sven Dennerlein, Michael Lidschreiber, Stefan Jakobs, Bettina Warscheid, Peter Rehling.

Mitochondria fulfill central functions in metabolism and energy supply. They express their own genome, which encodes key subunits of the oxidative phosphorylation system. However, central mechanisms underlying mitochondrial gene expression remain enigmatic. A lack of suitable technologies to target mitochondrial protein synthesis in cells has limited experimental access. Here, we silenced the translation of specific mitochondrial mRNAs in living human cells by delivering synthetic peptide-morpholino chimeras. This approach allowed us to perform a comprehensive temporal monitoring of cellular responses. Our study provides insights into mitochondrial translation, its integration into cellular physiology, and provides a strategy to address mitochondrial gene expression in living cells. The approach can potentially be used to analyze mechanisms and pathophysiology of mitochondrial gene expression in a range of cellular model systems.

DOI: https://doi.org/10.1126/science.adr3498
Res Sq. 2025 May 09. pii: rs.3.rs-6480518. [Epub ahead of print]

GPT2 mediates metabolic alterations in platinum-resistant ovarian cancer cells.

Adriana Ponton-Almodovar, Mary Priyanka Udumula, Vrinda Khullar, Faraz Rashid, Ramandeep Rattan, Jamie J Bernard, Sachi Horibata.

  Metabolic reprogramming is recognized as a hallmark of cancer frequently associated with drug resistance in ovarian cancer. This is problematic as ovarian cancer is one of the deadliest gynecologic cancers with platinum resistance contributing to poor survival. However, the mechanism by which ovarian cancer cell metabolism contributes to platinum resistance is not well understood. Herein, metabolic signatures were determined in platinum-resistant ovarian cancer cell lines compared to the more platinum-sensitive parental lines. Chemoresistant ovarian cancer cells showed increased oxidative phosphorylation (OXPHOS) compared to chemosensitive cells. This was associated with elevated levels of glutaminolysis and tricarboxylic acid (TCA)-related metabolites supporting their dependence on OXPHOS. Key enzymes involved in glutaminolysis, specifically, glutamic-pyruvic transaminase 2 (GPT2), were upregulated in chemoresistant compared to chemosensitive cells. Interestingly, high GPT2 gene expression is associated with worse prognosis in ovarian cancer patients, adding translational relevance to the pre-clinical findings. GPT2 knockout in chemoresistant cells restored the metabolic phenotype to that of the sensitive cells and reversed drug resistance. These data suggest that GPT2 is a critical link between glutaminolysis, the TCA cycle, and OXPHOS and is a potential target to attenuate the increased metabolic activity associated with a chemoresistant phenotype.

Keywords:  GPT2; glutamine; metabolism; ovarian cancer

DOI:  https://doi.org/10.21203/rs.3.rs-6480518/v1
J Med Chem. 2025 May 20.

Unexpected Discovery of a Novel Triphenylphosphonium Alkylalcohol That Triggers Cancer Cell Death via Mitophagy and Ferroptosis.

Ding Huang, Maojie Zhang, Haibo Yan, Ligang Mei, Aiming Yang, Yun He, Kin Yip Tam, Shao-Lin Zhang.

Mitochondria-targeted delivery is a promising strategy in anticancer drug development. Triphenylphosphine cation (TPP+) is the most widely used mitochondrial-targeting carrier due to the elevated mitochondrial membrane potential (MMP) in cancer cells. Here, we report the serendipitous discovery of a mitochondrial-targeting carrier, compound 23, which exhibited potent anticancer activity (IC50 = 70 nM, HCC827) with minimal toxicity to normal cells. Compound 23 selectively accumulates in cancer cell mitochondria, induces MMP depolarization, and activates mitophagy via PINK1-Parkin pathway. It also disruptes mitochondrial functions, elevates ROS levels, and inhibits the xCT-GSH-GPX4 axis, leading to lipid peroxidation and ferroptotic cell death. In vivo, 23 significantly suppressed the growth of HCC827 xenograft tumors at 10 mg/kg. These findings support compound 23 as a highly selective and effective mitochondrial-targeting anticancer agent for further investigation.

DOI: https://doi.org/10.1021/acs.jmedchem.5c00701
Nature. 2025 May 21.

Unravelling cysteine-deficiency-associated rapid weight loss.

Alan Varghese, Ivan Gusarov, Begoña Gamallo-Lana, Daria Dolgonos, Yatin Mankan, Ilya Shamovsky, Mydia Phan, Rebecca Jones, Maria Gomez-Jenkins, Eileen White, Rui Wang, Drew R Jones, Thales Papagiannakopoulos, Michael E Pacold, Adam C Mar, Dan R Littman, Evgeny Nudler.

Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic3-6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype7-9. Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.

DOI: https://doi.org/10.1038/s41586-025-08996-y
Nat Nanotechnol. 2025 May 21.

Nanoinducer-mediated mitochondria-selective degradation enhances T cell immunotherapy against multiple cancers.

Xueting Pan, Zhihang Wang, Mixiao Tan, Ziying Fu, Guangjun Nie, Hai Wang.

Cancer immunotherapy utilizing cytotoxic T lymphocytes has demonstrated significant promise in clinical applications, but cancer immunosuppressive mechanisms hamper further progress in T cell immunotherapy. Here we show a correlation between cancer cell mitochondrial content and their resistance to immunotherapy. Observing that cancer cells with higher mitochondrial content show increased resistance to CD8+ T cells, we developed mitochondrial nanoinducers designed to selectively target and degrade mitochondria within autophagosomes. The direct degradation of mitochondria not only enhances the recognition and activation of CD8+ T cells but also increases the susceptibility of cancer cells to CD8+ T cell-mediated cytotoxicity. We demonstrated the feasibility and efficacy of this strategy in multiple in vitro and in vivo tumour therapeutic models. This nanoinducer, designed to manipulate cellular mitochondrial degradation, holds promise as a versatile tool for enhancing adoptive T cell therapy, CAR-T cell therapy and tumour-vaccine-based immunotherapy.

DOI: https://doi.org/10.1038/s41565-025-01909-0
Nat Commun. 2025 May 19. 16(1): 4652

Dual Ribosome Profiling reveals metabolic limitations of cancer and stromal cells in the tumor microenvironment.

Daniela Aviles-Huerta, Rossella Del Pizzo, Alexander Kowar, Ali Hyder Baig, Giuliana Palazzo, Ekaterina Stepanova, Cinthia Claudia Amaya Ramirez, Sara D'Agostino, Edoardo Ratto, Catarina Pechincha, Nora Siefert, Helena Engel, Shangce Du, Silvia Cadenas-De Miguel, Beiping Miao, Victor M Cruz-Vilchez, Karin Müller-Decker, Ilaria Elia, Chong Sun, Wilhelm Palm, Fabricio Loayza-Puch.

The tumor microenvironment (TME) influences cancer cell metabolism and survival. However, how immune and stromal cells respond to metabolic stress in vivo, and how nutrient limitations affect therapy, remains poorly understood. Here, we introduce Dual Ribosome Profiling (DualRP) to simultaneously monitor translation and ribosome stalling in multiple tumor cell populations. DualRP reveals that cancer-fibroblast interactions trigger an inflammatory program that reduces amino acid shortages during glucose starvation. In immunocompetent mice, we show that serine and glycine are essential for optimal T cell function and that their deficiency impairs T cell fitness. Importantly, immune checkpoint blockade therapy imposes amino acid restrictions specifically in T cells, demonstrating that therapies create distinct metabolic demands across TME cell types. By mapping codon-resolved ribosome stalling in a cell‑type‑specific manner, DualRP uncovers metabolic crosstalk that shapes translational programs. DualRP thus offers a powerful, innovative approach for dissecting tumor cell metabolic interplay and guiding combined metabolic-immunotherapeutic strategies.

DOI: https://doi.org/10.1038/s41467-025-59986-7
Sci Adv. 2025 May 23. 11(21): eadv2930

Image-guided targeting of mitochondrial metabolism sensitizes pediatric malignant rhabdoid tumors to low-dose radiotherapy.

Wenxi Xia, Esther Need, Carmine Schiavone, Neetu Singh, Jiemin Huang, Matthew Goff, Joseph Cave, David L Gillespie, Randy L Jensen, Mark D Pagel, Prashant Dogra, Sixiang Shi, Shreya Goel.

Tumor hypoxia leads to radioresistance and markedly worse clinical outcomes for pediatric malignant rhabdoid tumors (MRTs). Our transcriptomics and bioenergetic profiling data reveal that mitochondrial oxidative phosphorylation is a metabolic vulnerability of MRT and can be exploited to overcome consumptive hypoxia by repurposing an FDA-approved antimalarial drug, atovaquone (AVO). We then establish the utility of oxygen-enhanced-multispectral optoacoustic tomography, a label-free, ionizing radiation-free imaging modality, to visualize and quantify spatiotemporal changes in tumor hypoxia in response to AVO. We show a potent but transient increase in tumor oxygenation upon AVO treatment that results in complete elimination of tumors in all tested mice when combined with 10-gray radiotherapy, a dose several times lower than the current clinic standard. Last, we use translational mathematical modeling for systematic evaluation of dosing regimens, administration timing, and therapeutic synergy in a virtual patient cohort. Together, our work establishes a framework for safe and pediatric patient-friendly image-guided metabolic radiosensitization of rhabdoid tumors.

DOI: https://doi.org/10.1126/sciadv.adv2930
Nat Cancer. 2025 May 20.

Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure.

Helen Carrasco Hope, Jana de Sostoa, Pierpaolo Ginefra, Massimo Andreatta, Yi-Hsuan Chiang, Catherine Ronet, Christine Pich-Bavastro, Jesús Corria Osorio, François Kuonen, Johan Auwerx, Patrizia D'Amelio, Ping-Chih Ho, Santiago J Carmona, George Coukos, Denis Migliorini, Nicola Vannini.

Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy. Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies.

DOI: https://doi.org/10.1038/s43018-025-00982-7
Cancer Res. 2025 May 20.

Recharacterization of the Tumor Suppressive Mechanism of RSL3 Identifies the Selenoproteome as a Druggable Pathway in Colorectal Cancer.

Stephen L DeAngelo, Liang Zhao, Sofia Dziechciarz, Myungsun Shin, Sumeet Solanki, Andrii Balia, Marwa O El-Derany, Cristina Castillo, Yao Qin, Nupur K Das, Hannah N Bell, Joao A Paulo, Yuezhong Zhang, Nicholas J Rossiter, Elizabeth C McCulla, Jianping He, Indrani Talukder, Billy Wai-Lung Ng, Zachary T Schafer, Nouri Neamati, Joseph D Mancias, Markos Koutmos, Yatrik M Shah.

Ferroptosis is a non-apoptotic form of cell death driven by iron-dependent lipid peroxide accumulation. Colorectal cancer (CRC) cells feature elevated intracellular iron and reactive oxygen species (ROS) that heighten ferroptosis sensitivity. The ferroptosis inducer (S)-RSL3 ([1S,3R]-RSL3) is widely described as a selective inhibitor of the selenocysteine-containing enzyme (selenoprotein) glutathione peroxidase 4 (GPX4), which detoxifies lipid peroxides utilizing glutathione. However, through chemical controls utilizing the (R) stereoisomer of RSL3 ([1R,3R]-RSL3) that does not bind GPX4, combined with inducible genetic knockdowns of GPX4 in CRC cell lines, we revealed here that GPX4 dependency does not always align with (S)-RSL3 sensitivity, questioning the current characterization of GPX4 as the primary target of (S)-RSL3. Affinity pull-down mass spectrometry with modified (S)-RSL3 probes identified multiple selenoprotein targets, indicating broad selenoprotein inhibition. Further investigation of the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC showed that the selenoprotein inhibitor auranofin, an FDA-approved gold-salt, chemically induced oxidative cell death and ferroptosis in CRC models in vitro and in vivo. Similarly, genetic perturbation of ALKBH8, a tRNA-selenocysteine methyltransferase required for selenoprotein translation, suppressed CRC growth. In summary, these findings recharacterize the mechanism of (S)-RSL3 beyond GPX4 inhibition and establish selenoproteome disruption as a CRC therapeutic strategy.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3478
J Biol Chem. 2025 May 14. pii: S0021-9258(25)02084-8. [Epub ahead of print] 110234

Antioxidant capacity of the iron-sulfur cluster assembly protein IscU2 is mediated by aspartate metabolism to promote tumor survival.

Xunjun Yang, Na Liang, Dandan Liu, Jimei Yan, Xiali Yang, Jinya Lv, Saijun Xiao, Xiujuan Wei, Xuyang Chen, Zhengquan Yang, Shanying Gui, Liqin Jin, Shihui Yu, Jianxin Lyu, Xiaojun Ren.

  Environmental nutrient levels affect cancer cell metabolism, activating adaptive mechanisms in cancer cells to deal with nutrient stress. However, it remains unclear how tumor cells sustain survival under nutrient-stress circumstances through metabolic reprogramming. Our study focused on nutrient deficiency-induced oxidative damage, revealing that increased expression of the iron-sulfur (Fe-S) cluster assembly protein, IscU2, is essential for the survival of pancreatic ductal adenocarcinoma (PDAC) cells in glucose-deficient conditions. Glucose deficiency induces IscU2 expression via the activation of the AMPK pathway, allowing IscU2 to exhibit antioxidant properties that are absent under glucose-sufficient conditions. Upregulated IscU2 stimulates aspartate synthesis by bolstering mitochondrial metabolism, including respiration and the tricarboxylic acid cycle, in a Fe-S cluster-dependent manner. Notably, oxidative stress and apoptosis induced by IscU2 depletion in glucose-deficient PDAC cells can be restored by aspartate-mediated NADPH production. These findings highlight the importance of IscU2 in PDAC cell metabolism and its essential function in supporting cell survival under nutrient-deficient conditions.

Keywords:  Aspartate; Fe-S clusters; IscU2; PDAC; oxidative stress

DOI:  https://doi.org/10.1016/j.jbc.2025.110234
Leukemia. 2025 May 22.

Targeting lipid metabolism in acute myeloid leukemia: biological insights and therapeutic opportunities.

Vilma Dembitz, Sophie C James, Paolo Gallipoli.

Metabolic rewiring is a hallmark of malignant transformation in leukemic cells and the potential offered by its therapeutic targeting has garnered significant attention. The development of clinically relevant metabolic targeted therapies in acute myeloid leukemia (AML) has mostly focused on targeting mitochondrial energy production, but progress has been hampered by generalized toxicities. An alternative strategy is to shift the focus from targeting energy production to targeting more specialized metabolic functions, such as energy storage, the regulation of oxidative stress and availability of cofactors needed for the function of specific metabolic reactions. Lipid metabolism plays a role in many of these metabolic functions and its importance in AML maintenance and response to therapy is being increasingly recognized but needs to be adequately interpreted in the context of its interaction with the microenvironment, particularly the adipose niche. In this review, we provide an overview of our current understanding of AML cellular metabolic dependencies on fatty acid and lipid metabolism and discuss their relevance in the context of functional interactions with adipocytes. We highlight unresolved questions about how to best target lipid metabolism and suggest approaches needed to fully understand the interplay between malignant cells and their niche in the context of metabolic dependencies.

DOI: https://doi.org/10.1038/s41375-025-02645-z
Cell Death Discov. 2025 May 20. 11(1): 242

Mitochondrial SLC25A10 promotes prostate cancer progression by inhibiting ferritinophagy.

Guopeng Yu, Kailei Chen, Bin Xu, Qi Cao.

Prostate cancer (PCa) is one of the most common malignancies in men worldwide and remains a major cause of cancer-related mortality. Despite advances in early diagnosis and treatment, a significant proportion of patients eventually progress to advanced or treatment-resistant disease, highlighting the urgent need for novel therapeutic targets and strategies. In this study, we systematically analyzed transcriptomic data from The Cancer Genome Atlas (TCGA) and performed Venn analysis to identify genes associated with PCa progression. Among the intersecting candidates, SLC25A10, a mitochondrial carrier protein, emerged as a potential key regulator of ferroptosis. Further expression analyses revealed that SLC25A10 is significantly upregulated in PCa tissues and correlates with poor prognosis. Functional gain- and loss-of-function experiments demonstrated that SLC25A10 promotes tumor cell proliferation, migration, and invasion, while exacerbating mitochondrial dysfunction and impairing autophagic flux. Mechanistically, mass spectrometry and co-immunoprecipitation (Co-IP) assays confirmed a direct interaction between SLC25A10 and P62, implicating this interaction in the suppression of autophagy and the promotion of ferroptotic vulnerability. Moreover, disruption of the SLC25A10/p62/KEAP1/Nrf2 signaling axis reactivated autophagy and inhibited PCa cell growth. Collectively, our findings uncover a novel oncogenic role of SLC25A10 in PCa and suggest that targeting the SLC25A10-mediated regulatory network may offer a promising therapeutic avenue for patients with advanced prostate cancer.

DOI: https://doi.org/10.1038/s41420-025-02528-3
Oncol Rev. 2025 ;19 1567860

Targeting mitochondrial ClpP: structural insights and therapeutic potential of ClpP agonists in cancer therapy.

Mowei Kong, Yang Yu, Shuai Shao, Chunxiang Zhang.

  Mitochondrial "powerhouses" play a central function in cellular metabolism and energy generation. Their dysregulation is directly correlated with a myriad of diseases, among them cancer. The serine protease ClpP, accompanied by its cochaperone ClpX, is a principal homeostatic regulator in mitochondrial function by degrading aberrant proteins in order to preserve mitochondrial integrity. Recently, evidence suggests ClpP is overexpressed in many cancer cells and, as such, is an appealing target for drug therapy. In this review, current information about the structure, physiological function, and therapeutic promise of mitochondrial ClpP in oncology is summarized. We provide an overview about the mechanistic rationale behind ClpP agonists as novel anticancer drugs, their regulation in cell signal transduction, and the major challenge in the creation of small molecules that specifically activate human ClpP, but not bacterial ClpP. The review highlights the therapeutic promise of ClpP agonists as a novel approach in cancer therapy, presenting their prospective potential for cancer treatment by focusing on an unexplored mitochondrial target.

Keywords:  ClpP protease; cancer biology tumor targeting; cellular signaling; mitochondrial dysfunction; targeted cancer therapy

DOI:  https://doi.org/10.3389/or.2025.1567860