bims-mibica 2025-02-09 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–02–09
29 papers selected by
Kelsey Fisher-Wellman, Wake Forest University

CRBN deletion enhances mitochondrial metabolism by stimulating mitochondrial calcium accumulation in non-small cell lung cancer.
Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma.
Structural basis for substrate binding, catalysis and inhibition of cancer target mitochondrial creatine kinase by a covalent inhibitor.
An avoidance segment resolves a lethal nuclear-mitochondrial targeting conflict during ribosome assembly.
BCL-2 inhibitors in hematological malignancies: biomarkers that predict response and management strategies.
Mitochondria-targeting of oxidative phosphorylation inhibitors to alleviate hypoxia and enhance anticancer treatment efficacy.
PSTK inhibition activates cGAS-STING, precipitating ferroptotic cell death in leukemic stem cells.
Mitochondrial heterogeneity: subpopulations with distinct metabolic activities.
CREB1-BCL2 drives mitochondrial resilience in RAS GAP-dependent breast cancer chemoresistance.
Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
Mitochondrial-ER Contact Sites and Tethers Influence the Biosynthesis and Function of Coenzyme Q.
Acidosis overrides molecular heterogeneity to shape therapeutically targetable metabolic phenotypes in colon cancers.
Activating AMPK improves pathological phenotypes due to mtDNA depletion.
Mitochondrial abnormalities as a target of intervention in acute myeloid leukemia.
Identification of mitochondrial carrier homolog 2 as an important therapeutic target of castration-resistant prostate cancer.
Metformin in overcoming enzalutamide resistance in castration-resistant prostate cancer.
GUK1 activation is a metabolic liability in lung cancer.
Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
Rhodoquinone carries electrons in the mammalian electron transport chain.
Deciphering molecular specificity in MCL-1/BAK interaction and its implications for designing potent MCL-1 inhibitors.
The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism.
CRIP1 inhibits cutaneous melanoma progression through TFAM-mediated mitochondrial biogenesis.
Venetoclax plus Daunorubicin and Cytarabine for Newly Diagnosed Acute Myeloid Leukemia: Results of a Phase 1b Study.
ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3.
Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis.
DNA repair pathways in the mitochondria.
Comprehensive analysis of mitochondrial solute carrier family 25 (SLC25) identifies member 19 (SLC25A19) as a regulatory factor in hepatocellular carcinoma.
Intranuclear TCA and mitochondrial overload: the nascent sprout of tumors metabolism.
Succinate supplementation alleviates liver cancer by inhibiting the FN1/SQLE axis-mediated cholesterol biosynthesis.

Life Sci. 2025 Feb 04. pii: S0024-3205(25)00077-3. [Epub ahead of print] 123444

CRBN deletion enhances mitochondrial metabolism by stimulating mitochondrial calcium accumulation in non-small cell lung cancer.

Seungheon Shin, Steve K Cho.

  CRBN (Cereblon), a substrate receptor of the CRL4 (Cullin4-RING E3 ubiquitin ligase) complex, has emerged as a key player in cancer metabolism. While its role in influencing metabolic phenotypes has been suggested, the precise functions of CRBN in cellular metabolism and cancer progression remain underexplored. This study investigates the impact of CRBN downregulation in lung cancer, focusing on mitochondrial metabolism and cellular functions. Data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) revealed significant reductions in CRBN expression at both mRNA and protein levels in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This downregulation was further confirmed in most lung cancer cell lines examined. Functional analyses of CRBN knockout (KO) cells revealed substantial alterations in mitochondrial metabolism, including enhanced oxidative phosphorylation, increased mitochondrial membrane potential (ΔΨm), and elevated production of mitochondrial reactive oxygen species (mROS). CRBN deficiency also accelerated tricarboxylic acid (TCA) cycle flux and increased mitochondrial calcium accumulation, contributing to elevated ΔΨm and potentially compromised mitochondrial integrity. Additionally, CRBN KO cells demonstrated increased cell migration, which could be mitigated by inhibiting mitochondrial calcium import. These findings suggest that CRBN plays a pivotal role in regulating mitochondrial function and metabolic activity in non-small cell lung cancer. The loss of CRBN enhances mitochondrial metabolism and contributes to increased cancer cell migration, providing new insights into the metabolic adaptations associated with CRBN deficiency in cancer progression.

Keywords:  Cereblon; Lung cancer; Mitochondrial activity; Mitochondrial calcium accumulation

DOI:  https://doi.org/10.1016/j.lfs.2025.123444
Nat Metab. 2025 Feb 06.

Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma.

Jiao Li, Kaimeng Huang, Meha Thakur, Fiona McBride, Ananthan Sadagopan, Daniel S Gallant, Prateek Khanna, Yasmin Nabil Laimon, Bingchen Li, Razan Mohanna, Maolin Ge, Cary N Weiss, Mingkee Achom, Qingru Xu, Sayed Matar, Gwo-Shu Mary Lee, Kun Huang, Miao Gui, Chin-Lee Wu, Kristine M Cornejo, Toni K Choueiri, Birgitta A Ryback, Sabina Signoretti, Liron Bar-Peled, Srinivas R Viswanathan.

Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic nature of most other renal cancers. Reliance on this TFE3 fusion-driven OXPHOS programme renders tRCCs vulnerable to NADH reductive stress, a metabolic stress induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, including EGLN1, which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1α and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability for OXPHOS-dependent tRCC cells. Our study defines tRCC as being dependent on a mitochondria-centred metabolic programme driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy in this cancer.

DOI: https://doi.org/10.1038/s42255-025-01218-9
Structure. 2025 Jan 27. pii: S0969-2126(25)00008-5. [Epub ahead of print]

Structural basis for substrate binding, catalysis and inhibition of cancer target mitochondrial creatine kinase by a covalent inhibitor.

Merve Demir, Laura Koepping, Ya Li, Lynn Fujimoto, Andrey Bobkov, Jianhua Zhao, Taro Hitosugi, Eduard Sergienko.

  Mitochondrial creatine kinases (MtCKs) are key players in maintaining energy homeostasis in cells that work with cytosolic creatine kinases for energy transport from mitochondria to cytoplasm. The inhibition of breast cancer growth by cyclocreatine targeting CKs indicates dependence of cancer cells on the "energy shuttle" for cell growth and survival. Hence, understanding key mechanistic features of creatine kinases and their inhibition plays an important role in the development of cancer therapeutics. Herein, we present mutational and structural investigations on understudied ubiquitous MtCK that showed closure of the loop comprising His61 is specific to and relies on creatine binding and mechanism of phosphoryl transfer depends on electrostatics of active site. We demonstrate that previously identified pan-CK covalent inhibitor CKi inhibit breast cancer cell proliferation; however, our biochemical and structural data indicated that inhibition by CKi is highly dependent on covalent link formation and conformational changes upon creatine binding are not observed.

Keywords:  Her2+ breast cancer; Mitochondrial creatine kinase; chemical probes; cryo-EM; energy homeostasis; enzyme mechanism; steady-state kinetics

DOI:  https://doi.org/10.1016/j.str.2025.01.008
Nat Cell Biol. 2025 Jan 31.

An avoidance segment resolves a lethal nuclear-mitochondrial targeting conflict during ribosome assembly.

Michaela Oborská-Oplová, Alexander Gregor Geiger, Erich Michel, Purnima Klingauf-Nerurkar, Sven Dennerlein, Yury S Bykov, Simona Amodeo, André Schneider, Maya Schuldiner, Peter Rehling, Vikram Govind Panse.

The correct sorting of nascent ribosomal proteins from the cytoplasm to the nucleus or to mitochondria for ribosome production poses a logistical challenge for cellular targeting pathways. Here we report the discovery of a conserved mitochondrial avoidance segment (MAS) within the cytosolic ribosomal protein uS5 that resolves an evolutionary lethal conflict between the nuclear and mitochondrial targeting machinery. MAS removal mistargets uS5 to the mitochondrial matrix and disrupts the assembly of the cytosolic ribosome. The resulting lethality can be rescued by impairing mitochondrial import. We show that MAS triages nuclear targeting by disabling a cryptic mitochondrial targeting activity within uS5 and thereby prevents fatal capture by mitochondria. Our findings identify MAS as an essential acquisition by the primordial eukaryote that reinforced organelle targeting fidelity while developing an endosymbiotic relationship with its mitochondrial progenitor.

DOI: https://doi.org/10.1038/s41556-024-01588-4
Front Oncol. 2024 ;14 1501950

BCL-2 inhibitors in hematological malignancies: biomarkers that predict response and management strategies.

Mariam Markouli, Maria N Pagoni, Panagiotis Diamantopoulos.

  Apoptosis is an essential characteristic of cancer and its dysregular promotes tumor growth, clonal evolution, and treatment resistance. B-cell lymphoma-2 (BCL-2) protein family members are key to the intrinsic, mitochondrial apoptotic pathway. The inhibition of the BCL-2 family pro-survival proteins, which are frequently overexpressed in B-cell malignancies and pose a fundamental carcinogenic mechanism has been proposed as a promising therapeutic option, with venetoclax (ABT-199) being the first FDA-approved BCL-2 inhibitor. Unfortunately, although BCL-2 inhibition has shown remarkable results in a range of B-cell lymphoid cancers as well as acute myeloid leukemia (AML), the development of resistance significantly reduces response rates in specific tumor subtypes. In this article, we explain the role of BCL-2 family proteins in apoptosis and their mechanism of action that justifies their inhibition as a potential treatment target in B-cell malignancies, including chronic lymphocytic leukemia, multiple myeloma, B-cell lymphomas, but also AML. We further analyze the tumor characteristics that result in the development of intrinsic or inherited resistance to BCL-2 inhibitors. Finally, we focus on the biomarkers that can be used to predict responses to treatment in the name of personalized medicine, with the goal of exploring alternative strategies to overcome resistance.

Keywords:  BAX/BAK; Bcl-2 inhibitors; DLBCL; acute myeloid leukemia; apoptosis; chronic lymphocytic leukemia; venetoclax

DOI:  https://doi.org/10.3389/fonc.2024.1501950
Clin Cancer Res. 2025 Feb 03.

Mitochondria-targeting of oxidative phosphorylation inhibitors to alleviate hypoxia and enhance anticancer treatment efficacy.

Anne P M Beerkens, Sandra Heskamp, Flavia V Reinema, Gosse J Adema, Paul N Span, Johan Bussink.

Hypoxia is a common feature of solid tumors and is associated with a poor response to anticancer therapies. Hypoxia also induces metabolic changes, such as a switch to glycolysis. This glycolytic switch causes acidification of the tumor microenvironment (TME), thereby attenuating the anticancer immune response. A promising therapeutic strategy to reduce hypoxia and thereby sensitize tumors to irradiation and/or antitumor immune responses is pharmacological inhibition of oxidative phosphorylation (OXPHOS). Several OXPHOS inhibitors (OXPHOSi) have been tested in clinical trials. However, moderate responses and/or substantial toxicity has hampered clinical implementation. OXPHOSi tested in clinical trials inhibit the oxidative metabolism in tumor cells as well as healthy cells. Therefore, new strategies are needed to improve the efficacy of OXPHOSi while minimizing side effects. To enhance the therapeutic window, available OXPHOSi have, for instance, been conjugated to triphenylphosphonium (TPP+) to preferentially target the mitochondria of cancer cells, resulting in increased tumor uptake compared to healthy cells, as cancer cells have a higher mitochondrial membrane potential. However, OXPHOS inhibition also induces reactive oxygen species (ROS), and subsequent antioxidant responses, which may influence the efficacy of therapies, such as platinum-based chemotherapy and radiotherapy. Here, we review the limitations of the clinically tested OXPHOSi metformin, atovaquone, tamoxifen, BAY 87-2243 and IACS-010759 and the potential of mito-targeted OXPHOSi and their influence on ROS production. Furthermore, the effect of the mitochondria-targeting moiety TPP+ on mitochondria is discussed as this affects mitochondrial bioenergetics.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-3296
Blood. 2025 Feb 05. pii: blood.2024026040. [Epub ahead of print]

PSTK inhibition activates cGAS-STING, precipitating ferroptotic cell death in leukemic stem cells.

Lingli He, Ting Zhao, Wei Zhong Leong, Azeem Sharda, Christina Mayerhofer, Shenglin Mei, Gracia M Bonilla, Juan Bautista Menendez-Gonzalez, Karin Gustafsson, Tsuyoshi Fukushima, Trine A Kristiansen, Ji-Won Lee, Yanxin Xu, Lei Chen, Jun Xia, Luis Angel Orozco, Bogdan Budnik, Ruslan Sadreyev, Zhixun Dou, David B Sykes, David T Scadden.

Differentiation arrest and dependence on oxidative metabolism are features shared among genetically diverse acute myeloid leukemias (AML). A phenotypic CRISPR-Cas9 screen in AML identified dependence on phosphoseryl-tRNA kinase (PSTK), an atypical kinase required for the biosynthesis of all selenoproteins. In vivo, PSTK inhibition (PSTKi) impaired AML cell growth and leukemic stem cell self-renewal. Notably, timed pharmacologic PSTKi effectively targeted chemo-resistant AML in murine and patient-derived xenograft models, showing selectivity for malignant cells over normal hematopoietic cells. Mechanistically, PSTKi-induced reactive oxygen species (ROS) triggering mitochondrial DNA release into the cytosol and activated cGAS-STING. This activation in turn disrupted iron metabolism augmenting ROS generation and amplifying ferroptosis. Together, these findings reveal a self-reinforcing PSTK-cGAS-STING-ROS loop culminating in an oxidative crisis and ferroptotic cell death of leukemic stem cells. The data highlight the potential for augmenting standard cancer chemotherapies using timed metabolic intervention to eliminate chemopersisting cells and thereby impede disease relapse.

DOI: https://doi.org/10.1182/blood.2024026040
Signal Transduct Target Ther. 2025 Feb 07. 10(1): 36

Mitochondrial heterogeneity: subpopulations with distinct metabolic activities.

Fabian den Brave, Swadha Mishra, Thomas Becker.

DOI: https://doi.org/10.1038/s41392-025-02130-0
Oncogene. 2025 Jan 31.

CREB1-BCL2 drives mitochondrial resilience in RAS GAP-dependent breast cancer chemoresistance.

Ki-Fong Man, Omeed Darweesh, Jinghui Hong, Alexandra Thompson, Charlotte O'Connor, Chiara Bonaldo, Mark N Melkonyan, Mo Sun, Rajnikant Patel, Leif W Ellisen, Tim Robinson, Dong Song, Siang-Boon Koh.

Triple-negative breast cancer (TNBC) is an aggressive and heterogenous breast cancer subtype. RASAL2 is a RAS GTPase-activating protein (GAP) that has been associated with platinum resistance in TNBC, but the underlying mechanism is unknown. Here, we show that RASAL2 is enriched following neoadjuvant chemotherapy in TNBC patients. This enrichment is specific to the tumour compartment compared to adjacent normal tissues, suggesting that RASAL2 upregulation is tumour-selective. Analyses based on 2D/3D cultures and patient-derived xenograft models reveal that RASAL2 confers cross-resistance to common DNA-damaging chemotherapies other than platinum. Mechanistically, we found that apoptotic signalling is significantly downregulated upon RASAL2 expression. This feature is characterised by substantial alterations in the expression of anti-versus pro-apoptotic factors, pointing to heterogeneous mechanisms. In particular, RASAL2 upregulates BCL2 via activation of the oncogenic transcription co-factor YAP. CREB1, a YAP-interacting protein, was identified as the common transcription factor that binds to the promoter regions of RASAL2 and BCL2, driving their collective expression. A subset of RASAL2 colocalises with BCL2 subcellularly. Both proteins decorate mitochondria, where the high levels of mitochondrial RASAL2-induced BCL2 expression render the organelles refractory to apoptosis. Accordingly, mitochondrial outer membrane permeabilisation assay using live mitochondria from RASAL2-high/chemoresistant tumour cells demonstrated attenuated release of death signal, cytochrome c, when exposed to pro-apoptotic factors BAX and tBID. Similarly, these cells were more resilient towards chemotherapy-induced mitochondrial depolarisation. Together, this work reveals a previously undocumented molecular link between RAS GAP and apoptosis regulation, providing a new mechanistic framework for targeting a subset of chemorefractory tumours.

DOI: https://doi.org/10.1038/s41388-025-03284-5
bioRxiv. 2025 Jan 23. pii: 2025.01.20.633997. [Epub ahead of print]

Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.

Sara Wong, Katherine R Bertram, Nidhi Raghuram, Thomas Knight, Adam L Hughes.

Lipid saturation is a key determinant of membrane function and organelle health, with changes in saturation triggering adaptive quality control mechanisms to maintain membrane integrity. Among cellular membranes, the mitochondrial outer membrane (OMM) is an important interface for many cellular functions, but how lipid saturation impacts OMM function remains unclear. Here, we show that increased intracellular unsaturated fatty acids (UFAs) remodel the OMM by promoting the formation of multilamellar mitochondrial-derived compartments (MDCs), which sequester proteins and lipids from the OMM. These effects depend on the incorporation of UFAs into membrane phospholipids, suggesting that changes in membrane bilayer composition mediate this process. Furthermore, elevated UFAs impair the assembly of the OMM protein translocase (TOM) complex, with unassembled TOM components captured into MDCs. Collectively, these findings suggest that alterations in phospholipid saturation may destabilize OMM protein complexes and trigger an adaptive response to sequester excess membrane proteins through MDC formation.
Significance Statement: Mitochondrial-derived compartments are multilamellar structures that sequester protein and lipids of the outer mitochondrial membrane in response to metabolic and membrane perturbations, but it is largely unknown how membrane fluidity influences this pathway.Increased levels of unsaturated phospholipids may disrupt the TOM complex, a large multi-subunit complex on the outer mitochondrial membrane, to promote the formation of mitochondrial-derived compartments, while increased levels of saturated phospholipids inhibits formation of mitochondrial-derived compartments.These findings reveal a link between phospholipid composition and protein stress in driving mitochondrial-derived compartment biogenesis, and thus mitochondrial quality control.

DOI: https://doi.org/10.1101/2025.01.20.633997
Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251316350

Mitochondrial-ER Contact Sites and Tethers Influence the Biosynthesis and Function of Coenzyme Q.

Noelle Alexa Novales, Hadar Meyer, Yeynit Asraf, Maya Schuldiner, Catherine F Clarke.

  Coenzyme Q (CoQ) is an essential redox-active lipid that plays a major role in the electron transport chain, driving mitochondrial ATP synthesis. In Saccharomyces cerevisiae (yeast), CoQ biosynthesis occurs exclusively in the mitochondrial matrix via a large protein-lipid complex, the CoQ synthome, comprised of CoQ itself, late-stage CoQ-intermediates, and the polypeptides Coq3-Coq9 and Coq11. Coq11 is suggested to act as a negative modulator of CoQ synthome assembly and CoQ synthesis, as its deletion enhances Coq polypeptide content, produces an enlarged CoQ synthome, and restores respiration in mutants lacking the CoQ chaperone polypeptide, Coq10. The CoQ synthome resides in specific niches within the inner mitochondrial membrane, termed CoQ domains, that are often located adjacent to the endoplasmic reticulum-mitochondria encounter structure (ERMES). Loss of ERMES destabilizes the CoQ synthome and renders CoQ biosynthesis less efficient. Here we show that deletion of COQ11 suppresses the respiratory deficient phenotype of select ERMES mutants, results in repair and reorganization of the CoQ synthome, and enhances mitochondrial CoQ domains. Given that ER-mitochondrial contact sites coordinate CoQ biosynthesis, we used a Split-MAM (Mitochondrial Associated Membrane) artificial tether consisting of an ER-mitochondrial contact site reporter, to evaluate the effects of artificial membrane tethers on CoQ biosynthesis in both wild-type and ERMES mutant yeast strains. Overall, this work identifies the deletion of COQ11 as a novel suppressor of phenotypes associated with ERMES deletion mutants and indicates that ER-mitochondria tethers influence CoQ content and turnover, highlighting the role of membrane contact sites in regulating mitochondrial respiratory homeostasis.

Keywords:  ER-mitochondrial encounter structure; artificial tether; coenzyme Q; mitochondria

DOI:  https://doi.org/10.1177/25152564251316350
Cancer Lett. 2025 Feb 01. pii: S0304-3835(25)00076-X. [Epub ahead of print] 217512

Acidosis overrides molecular heterogeneity to shape therapeutically targetable metabolic phenotypes in colon cancers.

Elena Richiardone, Maria Virginia Giolito, Rim Al Roumi, Jérôme Ambroise, Romain Boidot, Bernhard Drotleff, Bart Ghesquière, Barbara Lupo, Livio Trusolino, Alberto Bardelli, Sabrina Arena, Olivier Feron, Cyril Corbet.

  Colorectal cancer (CRC) represents a prototypical example of a cancer type for which inter- and intra-tumor heterogeneities remain major challenges for the clinical management of patients. Besides genotype-mediated phenotypic alterations, tumor microenvironment (TME) conditions are increasingly recognized to promote intrinsic diversity and phenotypic plasticity and sustain disease progression. In particular, acidosis is a common hallmark of solid tumors, including CRC, and it is known to induce aggressive cancer cell phenotypes. In this study, we report that long-term adaptation to acidic pH conditions is associated with common metabolic alterations, including a glycolysis-to-respiration switch and a higher reliance on the activity of phosphoglycerate dehydrogenase (PHGDH), in CRC cells initially displaying molecularly heterogeneous backgrounds. Pharmacological inhibition of PHGDH activity or mitochondrial respiration induces greater growth-inhibitory effects in acidosis-exposed CRC cells in 2D and 3D culture conditions, and in patient-derived CRC organoids. These data pave the way for drugs targeting the acidic tumor compartment as a "one-size-fits-all" therapeutic approach to delay CRC progression.

Keywords:  Colon cancer; PHGDH; acidosis; metabolism; microenvironment; mitochondrial respiration

DOI:  https://doi.org/10.1016/j.canlet.2025.217512
FEBS J. 2025 Feb 07.

Activating AMPK improves pathological phenotypes due to mtDNA depletion.

Gustavo Carvalho, Tran V H Nguyen, Bruno Repolês, Josefin M E Forslund, W M Ruchitha Rukmal Wijethunga, Farahnaz Ranjbarian, Isabela C Mendes, Choco Michael Gorospe, Namrata Chaudhari, Micol Falabella, Mara Doimo, Sjoerd Wanrooij, Robert D S Pitceathly, Anders Hofer, Paulina H Wanrooij.

  AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis that also plays a role in preserving mitochondrial function and integrity. Upon a disturbance in the cellular energy state that increases AMP levels, AMPK activity promotes a switch from anabolic to catabolic metabolism to restore energy homeostasis. However, the level of severity of mitochondrial dysfunction required to trigger AMPK activation is currently unclear, as is whether stimulation of AMPK using specific agonists can improve the cellular phenotype following mitochondrial dysfunction. Using a cellular model of mitochondrial disease characterized by progressive mitochondrial DNA (mtDNA) depletion and deteriorating mitochondrial metabolism, we show that mitochondria-associated AMPK becomes activated early in the course of the advancing mitochondrial dysfunction, before any quantifiable decrease in the ATP/(AMP + ADP) ratio or respiratory chain activity. Moreover, stimulation of AMPK activity using the specific small-molecule agonist A-769662 alleviated the mitochondrial phenotypes caused by the mtDNA depletion and restored normal mitochondrial membrane potential. Notably, the agonist treatment was able to partially restore mtDNA levels in cells with severe mtDNA depletion, while it had no impact on mtDNA levels of control cells. The beneficial impact of the agonist on mitochondrial membrane potential was also observed in cells from patients suffering from mtDNA depletion. These findings improve our understanding of the effects of specific small-molecule activators of AMPK on mitochondrial and cellular function and suggest a potential application for these compounds in disease states involving mtDNA depletion.

Keywords:  AMPK; AMP‐activated protein kinase; mitochondrial DNA depletion; polymerase ɣ

DOI:  https://doi.org/10.1111/febs.70006
Front Oncol. 2024 ;14 1532857

Mitochondrial abnormalities as a target of intervention in acute myeloid leukemia.

Elissa Tjahjono, Megan R Daneman, Bernadetta Meika, Alexey V Revtovich, Natalia V Kirienko.

  Acute myeloid leukemia (AML) is an aggressive hematological malignancy; it is the most common acute leukemia in adults. AML prognosis is often poor, and relapse often occurs after initial remission. Recurrent genetic abnormalities underlying this disease and the presence of leukemic stem cells complicate disease treatment. However, the complex metabolic reprogramming that enables the unrestrained cell growth seen in these cells may also be their Achilles' heel. In these cells, mitophagy operates as a double-edged sword. On one hand, it provides a source of building blocks for further cell division and serves as a method for removing damaged organelles, promoting cell survival. However, the profound metabolic changes to mitochondria also render these organelles more sensitive to damage and place them precariously close to excess mitophagic activation. This review discusses the dual role mitophagy plays in AML survival, the importance of targeting mitophagy to treat AML, and current progress in the area. The discovery and mechanism of action of multiple compounds that were used to inhibit or stimulate mitophagy and their effects on AML survival are also described. Further, we explore the combination strategy of mitophagy-targeting compounds with existing and/or novel chemotherapeutics to eradicate AML and discuss strategies to uncover new drug targets and novel mitochondria-targeting drugs.

Keywords:  acute myeloid leukemia; glutaminolysis; leukemic stem cells; mitochondria; mitophagy; oxidative phosphorylation

DOI:  https://doi.org/10.3389/fonc.2024.1532857
Cell Death Dis. 2025 Feb 05. 16(1): 70

Identification of mitochondrial carrier homolog 2 as an important therapeutic target of castration-resistant prostate cancer.

Yankui Liu, Anjie Chen, Yufan Wu, Jiang Ni, Rong Wang, Yong Mao, Ning Sun, Yuanyuan Mi.

We here investigate the expression of the mitochondrial carrier homolog 2 (MTCH2) and its potential function in castration-resistant prostate cancer (CRPC). Bioinformatic analyses reveal that MTCH2 overexpression is associated with critical clinical parameters of prostate cancer. Single-cell sequencing data indicate elevated MTCH2 expression in the prostate cancer epithelium. MTCH2 is also upregulated in locally treated CRPC tissue and various primary human CRPC cells. Using genetic silencing via shRNA and knockout (KO) through the CRISPR-sgRNA approach, we showed that the depletion of MTCH2 impaired mitochondrial function, resulting in a reduced oxygen consumption rate, diminished complex I activity, and decreased ATP levels, mitochondrial depolarization, and increased reactive oxygen species production in primary CRPC cells. The silencing or KO of MTCH2 significantly inhibited cell viability, proliferation, and migration, together with a marked increase in apoptosis in the primary CRPC cells. In contrast, ectopic expression of MTCH2 provided CRPC cells with pro-tumorigenic properties, enhancing ATP production and promoting cell proliferation and migration. MTCH2 silencing also markedly inhibited the growth of subcutaneous xenografts of the primary CRPC cells in nude mice. The MTCH2-silenced xenografts exhibited increased apoptosis, elevated lipid peroxidation, and decreased ATP levels. These results provide new insights into the role of MTCH2 in supporting mitochondrial function and CRPC progression.

DOI: https://doi.org/10.1038/s41419-025-07406-5
J Pharmacol Exp Ther. 2025 Jan;pii: S0022-3565(24)00092-2. [Epub ahead of print]392(1): 100034

Metformin in overcoming enzalutamide resistance in castration-resistant prostate cancer.

Kendall Simpson, Derek B Allison, Daheng He, Jinpeng Liu, Chi Wang, Xiaoqi Liu.

  Androgen deprivation is the standard treatment for patients with prostate cancer. However, the disease eventually progresses as castration-resistant prostate cancer (CRPC). Enzalutamide, an androgen receptor inhibitor, is a typical drug for treating CRPC and with continuous reliance on the drug, can lead to enzalutamide resistance. This highlights the necessity for developing novel therapeutic targets to combat the gain of resistance. Metformin has been recently investigated for its potential antitumorigenic effects in many cancer types. In this study, we used enzalutamide and metformin in combination to explore the possible rescued efficacy of enzalutamide in the treatment of enzalutamide-resistant CRPC. We first tested the effects of this combination treatment on cell viability, drug synergy, and cell proliferation in enzalutamide-resistant CRPC cell lines. After combination treatment, we observed a decrease in cell proliferation and viability as well as a synergistic effect of both enzalutamide and metformin in vitro. Following these results, we sought to explore how combination treatment affected mitochondrial fitness using mitochondrial stress test analysis and mitochondrial membrane potential shifts due to metformin's action in inhibiting complex I of oxidative phosphorylation. We employed 2 different strategies for in vivo testing using 22Rv1 and LuCaP35CR xenograft models. Finally, RNA sequencing revealed a potential link in the downregulation of rat sarcoma-mitogen-activated protein kinase signaling following combination treatment. SIGNIFICANCE STATEMENT: Increasing evidence suggests that oxidative phosphorylation might play a critical role in the development of resistance to cancer therapy. This study showed that targeting oxidative phosphorylation with metformin can enhance the efficacy of enzalutamide in castration-resistant prostate cancer in vitro.

Keywords:  Enzalutamide resistance; Metformin; Prostate cancer

DOI:  https://doi.org/10.1124/jpet.124.002424
Cell. 2025 Jan 28. pii: S0092-8674(25)00093-5. [Epub ahead of print]

GUK1 activation is a metabolic liability in lung cancer.

Jaime L Schneider, Kiran Kurmi, Yutong Dai, Ishita Dhiman, Shakchhi Joshi, Brandon M Gassaway, Christian W Johnson, Nicole Jones, Zongyu Li, Christian P Joschko, Toshio Fujino, Joao A Paulo, Satoshi Yoda, Gerard Baquer, Daniela Ruiz, Sylwia A Stopka, Liam Kelley, Andrew Do, Mari Mino-Kenudson, Lecia V Sequist, Jessica J Lin, Nathalie Y R Agar, Steven P Gygi, Kevin M Haigis, Aaron N Hata, Marcia C Haigis.

  Little is known about metabolic vulnerabilities in oncogene-driven lung cancer. Here, we perform a phosphoproteomic screen in anaplastic lymphoma kinase (ALK)-rearranged ("ALK+") patient-derived cell lines and identify guanylate kinase 1 (GUK1), a guanosine diphosphate (GDP)-synthesizing enzyme, as a target of ALK signaling in lung cancer. We demonstrate that ALK binds to and phosphorylates GUK1 at tyrosine 74 (Y74), resulting in increased GDP biosynthesis. Spatial imaging of ALK+ patient tumor specimens shows enhanced phosphorylation of GUK1 that significantly correlates with guanine nucleotides in situ. Abrogation of GUK1 phosphorylation reduces intracellular GDP and guanosine triphosphate (GTP) pools and decreases mitogen-activated protein kinase (MAPK) signaling and Ras-GTP loading. A GUK1 variant that cannot be phosphorylated (Y74F) decreases tumor proliferation in vitro and in vivo. Beyond ALK, other oncogenic fusion proteins in lung cancer also regulate GUK1 phosphorylation. These studies may pave the way for the development of new therapeutic approaches by exploiting metabolic dependencies in oncogene-driven lung cancers.

Keywords:  ALK; GDP; GUK1; Ras signaling; anaplastic lymphoma kinase; cancer metabolism; guanylate kinase 1; lung cancer; non-small cell lung cancer; tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.cell.2025.01.024
Science. 2025 Feb 06. eadf2034

Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.

Emily M Walker, Gemma L Pearson, Nathan Lawlor, Ava M Stendahl, Anne Lietzke, Vaibhav Sidarala, Jie Zhu, Tracy Stromer, Emma C Reck, Jin Li, Elena Levi-D'Ancona, Mabelle B Pasmooij, Dre L Hubers, Aaron Renberg, Kawthar Mohamed, Vishal S Parekh, Irina X Zhang, Benjamin Thompson, Deqiang Zhang, Sarah A Ware, Leena Haataja, Nathan Qi, Stephen C J Parker, Peter Arvan, Lei Yin, Brett A Kaufman, Leslie S Satin, Lori Sussel, Michael L Stitzel, Scott A Soleimanpour.

Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β-cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Indeed, pharmacologic blockade of the integrated stress response in vivo restored β-cell identity following loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.

DOI: https://doi.org/10.1126/science.adf2034
Cell. 2025 Jan 10. pii: S0092-8674(24)01420-X. [Epub ahead of print]

Rhodoquinone carries electrons in the mammalian electron transport chain.

Jonathan Valeros, Madison Jerome, Tenzin Tseyang, Paula Vo, Thang Do, Diana Fajardo Palomino, Nils Grotehans, Manisha Kunala, Alexandra E Jerrett, Nicolai R Hathiramani, Michael Mireku, Rayna Y Magesh, Batuhan Yenilmez, Paul C Rosen, Jessica L Mann, Jacob W Myers, Tenzin Kunchok, Tanner L Manning, Lily N Boercker, Paige E Carr, Muhammad Bin Munim, Caroline A Lewis, David M Sabatini, Mark Kelly, Jun Xie, Michael P Czech, Guangping Gao, Jennifer N Shepherd, Amy K Walker, Hahn Kim, Emma V Watson, Jessica B Spinelli.

  Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O2). In hypoxia, ubiquinol (UQH2) diverts these electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an electron carrier detected in mitochondria purified from certain mouse and human tissues that preferentially delivers electrons to fumarate through the reversal of succinate dehydrogenase, independent of environmental O2 levels. The RQ/fumarate ETC is strictly present in vivo and is undetectable in cultured mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC from the UQ/O2 to the RQ/fumarate pathway, we establish that these distinct ETCs support unique programs of mitochondrial function and that RQ confers protection upon hypoxia exposure in vitro and in vivo. Thus, in discovering the presence of RQ in mammals, we unveil a tractable therapeutic strategy that exploits flexibility in the ETC to ameliorate hypoxia-related conditions.

Keywords:  electron transport chain; hypoxia; ischemia; metabolism; mitochondria; rhodoquinone

DOI:  https://doi.org/10.1016/j.cell.2024.12.007
Cell Death Differ. 2025 Feb 03.

Deciphering molecular specificity in MCL-1/BAK interaction and its implications for designing potent MCL-1 inhibitors.

Hudie Wei, Haolan Wang, Shuang Xiang, Jiaqi Wang, Lingzhi Qu, Xiaojuan Chen, Ming Guo, Xiaoyun Lu, Yongheng Chen.

The intricate interplay among BCL-2 family proteins governs mitochondrial apoptosis, with the anti-apoptotic protein MCL-1 primarily exerting its function by sequestering the pore-forming effector BAK. Understanding the MCL-1/BAK complex is pivotal for the sensitivity of cancer cells to BH3 mimetics, yet the precise molecular mechanism underlying their interaction remains elusive. Herein, we demonstrate that a canonical BH3 peptide from BAK inadequately binds to MCL-1 proteins, whereas an extended BAK-BH3 peptide with five C-terminal residues exhibits a remarkable 65-fold increase in affinity. By elucidating the complex structures of MCL-1 bound to these two BAK-BH3 peptides at 2.08 Å and 1.98 Å resolutions, we uncover their distinct binding specificities. Notably, MCL-1 engages in critical hydrophobic interactions with the extended BAK-BH3 peptide, particularly at an additional p5 sub-pocket, featuring a π-π stacking interaction between MCL-1 Phe319 and BAK Tyr89. Mutations within this p5 sub-pocket substantially disrupt the MCL-1/BAK protein-protein interaction. Furthermore, the p5 sub-pocket of MCL-1 significantly influences the efficacy of MCL-1 inhibitors. Overall, our findings elucidate the molecular specificity underlying MCL-1 binding to BAK and underscore the significance of the p5 hydrophobic sub-pocket in their high-affinity interaction, thus providing novel insights for the development of BH3 mimetics targeting the MCL-1/BAK interaction as potential therapeutics for cancer treatment.

DOI: https://doi.org/10.1038/s41418-025-01454-2
Mol Cell. 2025 Feb 06. pii: S1097-2765(25)00036-X. [Epub ahead of print]85(3): 638-651.e9

The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism.

Wang Jiahui, Yu Xiang, Zhong Youhuan, Ma Xiaomin, Gao Yuanzhu, Zhou Dejian, Wang Jie, Fu Yinkun, Fan Shi, Su Juncheng, Huang Masha, Haigis Marcia, Wang Peiyi, Xu Yingjie, Yang Wen.

  Mitochondrial heat shock proteins and co-chaperones play crucial roles in maintaining proteostasis by regulating unfolded proteins, usually without specific target preferences. In this study, we identify a DNAJC-type co-chaperone: T cell activation inhibitor, mitochondria (TCAIM), and demonstrate its specific binding to α-ketoglutarate dehydrogenase (OGDH), a key rate-limiting enzyme in mitochondrial metabolism. This interaction suppresses OGDH function and subsequently reduces carbohydrate catabolism in both cultured cells and murine models. Using cryoelectron microscopy (cryo-EM), we resolve the human OGDH-TCAIM complex and reveal that TCAIM binds to OGDH without altering its apo structure. Most importantly, we discover that TCAIM facilitates the reduction of functional OGDH through its interaction, which depends on HSPA9 and LONP1. Our findings unveil a role of the mitochondrial proteostasis system in regulating a critical metabolic enzyme and introduce a previously unrecognized post-translational regulatory mechanism.

Keywords:  DNAJC; OGDH; TCAIM; charperon; metabolism; mitochondria; protein degradation; protein interaction; single-particle cryo-EM; α-ketoglutarate dehydrogenase

DOI:  https://doi.org/10.1016/j.molcel.2025.01.006
Sci Rep. 2025 Feb 04. 15(1): 4298

CRIP1 inhibits cutaneous melanoma progression through TFAM-mediated mitochondrial biogenesis.

Jianqiang Wu, Lixia Chen, Peijun Wen.

  Metastasis is the leading cause of death in patients with cutaneous melanoma. CRIP1 (cysteine-rich protein 1) has been reported to be associated with malignant progression of several cancers. However, the biological function and underlying mechanisms of CRIP1 in melanoma progression are largely unknown. Bioinformatic prediction of CRIP1 expression in melanoma and its association with clinical parameters and prognosis of patients. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blots (WB) were used to detect stable overexpression and knockdown of CRIP1 in melanoma cells. The function of CRIP1 in cutaneous melanoma cells was determined by in vitro functional assays. WB, immunofluorescence, OCR detection, mitochondrial DNA assay, and cytosolic ATP assay were used to determine the relationship between CRIP1 and mitochondrial biogenesis, relationship between TFAM. The expression level of CRIP1 in melanoma tissues is lower than that in normal tissues and suggests a poor prognosis for melanoma patients. Functionally, CRIP1 inhibits the proliferation, migration, and invasion of melanoma cells in vitro. Mechanistic studies revealed that CRIP1 inhibited mitochondrial biogenesis in melanoma cells, which included suppression of relative mitochondrial content, mitochondrial DNA copy number, ATP production, respiratory capacity, and expression levels of oxidative phosphorylation-related proteins. Further studies revealed that CRIP1 inhibits mitochondrial biogenesis and malignant progression in melanoma cells by suppressing the protein levels of TFAM. Our results suggest that CRIP1 inhibits the proliferation and invasive ability of cutaneous melanoma cells by suppressing TFAM-mediated mitochondrial biogenesis. Therefore, CRIP1 may be a potential therapeutic target for melanoma.

Keywords:  CRIP1; Melanoma; Mitochondrial biogenesis; TFAM

DOI:  https://doi.org/10.1038/s41598-025-88373-x
Blood. 2025 Feb 07. pii: blood.2024026700. [Epub ahead of print]

Venetoclax plus Daunorubicin and Cytarabine for Newly Diagnosed Acute Myeloid Leukemia: Results of a Phase 1b Study.

Ioannis Mantzaris, Mendel Goldfinger, Matan Uriel, Aditi Shastri, Nishi Shah, Kira Gritsman, Noah Kornblum, Lauren C Shapiro, Alejandro Sica, Anne Munoz, Nicole Chambers, Aradhika Dhawan, Jhannine Alyssa Verceles, Karen Fehn, Balda Tirone, Lamisha Shah, Shaunmonique Clark, Chenxin Zhang, Mimi Y Kim, Dennis L Cooper, Amit Verma, Marina Y Konopleva, Eric J Feldman.

Venetoclax combined with intensive chemotherapy shows promise for untreated acute myeloid leukemia (AML), but its integration with the '7+3' regimen remains underexplored. In a phase 1b study (NCT05342584), we assessed the safety and efficacy of venetoclax with daunorubicin and cytarabine in newly diagnosed AML patients. Thirty-four patients (median age 59 years; 62% non-white) received venetoclax at escalating durations (8, 11, or 14 days). Adverse events included febrile neutropenia (100%), sepsis (29%), and enterocolitis (23.5%), with no induction deaths. Median recovery times for neutrophils (>1.0K/uL) and platelets (>100K/uL) were under 30 days. Composite complete remission (CRc) was achieved in 85.3% of patients, with 86.2% being measurable residual disease (MRD)-negative. Responses spanned all ELN2022 risk categories. With a median follow-up of 9.6 (2-20) months, median duration of response, event-free survival and overall survival were not reached. Venetoclax (400 mg) combined with '7+3' chemotherapy was safe and effective in achieving MRD-negative remissions across all durations. Ven dose optimization is being explored in the expansion phase of this trial. Future multicenter studies should confirm our findings.

DOI: https://doi.org/10.1182/blood.2024026700
Nat Commun. 2025 Feb 06. 16(1): 1406

ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3.

Shiyang Wang, Xi Wu, Wenxin Bi, Jiuzhi Xu, Liyuan Hou, Guilin Li, Yuwei Pan, Hanfu Zhang, Mengzhen Li, Sujuan Du, Mingxin Zhang, Di Liu, Shuiling Jin, Xiaojing Shi, Yuhua Tian, Jianwei Shuai, Maksim V Plikus, Moshi Song, Zhaocai Zhou, Lu Yu, Cong Lv, Zhengquan Yu.

Aberrant release of mitochondrial reactive oxygen species (mtROS) in response to cellular stress is well known for promoting cancer progression. However, precise molecular mechanism by which mtROS contribute to epithelial cancer progression remains only partially understood. Here, using colorectal cancer (CRC) models, we show that upon sensing excessive mtROS, phosphatase PGAM5, which normally localizes to the mitochondria, undergoes aberrant cleavage by presenilin-associated rhomboid-like protein (PARL), becoming released into the cytoplasm. Cytosolic PGAM5 then directly binds to and dephosphorylates MST3 kinase. This, in turn, prevents STK25-mediated LATS1/2 phosphorylation, leading to YAP activation and CRC progression. Importantly, depletion of MST3 reciprocally promotes accumulation of cytosolic PGAM5 by inducing mitochondrial damage. Taken together, these findings demonstrate how mtROS promotes CRC progression by activating YAP via a post-transcriptional positive feedback loop between PGAM5 and MST3, both of which can serve as potential targets for developing next-generation anti-colon cancer therapeutics.

DOI: https://doi.org/10.1038/s41467-025-56444-2
Nat Commun. 2025 Feb 04. 16(1): 1358

Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis.

Xiaofan Sun, Yue Li, Juan Du, Fangshu Liu, Caiping Wu, Weihao Xiao, Guopan Yu, Xiaowei Chen, Robert Peter Gale, Hui Zeng.

Sphingolipid, ceramide for example, plays an essential role in regulating cancer cell death. Defects in the generation and metabolism of ceramide in cancer cells contribute to tumor cell survival and resistance to chemotherapy. Ceramide Transfer Protein (CERT) determines the ratio of ceramide and sphingomyelin in cells. Targeting CERT sensitizes solid cancer cells to chemotherapy. However, whether targeting CERT to induce ceramide accumulation thereby improving AML therapy efficiency remains elusive. Here, we show that knocking down CERT inhibits the growth and promotes the apoptosis of AML cells carrying FLT3-ITD mutation. Combining CERT inhibitor with FLT3 inhibitor exhibits synergistic effects on FLT3-ITD mutated acute myeloid leukemia (AML) cells. Additionally, co-treatment of HPA-12 and Crenolanib is effective in FLT3-ITD+ and FLT3-TKD+ AML patients. The synergistic effects are found to be mediated by the endoplasmic reticulum stress-GRP78/ATF6/CHOP axis and mitophagy. Our data provide an effective strategy to enhance the efficacy of FLT3 inhibitors in AML.

DOI: https://doi.org/10.1038/s41467-025-56520-7
DNA Repair (Amst). 2025 Feb 01. pii: S1568-7864(25)00010-2. [Epub ahead of print]146 103814

DNA repair pathways in the mitochondria.

Dillon E King, William C Copeland.

  Mitochondria contain their own small, circular genome that is present in high copy number. The mitochondrial genome (mtDNA) encodes essential subunits of the electron transport chain. Mutations in the mitochondrial genome are associated with a wide range of mitochondrial diseases and the maintenance and replication of mtDNA is crucial to cellular health. Despite the importance of maintaining mtDNA genomic integrity, fewer DNA repair pathways exist in the mitochondria than in the nucleus. However, mitochondria have numerous pathways that allow for the removal and degradation of DNA damage that may prevent accumulation of mutations. Here, we briefly review the DNA repair pathways present in the mitochondria, sources of mtDNA mutations, and discuss the passive role that mtDNA mutagenesis may play in cancer progression.

Keywords:  DNA repair; Mitochondria; MtDNA; Mutagenesis

DOI:  https://doi.org/10.1016/j.dnarep.2025.103814
Gene. 2025 Jan 30. pii: S0378-1119(25)00087-3. [Epub ahead of print]944 149299

Comprehensive analysis of mitochondrial solute carrier family 25 (SLC25) identifies member 19 (SLC25A19) as a regulatory factor in hepatocellular carcinoma.

Xueke Gao, Yangtao Xu, Xinyao Hu, Jiayu Chen, Daoming Zhang, Ximing Xu.

   BACKGROUND: The mitochondrial solute carrier family 25 (SLC25) is known to play a pivotal role in oncogenesis, yet its specific involvement in hepatocellular carcinoma (HCC) remains poorly elucidated.
METHODS: In this study, we performed a clustering analysis of HCC patients in the Cancer Genome Atlas database based on the expression levels of SLC25 members, and conducted clinical feature analysis for each patient within the clusters. Subsequently, we developed a prognostic model using a Lasso regression approach with SLC25A19, SLC25A49, and SLC25A51 as features, and generated a risk score for each HCC patient. We then identified SLC25A19 as a potential prognostic marker for HCC through single-cell analysis, and validated this finding using in vitro and in vivo experiments.
RESULTS: Our results revealed significant differences in the expression of most SLC25 family members in HCC patients, enabling the stratification of patients into three clusters, with those in cluster 1 exhibiting the most favorable prognosis and showing a correlation with enhanced immune infiltration. The risk scores derived from the features SLC25A19, SLC25A49, and SLC25A51 effectively predicted the prognosis of HCC patients, with area under the curve (AUC) values exceeding 0.7 in the test group. Single-cell analysis further demonstrated h eightened expression of SLC25A19 in the immune microenvironment of HCC, and in vitro experiments indicated that SLC25A19 may regulate the proliferation, migration, invasion, cycle, and apoptosis of liver cancer cells through the Wnt pathway. In the HepG2 animal model, overexpression of SLC25A19 significantly promotes tumor growth, while knockdown inhibits tumor growth. Analysis of patient tumor tissues shows that SLC25A19 is highly expressed in liver cancer tissues and is associated with CD8+ T cell infiltration.
CONCLUSIONS: In conclusion, our comprehensive analysis of the role of SLC25 in HCC unveiled SLC25A19 as a potential regulatory factor in HCC.

Keywords:  Bioinformatic analysis; Hepatocellular carcinoma; SLC25; SLC25A19; Single-cell analysis

DOI:  https://doi.org/10.1016/j.gene.2025.149299
Cancer Lett. 2025 Feb 03. pii: S0304-3835(25)00091-6. [Epub ahead of print] 217527

Intranuclear TCA and mitochondrial overload: the nascent sprout of tumors metabolism.

Weixi Yuan, Guozhong Lu, Yin Zhao, Xiang He, Senyi Liao, Zhe Wang, Xiaoyong Lei, Zhizhong Xie, Xiaoyan Yang, Shengsong Tang, Guotao Tang, Xiangping Deng.

  Abnormal glucose metabolism in tumors is a well-known form of metabolic reprogramming in tumor cells, the most representative of which, the Warburg effect, has been widely studied and discussed since its discovery. However, contradictions in a large number of studies and suboptimal efficacy of drugs targeting glycolysis have prompted us to further deepen our understanding of glucose metabolism in tumors. Here, we review recent studies on mitochondrial overload, nuclear localization of metabolizing enzymes, and intranuclear TCA (nTCA) in the context of the anomalies produced by inhibition of the Warburg effect. We provide plausible explanations for many of the contradictory points in the existing studies, including the causes of the Warburg effect. Furthermore, we provide a detailed prospective discussion of these studies in the context of these new findings, providing new ideas for the use of nTCA and mitochondrial overload in tumor therapy.

Keywords:  Acquired drug resistance in tumors; Metabolism in the nucleus; Mitochondrial overload; Nuclear TCA cycle; Nuclear localization of metabolic enzymes; Tumor heterogeneity; Tumor immune escape; Tumor metabolism; Warburg effect

DOI:  https://doi.org/10.1016/j.canlet.2025.217527
iScience. 2025 Feb 21. 28(2): 111731

Succinate supplementation alleviates liver cancer by inhibiting the FN1/SQLE axis-mediated cholesterol biosynthesis.

Shuyuan Chang, Ayaka Tomii, Yunfei Zhou, Xun Yang, Yihong Dong, Jun Yan, Aodi Wu, Yumeng Wang, Qingxin Zhang, Hongxue Meng, Lei Yu, Wei Sun, Dabin Liu.

  Succinate is a crucial metabolite in the TCA cycle and contributes to cancer development. However, the role of exogenous succinate in hepatocellular carcinoma (HCC) is unclear. Here, we report that the concentration of succinate in HCC tissues is lower compared to adjacent normal tissues, as determined by spatial metabolomics and quantitative metabolomics analysis. Succinate supplementation exhibits an anti-tumorigenic effect, inhibiting cell proliferation and colony formation in liver cancer cells but not in non-tumor LO2 cells. Additionally, succinate supplementation significantly reduces tumor formation in xenograft nude mice models and carcinogen-induced WT mice models. The anti-tumorigenic function of succinate is mechanistically mediated by FN1-activated SQLE-related cholesterol biosynthesis. Our study demonstrates that exogenous succinate acts as a cholesterol biosynthesis inhibitor to suppress HCC both in vitro and in vivo, highlighting its potential therapeutic applications.

Keywords:  Biological sciences; Cancer; Cell biology

DOI:  https://doi.org/10.1016/j.isci.2024.111731