bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–09–28
seventeen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
  2. The ubiquitin-binding protein ANKRD13A mediates VCP-dependent mitochondrial outer membrane rupture during PINK1/Parkin-mediated mitophagy.
  3. TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.
  4. Predictors of response and rational combinations for the novel MCL-1 inhibitor MIK665 in acute myeloid leukemia.
  5. Inhibition of BCL-2 and MCL-1 disrupts mitochondrial respiration and overcomes radioresistance in choroidal melanoma.
  6. Convergent pathways of reductive mitochondrial evolution characterised with hypercubic inference.
  7. Mitochondria-specific photorelease of ceramide induces apoptosis.
  8. Purine nucleotides are competitive inhibitors of apo-GOT1.
  9. LncRNA AC021683.2 promotes chemotherapy resistance in acute myeloid leukemia.
  10. Mitochondrial uncoupling, energy substrate utilization, and brown adipose tissue as therapeutic targets in cancer.
  11. A drug-diet combination could improve childhood cancer treatment.
  12. Rucaparib induces mitochondrial fragmentation and apoptosis in prostate cancer cells by targeting Drp1.
  13. Tissue injury leads to the accumulation of somatic mtDNA mutations.
  14. Mitochondria expel tainted DNA - spurring age-related inflammation.
  15. Gatekeepers of mitochondrial metabolism: the emerging role of the SLC25 family in leukemia.
  16. FLT3L-based drug conjugate effectively targets chemoresistant leukemia stem cells in acute myeloid leukemia.
  17. The role of succinylation-mediated metabolic reprogramming in tumor progression.
  1. Nature. 2025 Sep 24.
    Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
    Amir Bahat, Dusanka Milenkovic, Eileen Cors, Mabel Barnett, Sadig Niftullayev, Athanasios Katsalifis, Marc Schwill, Petra Kirschner, Thomas MacVicar, Patrick Giavalisco, Louise Jenninger, Anders R Clausen, Vincent Paupe, Julien Prudent, Nils-Göran Larsson, Manuel Rogg, Christoph Schell, Isabella Muylaert, Erik Lekholm, Hendrik Nolte, Maria Falkenberg, Thomas Langer.
      Metabolic dysregulation can lead to inflammatory responses1,2. Imbalanced nucleotide synthesis triggers the release of mitochondrial DNA (mtDNA) to the cytosol and an innate immune response through cGAS-STING signalling3. However, how nucleotide deficiency drives mtDNA-dependent inflammation has not been elucidated. Here we show that nucleotide imbalance leads to an increased misincorporation of ribonucleotides into mtDNA during age-dependent renal inflammation in a mouse model lacking the mitochondrial exonuclease MGME14, in various tissues of aged mice and in cells lacking the mitochondrial i-AAA protease YME1L. Similarly, reduced deoxyribonucleotide synthesis increases the ribonucleotide content of mtDNA in cell-cycle-arrested senescent cells. This leads to mtDNA release into the cytosol, cGAS-STING activation and the mtDNA-dependent senescence-associated secretory phenotype (SASP), which can be suppressed by exogenously added deoxyribonucleosides. Our results highlight the sensitivity of mtDNA to aberrant ribonucleotide incorporation and show that imbalanced nucleotide metabolism leads to age- and mtDNA-dependent inflammatory responses and SASP in senescence.
    DOI:  https://doi.org/10.1038/s41586-025-09541-7
  2. J Biol Chem. 2025 Sep 18. pii: S0021-9258(25)02591-8. [Epub ahead of print] 110739
    The ubiquitin-binding protein ANKRD13A mediates VCP-dependent mitochondrial outer membrane rupture during PINK1/Parkin-mediated mitophagy.
    Wei-Hua Chu, Yu-Shan Lin, Jing Guo, Wann-Neng Jane, Wong-Jing Wang, Yu-Yang Lin, Pei-Han Liu, Po-Yu Huang, Wei-Chung Chiang.
      PINK1/Parkin-mediated mitophagy is a major homeostatic mechanism by which cells selectively remove damaged, depolarized mitochondria. A signature event in this form of mitophagy is the rupture of the mitochondrial outer membrane (OMM), a process required for the proper disposal of the damaged, depolarized mitochondria. The OMM rupture results in the topological exposure of mitochondrial inner membrane (IMM) mitophagy receptors, which are recognized by autophagy machinery, thus promoting the turnover of the depolarized mitochondria. However, due to the lack of efficient tools to measure OMM rupture, our mechanistic understanding of this process has been limited. In this study, we identified ANKRD13A as a novel mitophagy factor that interacts with multiple mitochondrial proteins and re-localizes to the depolarized mitochondria. ANKRD13A promotes PINK1/Parkin-mediated mitophagy by recruiting Valosin-containing protein (VCP), an AAA-ATPase that functions to remodel protein complexes or membranes via the extraction of protein substrates. Through the development of a novel biosensor that fluorescently marks the sites of OMM rupture, we visualized the OMM rupture events in cellulo and revealed that VCP and its recruitment factors, including ANKRD13A, are required for the rupture of OMM. This finding demonstrated that VCP-dependent remodeling of OMM during PINK1/Parkin-mediated mitophagy is a key driving force behind the OMM rupture. Furthermore, our newly developed biosensor represents an effective, reliable method to detect OMM rupture during PINK1/Parkin-mediated mitophagy, and it is valuable for future mechanistic investigation of this process.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110739
  3. bioRxiv. 2025 Sep 16. pii: 2025.09.11.675705. [Epub ahead of print]
    TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.
    Alia K Syeda, Shekoufeh Almasi, J Cory Benson, Barry E Kennedy, Ryan M Yoast, Scott M Emrich, Logan Slade, Shanmugasundaram Pakkiriswami, Vishnu V Vijayan, Shashi Gujar, Thomas Pulinilkunnil, Mohamed Trebak, Yassine El Hiani.
      Inter-organelle signaling mechanisms, particularly those at the lysosomes-mitochondria interface, are critical for cancer cell metabolism, mitophagy and survival. However, the incomplete understanding of these mechanisms has limited the development of effective therapies, especially for triple-negative breast cancers (TNBC). Here, we demonstrate the lysosomal Ca²⁺-release channel TRPML1 as a master regulator of mitochondrial bioenergetics in TNBC cells. TRPML1 knockdown (ML1-KD) in TNBC cells selectively compromises mitochondrial respiration, reprograms cell metabolism, and induces mitochondrial fragmentation without impacting non-cancerous cells. Mitochondria of ML1-KD TNBC cells sequester around the endoplasmic reticulum (ER), increasing mitochondria-ER contact sites at the expense of mitochondria-lysosomes contacts. Mechanistically, ML1-KD reduces lysosomal acidification, thus hindering autophagic flux and completion of autophagy. ML1-KD inhibits TFEB-mediated mitophagy and oxidative defense mechanisms while causing mitochondrial Ca 2+ overload, further impairing mitochondrial function. These alterations render ML1-KD TNBC cells highly sensitive to doxorubicin and paclitaxel at low doses that are typically ineffective on their own. Together, our findings establish TRPML1 as a critical inter-organelle regulator and highlight its potential as a therapeutic target to exploit the metabolic vulnerabilities of TNBC cells.
    DOI:  https://doi.org/10.1101/2025.09.11.675705
  4. Mol Oncol. 2025 Sep 21.
    Predictors of response and rational combinations for the novel MCL-1 inhibitor MIK665 in acute myeloid leukemia.
    Joseph Saad, Rhiannon Newman, Elmira Khabusheva, Sofia Aakko, Eric Durand, Mahesh Tambe, Heikki Kuusanmäki, Alun Parsons, Juho J Miettinen, Komal Kumar Javarappa, Ezgi June Olgac, Nemo Ikonen, Mika Kontro, Kimmo Porkka, Heiko Maacke, Janghee Woo, Ensar Halilovic, Caroline A Heckman.
      Despite promising anti-leukemic activity of MCL-1 inhibitors in preclinical studies of acute myeloid leukemia (AML), clinical progress has been hindered by limited knowledge of target patient subgroups. To stratify patients for MCL-1 inhibitor treatment, we evaluated the sensitivity of 42 primary AML samples to MCL-1 inhibitor MIK665 (S64315) and analyzed their molecular profiles. We observed that MIK665-sensitive samples had a more differentiated phenotype, whereas resistant samples displayed higher levels of ABCB1 (MDR1) and the anti-apoptotic protein BCL-XL. Moreover, ABCB1 expression had good predictive performance in identifying resistant samples. To induce sensitivity, we treated MIK665-resistant samples with ABCB1 inhibitors elacridar or tariquidar, BCL-XL inhibitor A1331852, or BCL-2 inhibitor venetoclax in combination with MIK665. The combination of MIK665 with each of elacridar, tariquidar, or venetoclax effectively eliminated AML blasts compared to the agents alone, while the combination with A1331852 showed limited efficacy for this patient subgroup. Additionally, the combination of MIK665 with venetoclax restored sensitivity in samples with primary venetoclax resistance. Overall, this study indicates that elevated ABCB1 expression is a potentially targetable resistance mechanism in the context of MIK665 resistance, and that a combination of MIK665 with venetoclax may be effective for overcoming resistance to either MCL-1 or BCL-2 inhibition.
    Keywords:  MCL‐1 inhibition; acute myeloid leukemia; apoptosis; combination therapies; multidrug resistance‐associated proteins; prognostic biomarkers
    DOI:  https://doi.org/10.1002/1878-0261.70130
  5. Biochem Biophys Res Commun. 2025 Sep 14. pii: S0006-291X(25)01366-X. [Epub ahead of print]784 152650
    Inhibition of BCL-2 and MCL-1 disrupts mitochondrial respiration and overcomes radioresistance in choroidal melanoma.
    Yi Ding, Qing Huang.
      Choroidal melanoma is the most common primary intraocular malignancy in adults. Radioresistance is a major therapeutic obstacle in choroidal melanoma with underlying mechanisms poorly understood. In this study, we established radioresistant OCM-3-r and 92-1-r cell lines and identified upregulation of BCL-2 as a key survival mechanism. BCL-2 knockdown impaired mitochondrial respiration, reduced ATP production, and induced apoptosis. Pharmacological inhibition with venetoclax recapitulated these effects in resistant cells, suppressing mitochondrial function and triggering dose-dependent apoptosis. In vivo, venetoclax significantly inhibited tumor growth without affecting body weight and increased cleaved caspase-3 expression in xenografts. However, venetoclax alone did not improve survival. Combination therapy with venetoclax and the MCL-1 inhibitor MIK665 exhibited strong synergy, resulting in enhanced tumor regression and significantly prolonged survival. These findings demonstrate that dual inhibition of BCL-2 and MCL-1 effectively overcomes radioresistance in choroidal melanoma by disrupting mitochondrial function and promoting apoptosis.
    Keywords:  Bcl-2; Choroidal melanoma; MIK665; Mcl-1; Radioresistance; Venetoclax
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152650
  6. J Evol Biol. 2025 Sep 24. pii: voaf111. [Epub ahead of print]
    Convergent pathways of reductive mitochondrial evolution characterised with hypercubic inference.
    Robert C Glastad, Iain G Johnston.
      For a striking example of mitochondrial behaviour beyond ATP generation, consider mitochondrion-related organelles (MROs). Hydrogenosomes, mitosomes, and other reduced mitochondrial forms have evolved through the loss of physical and functional features, from individual electron transport chain (ETC) complexes to oxidative phosphorylaytion and the very ability to produce ATP (and further). Reduction of mitochondria is a dramatic example of convergent evolution, occuring in every eukaryotic kingdom and many parallel times. Here, we use hypercubic inference, a class of methods from evolutionary accumulation modelling (EvAM), to explore the pathways of convergent mitochondrial reduction across eukaryotes. We find that most MRO diversity can be explained by small variations on two distinct pathways, starting with either the loss of Complex I or the loss of Complexes III/IV or TCA cycle steps, which tend to proceed over different characteristic timescales. We show that different clades, including ciliates and apicomplexans, reflect particular instances of these pathways. Using metabolic modelling, we connect the structure of these evolutionary pathways to the metabolic impact of the changes involved, suggesting a plausible explanation for the dramatically convergent nature of reductive evolution. We discuss this approach in connection with related theory on the genetic and functional reduction of mitochondria across organisms.
    Keywords:  convergent evolution; eukaryotic evolution; metabolism; mitochondria; mitochondrion-related organelles; reductive evolution
    DOI:  https://doi.org/10.1093/jeb/voaf111
  7. J Lipid Res. 2025 Sep 19. pii: S0022-2275(25)00169-5. [Epub ahead of print] 100907
    Mitochondria-specific photorelease of ceramide induces apoptosis.
    Christian Schröer, Matthijs Kol, Anna Koch, Emely Döffinger, Murali Annamalai, Joost C M Holthuis.
      Deciphering the mechanisms by which bioactive intermediates of lipid metabolism influence cell behavior is a challenging task. We previously demonstrated that de novo synthesized ceramides are authentic transducers of apoptosis and that their CERT-mediated diversion to mitochondria is sufficient to initiate BAX-dependent apoptosis. To further unravel the mechanism by which mitochondrial ceramides commit cells to death, we here developed a novel mitochondria-targeted and photocaged short-chain ceramide with a clickable alkyne group for derivatization with a fluorescent reporter. We show that this compound readily and selectively accumulates inside mitochondria in a biologically inert state. Subsequent photorelease of the ceramide moiety triggered apoptosis, as evidenced by proteolytic cleavage of central components of the caspase-dependent cell death pathway. Our findings reinforce the notion that ceramides can initiate apoptotic cell death by acting directly on mitochondria and establish mitochondria-targeted photocaged ceramides as novel tools to elucidate the underlying mechanism with the spatiotemporal precision of light.
    Keywords:  caspase-9; chemical synthesis; click chemistry; inner mitochondrial membrane; mitochondrial apoptosis; photocage, sphingolipids
    DOI:  https://doi.org/10.1016/j.jlr.2025.100907
  8. bioRxiv. 2025 Sep 17. pii: 2025.09.17.676921. [Epub ahead of print]
    Purine nucleotides are competitive inhibitors of apo-GOT1.
    Narges Pourmandi, Arjun Jha, Kendall Muzzarelli, Hyunsu Lee, Zahra Assar, Gordon J Murray, Joseph H LaPointe, Thomas P Roddy, Gianna Medeiros, Shomit Sengupta, Costas A Lyssiotis.
      The malate-aspartate shuttle (MAS) plays a key role in cellular metabolism by transferring electrons from cytosolic NADH into the mitochondrial matrix, thereby supporting oxidative phosphorylation, in addition to the citric acid cycle and amino acid metabolism. Here, we sought to identify allosteric regulatory metabolites of the MAS enzymes cytosolic glutamic-oxaloacetic transaminase 1 (GOT1) and mitochondrial GOT2. Using the Atavistik Metabolite Proprietary Screening platform, we identified several structurally similar metabolite hits- most notably deoxyadenosine monophosphate (dAMP) and deoxyguanosine monophosphate (dGMP)-as candidate interactors with GOT1. Follow-up thermal shift assays revealed that dAMP and dGMP destabilize GOT1 in the absence of its cofactor, pyridoxal 5'-phosphate (PLP), but have no destabilizing effect when PLP is present. Crystallographic analysis confirmed that dAMP and dGMP bind in the PLP pocket of GOT1, suggesting competitive binding. Together, these results indicate that nucleotide metabolites can interact with GOT1, offering potential insights into MAS regulation and therapeutic intervention strategies.
    DOI:  https://doi.org/10.1101/2025.09.17.676921
  9. iScience. 2025 Sep 19. 28(9): 113439
    LncRNA AC021683.2 promotes chemotherapy resistance in acute myeloid leukemia.
    Lan Li, Xue-Ni An, Yong-Tong Ruan, Xin Liang, Jing-Lan Hao, Guang-Xun Gao, Jun-Fang Bi, Yan-Rong Gao, Xiao Lu, Hai-Long Tang, Ping Gao, Xiao-Ming Dong.
      Acute myeloid leukemia (AML) is an aggressive clonal malignancy of hematopoietic progenitors with poor clinical outcomes. Though many patients respond well to induction chemotherapy, relapse occurs. The mechanisms underlying AML chemoresistance remain unclear. In our study, we performed whole transcriptome sequencing (WTS) on diagnosed AML samples sensitive or resistant to IA (idarubicin and cytarabine) induction treatment. We observed that lncRNA AC021683.2 is upregulated in IA-resistant patients and associated with poor prognosis. AC021683.2 depletion increased the chemosensitivity of AML cells to Ara-C both in vitro and in vivo by accelerating BCLAF1 ubiquitination and degradation, and AC021683.2 depletion enhanced sensitivity partially by depending on BCLAF1. Both AC021683.2 and BCLAF1 positively correlated with RAD50, which mediated their roles in Ara-C-resistant AML cells. These findings demonstrated that the lncRNA AC021683.2 enhances the resistance of AML/Ara-C-resistant cells to Ara-C in vitro and in vivo, offering a potential target for treating Ara-C-resistant AML.
    Keywords:  Biochemistry; Cancer; Pharmacology
    DOI:  https://doi.org/10.1016/j.isci.2025.113439
  10. NPJ Metab Health Dis. 2025 Sep 22. 3(1): 37
    Mitochondrial uncoupling, energy substrate utilization, and brown adipose tissue as therapeutic targets in cancer.
    Maurizio Ragni, Chiara Ruocco, Enzo Nisoli.
      Mitochondria play a central role in regulating cellular energy metabolism, redox homeostasis, and biosynthesis. Mitochondrial uncoupling, through the alteration in the permeability of the inner mitochondrial membrane (IMM) to the leak of protons without adenosine triphosphate (ATP) synthesis, regulates thermogenesis, glucose and lipid metabolism, and reactive oxygen species (ROS) generation. In brown adipose tissue (BAT), proton leak via uncoupling protein 1 (UCP1) is essential for thermogenesis and has been shown to improve systemic glucose homeostasis, and recent studies indicate that BAT activation can also suppress tumor growth by competing with cancer cells for glucose. Several small-molecule mitochondrial uncouplers have demonstrated anticancer effects in preclinical models, although endogenous UCPs-particularly UCP2-are often upregulated in tumors, where they may support tumor growth by buffering ROS and increasing metabolic flexibility. These seemingly contradictory observations highlight the context-dependent effects of mitochondrial uncoupling in cancer. Here, we review current understanding of mitochondrial uncoupling mechanisms, the roles of UCP isoforms, and the metabolic interplay between BAT, cancer cells, and the tumor microenvironment, with a focus on therapeutic implications.
    DOI:  https://doi.org/10.1038/s44324-025-00080-3
  11. Nature. 2025 Sep 24.
    A drug-diet combination could improve childhood cancer treatment.
    Frank Speleman, Louis Delhaye.
      
    Keywords:  Cancer; Medical research; Metabolism
    DOI:  https://doi.org/10.1038/d41586-025-02824-z
  12. Invest New Drugs. 2025 Sep 21.
    Rucaparib induces mitochondrial fragmentation and apoptosis in prostate cancer cells by targeting Drp1.
    Xiaodong Lu, Yishu Lin, Hao Tang, Zhigang Chen, Kewei Tang.
      Mitochondrial dynamics, particularly the balance between fission and fusion, are critical in regulating cellular metabolism, apoptosis, and cancer progression. Dysregulation of this balance contributes to tumor survival and therapeutic resistance in castration-resistant prostate cancer (CRPC). Rucaparib, a clinically approved poly (ADP-ribose) polymerase (PARP) inhibitor, is primarily known for its role in DNA damage repair; however, its impact on mitochondrial function remains largely unexplored. In this study, we demonstrate that Rucaparib induces significant cytotoxicity and apoptosis in PC-3 CRPC cells in a time- and concentration-dependent manner, characterized by increased Bax/Bcl-2 ratio, cytochrome c release, and caspase-3 activation. Mechanistically, Rucaparib disrupts mitochondrial integrity by reducing mitochondrial membrane potential (MMP), inhibiting Complex IV activity, and depleting ATP levels. Confocal imaging and biochemical assays reveal that Rucaparib triggers mitochondrial fragmentation by promoting phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and enhancing its translocation to mitochondria. This process is accompanied by elevated intracellular Ca2+ levels and activation of calcium/calmodulin-dependent protein kinase II (CaMKII), suggesting a Ca2⁺/CaMKII/Drp1 signaling axis. Importantly, pharmacological inhibition of CaMKII with KN-93 reverses Drp1 mitochondrial translocation, restores mitochondrial morphology, and partially rescues ATP production, confirming the functional role of CaMKII in Rucaparib-induced mitochondrial dysfunction. These findings uncover a previously unrecognized mechanism of Rucaparib action beyond DNA repair inhibition, highlighting its ability to target mitochondrial dynamics and bioenergetics through Ca2+/CaMKII/Drp1 signaling. Our results provide new insights into the multifaceted anticancer mechanisms of Rucaparib and suggest that modulation of mitochondrial fission may offer a promising therapeutic avenue for CRPC.
    Keywords:  ATP; Castration-resistant prostate cancer (CRPC); Drp1; Mitochondrial dynamics; Rucaparib
    DOI:  https://doi.org/10.1007/s10637-025-01586-9
  13. Nat Rev Mol Cell Biol. 2025 Sep 22.
    Tissue injury leads to the accumulation of somatic mtDNA mutations.
    Kim Baumann.
      
    DOI:  https://doi.org/10.1038/s41580-025-00904-6
  14. Nature. 2025 Sep 26.
    Mitochondria expel tainted DNA - spurring age-related inflammation.
    Gemma Conroy.
      
    Keywords:  Ageing; Cell biology; Genetics; Metabolism
    DOI:  https://doi.org/10.1038/d41586-025-03064-x
  15. Haematologica. 2025 Sep 25.
    Gatekeepers of mitochondrial metabolism: the emerging role of the SLC25 family in leukemia.
    Arnon Haran, Boaz Nachmias.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.288787
  16. Cell Rep Med. 2025 Sep 19. pii: S2666-3791(25)00438-0. [Epub ahead of print] 102365
    FLT3L-based drug conjugate effectively targets chemoresistant leukemia stem cells in acute myeloid leukemia.
    Dengyang Zhang, Yao Guo, Zhiyong Peng, Yan Xiao, Zhiguang Chang, Liuting Yu, Yuming Zhao, Qi Zhang, Lingling Ma, Shuping Li, Chi-Kong Li, Kam Tong Leung, Zhizhuang Joe Zhao, Chun Chen, Yun Chen.
      Acute myeloid leukemia (AML) is a heterogeneous malignancy with poor prognosis due to relapse and chemotherapy resistance. FLT3 mutations promote AML and predict adverse outcomes. As most AML cells express FLT3, it represents a promising therapeutic target. In this study, we develop FL-Fc-DM1, a FLT3-targeted conjugate linking FLT3 ligand-Fc to DM1. FL-Fc-DM1 demonstrates potent anti-leukemic activity in vitro, ex vivo, and in both cell line- and patient-derived xenograft models. Notably, it effectively targets cytarabine-resistant AML cells by promoting cell cycle entry and inducing apoptosis. FL-Fc-DM1 also significantly reduces functional leukemia stem cell frequency, as demonstrated by limiting dilution transplantation assays. The therapeutic efficacy can be further strengthened by BH3 mimetics. Importantly, toxicity assessments in a humanized mouse model show limited impact on normal human hematopoiesis at therapeutic doses. Our findings suggest that FL-Fc-DM1 is a promising candidate for AML treatment, even for cell cycle-arrested or slow-cycling chemo-resistant AML cells.
    Keywords:  AML; DM1; FLT3; FLT3L; cell cycle; chemotherapy resistance; ligand-drug conjugate
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102365
  17. Mol Biol Rep. 2025 Sep 26. 52(1): 954
    The role of succinylation-mediated metabolic reprogramming in tumor progression.
    Siyi He, Chunduo Wang, Ranran Li, Kexin Xu, Wuzhiyi Zhang, Binbin Feng, Shengtao Cheng, Jihua Ren, Juan Chen.
      Metabolic reprogramming is a hallmark of tumors, whereby cancer cells remodel their own metabolism to meet the biosynthetic, energetic, and signaling demands required for rapid proliferation and malignant transformation. Posttranslational modifications (PTMs) serve as dynamic molecular switches that fine-tune cellular metabolic networks by precisely modulating the activity, stability, and subcellular localization of metabolic enzymes. This regulatory plasticity drives context-dependent metabolic reprogramming in tumor cells, enabling them to adapt to fluctuating physiological demands or pathological stressors while establishing tumor-specific metabolic signatures critical for survival and progression. Among PTMs, lysine succinylation-a recently identified modification catalyzed by succinyl-CoA-has emerged as a critical regulator of cancer metabolism. This unique modification involves the transfer of a negatively charged four-carbon succinyl group to lysine residues, inducing conformational and functional changes in target proteins. Notably, succinylation is evolutionarily conserved across eukaryotes and prokaryotes and has a broad influence on central metabolic pathways, including the tricarboxylic acid (TCA) cycle, amino acid metabolism, and lipid homeostasis. Mounting evidence highlights its dual roles in both sustaining tumorigenic metabolism and directly activating oncogenic signaling cascades. This review summarizes current insights into how succinylation rewires tumor metabolism and delineates its mechanistic contributions to cancer progression.
    Keywords:  Cancer; Lysine succinylation; Metabolic reprogramming; Posttranslational modification; Succinyl-CoA
    DOI:  https://doi.org/10.1007/s11033-025-11061-6
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