bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–08–10
eighteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Feasibility and Safety of Targeting Mitochondria Function and Metabolism in Acute Myeloid Leukemia.
  2. Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.
  3. Saturated lipid stress attenuates mitochondrial genome synthesis in human cells.
  4. Cysteine Oxidation of a Redox Hub within Complex I can Facilitate Electron Transport Chain Supercomplex Formation.
  5. Distinct proteomic and acylproteomic adaptations to succinate dehydrogenase loss in two cell contexts.
  6. Alanine Catabolism as a Targetable Vulnerability for MYC-Driven Liver Cancer.
  7. Harnessing PUMA's lethal potential: BCL-2 family dynamics and novel strategies to combat cancer recurrence.
  8. RNA-mediated inhibition of mitochondrial SHMT2 impairs cancer cell proliferation.
  9. Mitochondrial metabolism and cancer therapeutic innovation.
  10. BCL-2 Inhibitor Regulates Number, Function, and Antitumor Immunity of T Cells by Influencing Glycolysis in AML.
  11. PPARγ-induced upregulation of fatty acid metabolism confers resistance to venetoclax and decitabine therapy in AML.
  12. Daily briefing: Respiratory illness can 'wake up' dormant cancer cells.
  13. The ALDH2-PKC delta-SHMT2 axis regulates cellular metabolic plasticity to promote leukemia stem cells self-renewal and evasion of chemotherapy in AML.
  14. Survivin can alter mitochondrial architecture by regulating phosphatidylethanolamine synthesis.
  15. Development of succinate dehydrogenase subunit B-deficient tumor models for preclinical immunotherapy testing.
  16. Genetic mapping of lifespan and mitochondrial stress response in C. elegans.
  17. Mitochondrial DNA release and cGAS-STING activation: Emerging insights into anti-tumor immunity.
  18. NADH reductive stress drives metabolic reprogramming.
  1. Curr Pharmacol Rep. 2024 Dec;10(6): 388-404
    Feasibility and Safety of Targeting Mitochondria Function and Metabolism in Acute Myeloid Leukemia.
    Patryk Firmanty, Monika Chomczyk, Shubhankar Dash, Marina Konopleva, Natalia Baran.
       Purpose of Review: Acute myeloid leukemia (AML) is a clonal blood neoplasm with dismal prognosis. Despite the introduction of many novel targeted agents, cytotoxic chemotherapy has remained the standard of care for AML. Differences in mitochondrial metabolism between normal and leukemic cells can be targeted by novel AML therapies, but these agents require a comprehensive efficacy and cytotoxicity evaluation.
    Recent Findings: Metabolic alterations in AML blasts increase their sensitivity to therapies targeting mitochondrial metabolism. Targeting altered mitochondrial metabolism, that is crucial for leukemia cell growth and survival, could be a breakthrough in AML treatment. Therefore, BH3 family proteins, mitochondrial complexes, the tricarboxylic acid cycle, and amino acid (AA) and fatty acid metabolism are common treatment targets in AML. Although many drugs targeting these vulnerabilities showed acceptable safety profiles and promising efficacy in preclinical studies, clinical trials often do not confirm these results limited by narrow therapeutic window. The most effective regimens are based on drug combinations with synergistic or additive activity.
    Summary: In this review, we present an overview of the most recent studies targeting mitochondrial metabolism in AML. We highlight that targeting of the specific energy metabolism dependencies of AML blasts provides an opportunity to achieve long-term responses with a reasonable safety profile. We emphasize that currently used drugs and their combinations display dose-limiting toxicities or are not efficient enough to completely eradicate leukemic stem cells. Thus, further studies of complex metabolic rewiring of leukemia cells before and after combinatorial therapies are warranted.
    Keywords:  Acute myeloid leukemia; Metabolic reprogramming; Mitochondrial metabolism; Safety; Therapeutic interventions
    DOI:  https://doi.org/10.1007/s40495-024-00378-8
  2. Cell Metab. 2025 Jul 30. pii: S1550-4131(25)00333-X. [Epub ahead of print]
    Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.
    Joseph Longo, Lisa M DeCamp, Brandon M Oswald, Robert Teis, Alfredo Reyes-Oliveras, Michael S Dahabieh, Abigail E Ellis, Michael P Vincent, Hannah Damico, Kristin L Gallik, Nicole M Foy, Shelby E Compton, Colt D Capan, Kelsey S Williams, Corinne R Esquibel, Zachary B Madaj, Hyoungjoo Lee, Dominic G Roy, Connie M Krawczyk, Brian B Haab, Ryan D Sheldon, Russell G Jones.
      Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8+ T cell expansion and cytotoxic function in vivo. Using 13C-based stable isotope tracing, we demonstrate that CD8+ effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UDP-Glc pyrophosphorylase 2 (UGP2), UDP-Gal-4-epimerase (GALE), or UDP-Glc ceramide glucosyltransferase (UGCG) impairs CD8+ T cell expansion upon pathogen challenge. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and optimal T cell receptor (TCR) signaling. Moreover, UGCG-deficient CD8+ T cells display reduced granzyme expression, cytolytic activity, and tumor control in vivo. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-beyond energy production-that is required for CD8+ T cell responses in vivo.
    Keywords:  CD8(+) T cells; UGCG; cytotoxic function; glucose; glycosphingolipids; immunometabolism; lipid rafts; lipidomics; metabolomics; nucleotide sugar metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.07.006
  3. bioRxiv. 2025 Jul 29. pii: 2025.07.28.667051. [Epub ahead of print]
    Saturated lipid stress attenuates mitochondrial genome synthesis in human cells.
    Casadora Boone, Sophie Judge, Ahmad Shami, Bezawit Danna, Andrea B Ball, Tejashree Pradip Waingankar, Hera Saqub, Ajit S Divakaruni, Samantha C Lewis.
      Fatty acids are trafficked between organelles to support membrane biogenesis and act as signaling molecules to rewire cellular metabolism in response to starvation, overnutrition, and environmental cues. Mitochondria are key cellular energy converters that harbor their own multi-copy genome critical to metabolic control. In homeostasis, mitochondrial DNA (mtDNA) synthesis is coupled to mitochondrial membrane expansion and division at sites of contact with the endoplasmic reticulum (ER). Here, we provide evidence from cultured hepatocytes that mtDNA synthesis and lipid droplet biogenesis occur at spatially and functionally distinct ER-mitochondria membrane contact sites. We find that, during saturated lipid stress, cells pause mtDNA synthesis and mitochondrial network expansion secondary to rerouted fatty acid trafficking through the ER and lipid droplet biogenesis, coincident with a defect in soluble protein import to the ER lumen. The relative composition of fatty acid pools available to cells is critical, as monounsaturated fatty acid supplementation rescued both ER proteostasis and mtDNA synthesis, even in the presence of excess saturated fat. We propose that shutoff of mtDNA synthesis conserves mtDNA-to-mitochondrial network scaling until cells can regain ER homeostasis.
    Summary: Overnutrition of cultured human cells causes endoplasmic reticulum dysfunction, which downregulates mitobiogenesis in turn by constraining mtDNA synthesis.
    DOI:  https://doi.org/10.1101/2025.07.28.667051
  4. J Biol Chem. 2025 Jul 31. pii: S0021-9258(25)02406-8. [Epub ahead of print] 110555
    Cysteine Oxidation of a Redox Hub within Complex I can Facilitate Electron Transport Chain Supercomplex Formation.
    Runtai Chen, Seyed Amirhossein Tabatabaei Dakhili, Rokas Geruskis, Yuan Yuan Zhao, Steven Lockhart, Lusine Tonoyan, Arno Siraki, Guocheng Huang, Adam Kinnaird, Darren H Freed, Shelley Minteer, Evangelos D Michelakis, John R Ussher, Gopinath Sutendra.
      The mitochondrial Electron Transport Chain (ETC) is a four complex unit that could be considered the most essential infrastructure within the mitochondria, as it primarily functions to generate the mitochondrial membrane potential (ΔΨm, the cells equivalent to battery capacity), which can then be utilized for ATP synthesis or heat production. Another important aspect of ETC function is the generation of mitochondrial reactive oxygen species (mtROS), which are essential physiologic signaling mediators that can be toxic to the cell if their levels become too high. Currently, it remains unresolved how a highly utilized and functioning ETC can sense excessive mtROS generation and adapt, to enhance ΔΨm. Here we identified a redox hub consisting of cysteine (Cys) residues 64, 75, 78 and 92 within Ndufs1 of complex I of the ETC. Oxidation of these Cys residues promotes the incorporation of complex I into the respirasome supercomplex. Mechanistically, oxidation of the redox hub increased the distance between Fe-S clusters N5 and N6a in complex I, compromising complex I activity. This impairment was rescued by integration with complex III2 and IV into the respirasome supercomplex. Compared to parental cells or Ndufs1-KO cells, C92D (an oxidation mimetic) Ndufs1-knockin A549 cells had higher levels of ETC supercomplexes, ΔΨm and oxygen consumption rates, while isolated mitochondrial membranes generated more electrical current when integrated onto a biobattery platform. Knockdown of complex III2 significantly reduced complex I activity (within the respirasome) from C92D Ndufs1-knockin cells, but not parental A549 cells. Finally, disruption of ETC supercomplexes with the small molecule drug MitoTam increased the therapeutic efficacy of mtROS inducing chemotherapeutics in both C92D Ndufs1-knockin or metastatic lung cancer cells. These findings provide new insights into how the ETC can initiate supercomplex transformation.
    Keywords:  Cancer Resistance; Cysteine Oxidation; Electron Transport Chain; Mitochondria; Reactive Oxygen Species; Supercomplex
    DOI:  https://doi.org/10.1016/j.jbc.2025.110555
  5. bioRxiv. 2025 Aug 02. pii: 2025.08.01.668168. [Epub ahead of print]
    Distinct proteomic and acylproteomic adaptations to succinate dehydrogenase loss in two cell contexts.
    Sherry X Zhou, Benjamin Madden, Cristine Charlesworth, Taro Hitosugi, Judith Favier, Louis J Maher.
       BACKGROUND: The tricarboxylic acid (TCA) cycle and electron transport chain (ETC) are key metabolic pathways required for cellular ATP production. While loss of components in these pathways typically impairs cell survival, such defects can paradoxically promote tumorigenesis in certain cell types. One such example is loss of succinate dehydrogenase (SDH), which functions in both the TCA cycle and as Complex II of the ETC. Deleterious mutations in SDH subunits can cause pheochromocytoma and paraganglioma (PPGL), rare hereditary neuroendocrine tumors of chromaffin cells in the adrenal gland and the nerve ganglia, respectively. Why tumor formation upon SDH loss is limited to certain tissues remains unclear. We hypothesized that the metabolic and proteomic perturbations resulting from SDH loss are cell-type specific, favoring survival of chromaffin cells.
    METHODS: We comprehensively examined the proteomic, acetylproteomic, and succinylproteomic effects of SDH loss in two cell models, immortalized mouse chromaffin cells (imCCs) and immortalized mouse embryonic fibroblasts (iMEFs). Perturbations in metabolite levels were determined by mass spectrometry. Effects of SDH loss on fatty acid β-oxidation (FAO) were assessed by stable isotope tracing and pharmacologic inhibition.
    RESULTS: SDH-loss imCCs show significant upregulation of mitochondrial proteins, including TCA cycle and FAO enzymes, with pronounced downregulation of nuclear proteins. Both imCCs and iMEFs demonstrate significant energy deficiency upon SDH loss, but FAO activity is uniquely increased in SDH-loss imCCs. While SDH loss increases both lysine-reactive acetyl-CoA and succinyl-CoA, SDH-loss imCCs and iMEFs show disproportionate hyperacetylation but mixed succinylation. Surprisingly, SDH-loss imCCs, but not iMEFs, display disproportionate hypoacetylation and hyposuccinylation of mitochondrial proteins.
    CONCLUSIONS: SDH loss differentially impacts the proteomes and acylproteomes of imCCs and iMEFs, with compartment-specific effects. These findings reveal cell type-specific adaptations to SDH loss. The plasticity of the response of imCCs may underlie the tissue-specific susceptibility to tumorigenesis and could illuminate therapeutic vulnerabilities of SDH-loss tumors.
    DOI:  https://doi.org/10.1101/2025.08.01.668168
  6. bioRxiv. 2025 Aug 01. pii: 2025.07.29.667471. [Epub ahead of print]
    Alanine Catabolism as a Targetable Vulnerability for MYC-Driven Liver Cancer.
    Tonatiuh Montoya, Joyce V Lee, Longhui Qiu, Abigail Krall, Nedas Matulionis, Yurim Seo, Brian N Finck, Robin K Kelley, Heather Christofk, Andrei Goga.
      Liver cancer is a leading cause of cancer-related death world-wide in part due to the shortage of effective therapies, and MYC overexpression defines an aggressive and especially difficult to treat subset of patients. Given MYC's ability to reprogram cancer cell metabolism, and the liver's role as a coordinator of systemic metabolism, we hypothesized that MYC induces metabolic dependencies that could be targeted to attenuate liver tumor growth. We discovered that MYC-driven liver cancers catabolize alanine in a GPT2-dependent manner to sustain their growth. GPT2 is the predominant alanine-catabolizing enzyme expressed in MYC-driven liver tumors and genetic ablation of GPT2 limited MYC-driven liver tumorigenesis. In vivo isotope tracing studies uncovered a role for alanine as a substrate for a repertoire of pathways including the tricarboxylic acid cycle, nucleotide production, and amino acid synthesis. Treating transgenic MYC-driven liver tumor mouse models with L-Cycloserine, a compound that inhibits GPT2, was sufficient to diminish the frequency of mouse tumor formation and attenuate growth of established human liver tumors. Thus, we identify a new targetable metabolic dependency that MYC-driven liver tumors usurp to ensure their survival.
    DOI:  https://doi.org/10.1101/2025.07.29.667471
  7. Cancer Treat Res Commun. 2025 Jul 29. pii: S2468-2942(25)00111-X. [Epub ahead of print]44 100975
    Harnessing PUMA's lethal potential: BCL-2 family dynamics and novel strategies to combat cancer recurrence.
    Moustafa A Mansour, Mohamed Abdel-Fattah El-Salamoni, Hamdi Nabawi Mostafa.
      Cancer cells often survive treatment by blocking the natural process of cell death, allowing them to return and grow again. The BCL-2 protein family plays a central role in this process, controlling whether a cell lives or dies. Among its members, the BH3-only proteins initiate the apoptotic cascade in response to cellular stress. PUMA (p53-upregulated modulator of apoptosis), a pro-apoptotic BH3-only protein, is the most potent of its subclass, binding all major anti-apoptotic BCL-2 family members (Bcl-xL, Bcl-2, Mcl-1, and Bcl-w) to counteract their inhibition of Bax and Bak. Upon activation, Bax/Bak form pores in the mitochondrial membrane, releasing apoptogenic factors such as cytochrome c, SMAC, and apoptosis-inducing factor, ultimately triggering caspase-mediated cell death. Due to its upstream role in apoptosis, PUMA deficiency or inhibition by anti-apoptotic proteins promotes cancer development and therapy resistance. Conversely, elevated PUMA expression sensitizes cancer cells to chemo- and radiotherapy. Accumulating evidence positions PUMA as a universal sensor of cell death stimuli and a promising therapeutic target in cancer. This article critically examines PUMA's regulation, function, and potential as a target for cancer treatment.
    Keywords:  BCL-2 family; BH3 mimetics; Cancer therapeutics; PUMA; apoptosis resistance; p53-independent apoptosis
    DOI:  https://doi.org/10.1016/j.ctarc.2025.100975
  8. Cell Death Discov. 2025 Aug 06. 11(1): 369
    RNA-mediated inhibition of mitochondrial SHMT2 impairs cancer cell proliferation.
    Francesca Romana Liberati, Sharon Spizzichino, Sara Di Russo, Giulia Elizabeth Borsatti, Agnese Riva, Maria Chiara Magnifico, Amani Bouzidi, Giorgio Giardina, Marzia Arese, Chiara Scribani Rossi, Dalila Boi, Giovanna Boumis, Federica Di Fonzo, Giulia Guarguaglini, Roberto Contestabile, Angela Tramonti, Alberto Macone, Alessandro Paiardini, Serena Rinaldo, Alessio Paone, Francesca Cutruzzolà.
      Targeting metabolic reprogramming is crucial for cancer treatment. Recent advances highlight RNA's ability to directly regulate enzyme activity through riboregulation. In this study, we used an RNA-based approach to inhibit the mitochondrial enzyme Serine hydroxymethyltransferase 2 (SHMT2), which lacks a selective in vivo inhibitor. SHMT2, often overexpressed in various cancers, is pivotal in one-carbon metabolism, a pathway vital for cell proliferation. Our results show that RNA effectively inhibits SHMT2's serine-to-glycine conversion in vitro (IC50 = 4.4 ± 0.2 nM). By using a mitochondrial import signal, we successfully delivered the inhibitory RNA into the mitochondria of lung cancer cells, reducing cell viability in vitro and tumor growth in vivo in a xenograft mouse model. These findings suggest that RNA-based strategies could be extended to selectively target other RNA-binding metabolic enzymes, offering potential solutions where small molecule inhibitors fall short or to counteract drug resistance.
    DOI:  https://doi.org/10.1038/s41420-025-02646-y
  9. Signal Transduct Target Ther. 2025 Aug 04. 10(1): 245
    Mitochondrial metabolism and cancer therapeutic innovation.
    Hongxiang Du, Tianhan Xu, Sihui Yu, Sufang Wu, Jiawen Zhang.
      Mitochondria are dynamic organelles that are essential for cellular energy generation, metabolic regulation, and signal transduction. Their structural complexity enables adaptive responses to diverse physiological demands. In cancer, mitochondria orchestrate multiple cellular processes critical to tumor development. Metabolic reprogramming enables cancer cells to exploit aerobic glycolysis, glutamine metabolism, and lipid alterations, supporting uncontrolled growth, survival, and treatment resistance. Genetic and epigenetic alterations in mitochondrial and nuclear DNA disrupt oxidative phosphorylation, tricarboxylic acid cycle dynamics, and redox homeostasis, driving oncogenic progression. Mitochondrial dysfunction in tumors is highly heterogeneous, influencing disease phenotypes and treatment responses across cancer types. Within the tumor microenvironment, mitochondria profoundly impact immune responses by modulating T-cell survival and function, macrophage polarization, NK cell cytotoxicity, and neutrophil activation. They also mediate stromal cell functions, particularly in cancer-associated fibroblasts and tumor endothelial cells. Although targeting mitochondrial function represents a promising therapeutic strategy, mitochondrial heterogeneity and adaptive resistance mechanisms complicate interventional approaches. Advances in mitochondrial genome editing, proteomics, and circulating mitochondrial DNA analysis have enhanced tumor diagnostic precision. This review synthesizes the developmental landscape of mitochondrial research in cancer, comprehensively summarizing mitochondrial structural dynamics, metabolic plasticity, signaling networks, and interactions with the tumor microenvironment. Finally, we discuss the translational challenges in developing effective mitochondria-based cancer interventions.
    DOI:  https://doi.org/10.1038/s41392-025-02311-x
  10. Cancer Sci. 2025 Aug 07.
    BCL-2 Inhibitor Regulates Number, Function, and Antitumor Immunity of T Cells by Influencing Glycolysis in AML.
    Xiaohuan Peng, Yanhong Li, Futian Tang, Yanling Ma, Jun Bai, Lijuan Li, Liansheng Zhang.
      BCL-2 is one of the key genes in the mitochondrial apoptotic pathway, and BCL-2 inhibitor Venetoclax (VEN) is the preferred targeted drug for acute myeloid leukemia (AML) patients. However, the effects of VEN on immune cells and antitumor immune responses in AML patients are poorly understood. We first tested the influence of VEN on AML cells and immune cells. Subsequently, we sorted CD4+ T cells and CD8+ T cells from newly diagnosed AML patients in vitro and constructed a peripheral blood mononuclear cell (PBMC)-humanized AML mouse model to explore the effects of VEN on the T cell number, function, and antitumor immune responses, while actively seeking potential mechanisms. VEN could effectively induce leukemia cell apoptosis and affect the lymphocyte proportion and cytokine levels in the tumor immune microenvironment of AML. T cells of AML patients had apoptosis resistance to VEN, possibly due to their relatively low expression levels of BCL-2 protein. VEN could regulate the secretory function and activation status of T cells in AML, which mainly manifested in promoting IFN-γ and Perforin and Granzyme B secretion, upregulating PD-1 expression, promoting T cell activation, and increasing the proportion of memory T cells. Finally, it was also observed that VEN could enhance T cell-mediated antitumor immune responses in AML. Mechanistically, VEN modulates the glycolysis pathway of T cells to regulate their number, function, and antitumor immune responses. This research provided a new perspective that molecular-targeted drugs can promote tumor cell death through a unique immune-dependent mechanism.
    Keywords:  BCL‐2 inhibitor; T cells; acute myeloid leukemia; glycolysis; tumor immune microenvironment; venetoclax
    DOI:  https://doi.org/10.1111/cas.70139
  11. Blood Neoplasia. 2025 Aug;2(3): 100121
    PPARγ-induced upregulation of fatty acid metabolism confers resistance to venetoclax and decitabine therapy in AML.
    Kotoko Yamatani, Tatsuro Watanabe, Kaori Saito, Abdullah Khasawneh, Abhishek Maiti, Zhihong Zeng, Kala Hayes, Shinya Kimura, Courtney D DiNardo, Xiaoping Su, Shuko Nojiri, Yasushi Okazaki, Michael Andreeff, Marina Konopleva, Yoko Tabe.
      The combination of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax (VEN) and the hypomethylating agent decitabine (DEC; VEN/DEC) constitutes a primary therapeutic strategy for treating older adults with acute myeloid leukemia (AML). However, a notable subset of patients exhibits resistance to VEN/DEC, demonstrating either no disease response or relapse after initial remission. This study aimed to elucidate the molecular mechanisms underlying this resistance through analyses of gene expression and DNA methylation profiles. We conducted comprehensive RNA sequencing analysis and DNA methylation profiling on AML samples from 35 patients undergoing VEN/DEC therapy. The RNA sequencing analysis revealed that several genes related to fatty acid metabolism were significantly upregulated in leukemia cells from patients who received VEN/DEC treatment and relapsed or failed to respond. Increased expression of peroxisome proliferator-activated receptor gamma (PPARG) occurred after treatment and correlated with decitabine-induced promoter hypomethylation. Subsequent in vitro validation demonstrated that decitabine treatment results in hypomethylation of the PPARG promoter, elevating PPARG levels and promoting a metabolic environment characterized by enhanced fatty acid oxidation pathways conducive to VEN/DEC resistance. Furthermore, pharmacological inhibition using either a PPARγ antagonist or a fatty acid oxidation inhibitor enhanced the sensitivity of resistant cells to VEN/DEC, underscoring the crucial role of PPARγ in the development of therapeutic resistance. These findings not only shed light on the metabolic adaptation that contributes to VEN/DEC resistance in AML but also identify PPARγ as a potential therapeutic target for overcoming such resistance, providing new opportunities to improve the efficacy of VEN/DEC-based therapy in AML.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100121
  12. Nature. 2025 Jul 31.
    Daily briefing: Respiratory illness can 'wake up' dormant cancer cells.
    Jacob Smith.
      
    DOI:  https://doi.org/10.1038/d41586-025-02493-y
  13. Cancer Lett. 2025 Jul 31. pii: S0304-3835(25)00532-4. [Epub ahead of print] 217963
    The ALDH2-PKC delta-SHMT2 axis regulates cellular metabolic plasticity to promote leukemia stem cells self-renewal and evasion of chemotherapy in AML.
    Xiuying Hu, Tianzhen Hu, Shuyun Cao, Lin Zheng, Ming Ni, Qin Shang, Yanju Li, Hong Luo, Naiqin Zhao, Li Wang, Yaming Zhang, Jiangyuan Zhao, Bingqing Cheng, Chengyun Pan, Tianzhuo Zhang, Li Jiang, Qian Kang, Qin Fang, Jishi Wang.
      Leukemia stem cells (LSCs) exhibit unique characteristics distinct from those of leukemia cells and are insensitive to conventional chemotherapeutics; thus, these cells ultimately contribute to treatment failure and relapse in acute myeloid leukemia (AML) patients. A critical challenge remains as strategies are needed to precisely target the diverse molecular drivers of leukemia stem cells (LSCs), particularly in the context of their protective microenvironment, to achieve optimal therapeutic outcomes. In this study, we investigated the role of aldehyde dehydrogenase 2 (ALDH2) in chemotherapy resistance in patients with relapsed/refractory AML and demonstrated that elevated ALDH2 expression in LSCs is closely associated with AML relapse and treatment resistance. Mechanistically, ALDH2 sustains mitochondrial homeostasis in LSCs by increasing the expression of protein kinase C delta (PKC delta) and serine hydroxymethyltransferase 2 (SHMT2), revealing a previously unidentified mechanism of metabolic reprogramming that facilitates LSC adaptation to chemotherapy-induced stress. The ALDH2‒PKC delta-SHMT2 axis plays a pivotal role in conferring resistance to chemotherapy in LSCs. Notably, rhoifolin, a compound designed to inhibit the specific binding site of ALDH2-PKC delta, significantly increased chemosensitivity. It could target LSCs within the bone marrow microenvironment, work synergistically with conventional chemotherapy drugs, and exhibit no toxicity toward normal cells. These findings underscore the therapeutic potential of targeting the ALDH2‒PKC delta axis as a novel and effective strategy for the treatment of AML and the eradication of minimal residual disease.
    Keywords:  ALDH2; Chemoresistance; Leukemia stem cells; Metabolic plasticity; PKC delta; SHMT2
    DOI:  https://doi.org/10.1016/j.canlet.2025.217963
  14. J Cell Sci. 2025 Aug 01. pii: jcs263689. [Epub ahead of print]138(15):
    Survivin can alter mitochondrial architecture by regulating phosphatidylethanolamine synthesis.
    Lucia Dunajová, Amelia Townley, Sophie Rochette, Denise McLean, Jamie R M Webster, Sally P Wheatley.
      Survivin (encoded by BIRC5) is an essential protein with established roles in mitosis and the inhibition of apoptosis. It is overexpressed in cancers, its abundance correlating with resistance to radiotherapies and chemotherapies. Survivin expression is normally limited to G2 and M phases; however, in cancer cells, it is also present during interphase and gains access to the mitochondria. Phosphatidylethanolamine (PE) is a phospholipid that facilitates negative curvature of membranes. It is enriched in the cytokinetic furrow and mitochondria, where it enables tight packing of the cristae and the increased accommodation of proteins. Here, we report the remarkable discovery that mitochondrial survivin regulates phosphatidylserine decarboxylase activity, thereby affecting PE availability. This novel molecular insight suggests that some apparently disparate roles of this 'multitasking' protein might be fundamentally linked to membrane architecture, and offers a new perspective on its contribution to cancer and potentially other metabolic disorders.
    Keywords:  Cancer; Mitochondria; Phosphatidylethanolamine; Phosphatidylserine decarboxylase; Phospholipid; Survivin
    DOI:  https://doi.org/10.1242/jcs.263689
  15. Cancer Lett. 2025 Aug 05. pii: S0304-3835(25)00538-5. [Epub ahead of print]632 217969
    Development of succinate dehydrogenase subunit B-deficient tumor models for preclinical immunotherapy testing.
    Katerina Hadrava Vanova, Ondrej Uher, Michal Kraus, Sona Miklovicova, Katerina Honigova, Stanislaw Gwiezdzinski, Timothy J Garrett, Hans Ghayee, Michal Masarik, Herui Wang, Zhengping Zhuang, Jiri Neuzil, Chunzhang Yang, Karel Pacak.
      Immunotherapy has advanced the treatment landscape for many challenging cancers by harnessing the immune system to eliminate tumor cells. However, its efficacy in rare tumors such as pheochromocytoma and paraganglioma (PCC/PGL), particularly those with succinate dehydrogenase B (SDHB) mutations, remains underexplored. These tumors often exhibit complex tumor microenvironments and immune evasion mechanisms, and their low incidence hinders clinical trials development. Together, these challenges underscore the need for robust preclinical models that closely mirror human disease and support therapeutic discovery. In this study, we developed and characterized murine models of SDHB-deficient tumors using CRISPR-mediated gene editing in pheochromocytoma (MPC and MTT) and renal carcinoma (RenCa) cell lines. These models recapitulate key metabolic and immunological features of human SDHB-mutated tumors, which exhibit loss of SDHB protein expression, providing a relevant platform for evaluating immunotherapeutic strategies. We subsequently tested intratumoral immunotherapy with Mannan-BAM, TLR ligands, and an Anti-CD40 antibody (MBTA), a combination designed to overcome tumor-induced immune suppression. Our results indicate that SDHB-deficient PCC tumors exhibit increased antigen presentation and strong immune activation, leading to rejection or delayed progression in immunocompetent mice. In contrast, Sdhb knock-out RenCa tumors consistently formed, allowing therapeutic testing. MBTA therapy effectively eradicated these tumors, prevented metastasis, and induced long-term immune memory. These findings highlight the value of genetically engineered, tissue-specific murine models in predicting immunotherapy outcomes in rare cancers. Moreover, they support the therapeutic potential of MBTA for treating SDHB-deficient renal cell carcinoma and provide a rationale for further translational studies.
    Keywords:  Immunotherapy; Metastasis; Paraganglioma; Pheochromocytoma; Renal cell carcinoma; Succinate dehydrogenase subunit B; Tumor growth
    DOI:  https://doi.org/10.1016/j.canlet.2025.217969
  16. Res Sq. 2025 Jul 31. pii: rs.3.rs-7093535. [Epub ahead of print]
    Genetic mapping of lifespan and mitochondrial stress response in C. elegans.
    Johan Auwerx, Xiaoxu Li, Weisha Li, Arwen Gao, YunYun Zhu, Elena Katsyuba, Katherine Overmyer, Terytty Yang Li, Ziwen Wang, Luc Legon, Lucie Plantade, Laurent Mouchiroud, Matteo Cornaglia, Hao Li, Riekelt Houtkooper, Joshua Coon.
      The mitochondrial unfolded protein response (UPRmt) is one of the mito-nuclear regulatory circuits that restores mitochondrial function upon stress conditions, promoting metabolic health and longevity. However, the complex gene interactions that govern this pathway and its role in aging and healthspan remain to be fully elucidated. Here, we activated the UPRmt using doxycycline (Dox) in a genetically diverse C. elegans population comprising 85 strains and observed large variation in Dox-induced lifespan extension across these strains. Through multi-omic data integration, we identified an aging-related molecular signature that was partially reversed by Dox. To identify the mechanisms underlying Dox-induced lifespan extension, we applied quantitative trait locus (QTL) mapping analyses and found one UPRmt modulator, fipp-1/FIP1L1, which was functionally validated in C. elegans and humans. In the human UK Biobank, FIP1L1 was associated with metabolic homeostasis, highlighting its translational relevance. Overall, our dataset (https://lisp-lms.shinyapps.io/RIAILs_Dox/) serves as a unique resource to dissect lifespan and mitochondrial stress response modulators in a large genetic reference population.
    DOI:  https://doi.org/10.21203/rs.3.rs-7093535/v1
  17. Pathol Res Pract. 2025 Aug 05. pii: S0344-0338(25)00351-6. [Epub ahead of print]273 156158
    Mitochondrial DNA release and cGAS-STING activation: Emerging insights into anti-tumor immunity.
    Ghfren S Aloraini.
      Mitochondrial DNA (mtDNA) leakage into the cytosol has emerged as a critical modulator of cancer immunity, bridging the gap between cellular stress and antitumor immune responses. Under genomic instability, metabolic stress, or therapy-induced damage, mtDNA escapes into the cytosol, where it activates the cGAS-STING pathway a central regulator of innate immunity. This pathway not only triggers type I interferon (IFN) responses but also influences dendritic cell maturation, T cell infiltration, and immunogenic cell death, shaping the tumor microenvironment (TME) toward immune activation or suppression. Recent studies reveal that mtDNA leakage is not merely a passive byproduct of mitochondrial dysfunction but is dynamically regulated by autophagy, mitochondrial outer membrane permeabilization (MOMP), and interactions with noncoding RNAs. Furthermore, tumors exploit mtDNA degradation mechanisms (e.g., TREX1 exonuclease) or STING silencing to evade immune detection, highlighting this axis as a therapeutic vulnerability. This review synthesizes current knowledge on mtDNA-driven cGAS-STING activation in cancer, its dual role in promoting inflammation versus immune escape, and the therapeutic potential of targeting mtDNA release or STING signaling to enhance immunotherapy. We also explore emerging strategies, such as mtDNA-stabilizing agents and STING agonists, in combination with checkpoint blockade. Deciphering the nuances of mtDNA sensing in different cancers may unlock novel biomarkers and precision immunotherapies for resistant malignancies.
    Keywords:  CGAS-STING; Cancer Immunity; Mitochondrial DNA; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.prp.2025.156158
  18. Trends Cell Biol. 2025 Aug 05. pii: S0962-8924(25)00157-6. [Epub ahead of print]
    NADH reductive stress drives metabolic reprogramming.
    Ronghui Yang, Zihao Guo, Binghui Li.
      Cellular metabolism is intricately regulated by redox signaling, with the NADH/NAD+ couple serving as a central hub. Emerging evidence reveals that NADH reductive stress, marked by NADH accumulation, is not merely a passive byproduct of metabolic dysfunction but an active regulatory signal driving metabolic reprogramming. In this Review, we synthesize recent advances in understanding NADH reductive stress, including its origins, regulatory mechanism, and manipulation. We examine its broad impact on cellular metabolism, its interplay with oxidative and energy stress, and its pathogenic roles in a range of diseases. By integrating these findings, we propose NADH reductive stress as a master regulator for metabolic reprogramming and highlight new avenues for mechanistic exploration and therapeutic intervention.
    Keywords:  NADH reductive stress; NADH-reductive-stress-associated diseases; energy stress; metabolic reprogramming; oxidative stress
    DOI:  https://doi.org/10.1016/j.tcb.2025.07.005
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