bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–02–08
twelve papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.
  2. Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
  3. LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
  4. Metastasis gets a little help from immune cell mitochondria.
  5. ZNF395 Is a Hypoxia-Responsive Regulator of Mitochondrial Glutaminolysis in Clear Cell Renal Cell Carcinoma.
  6. BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia.
  7. Honokiol blocks tumor development and metastasis through mitochondrion-targeted effects.
  8. Proteomics landscape of early T-cell precursor acute lymphoblastic leukemia reveals deficient oxidative phosphorylation signatures.
  9. PU.1 inhibition sensitizes stem-monocytic AML to BCL2 blockade.
  10. Multiomic analysis of clonal development reveals new regulators of leukemic cell growth.
  11. The mitochondrial intermembrane space nuclease Nuc1 (endonuclease G) prevents mitophagy-mediated mtDNA escape in yeast.
  12. Mitochondrial complex I subunit NDUFS4 overexpression drives glioma progression by regulating mitochondrial function and COX5B.
  1. Nat Metab. 2026 Feb 06.
    SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.
    Liucheng Li, Jianwei You, Zi-Qing Chai, Xueshan Li, Xinlei Cai, Lin Wang, Fang Yang, Lingzhi Zhu, Wen Mi, Xinyi Xia, Haohang Yan, Fei Li, Juan Wang, Tong-Jin Zhao, Ligong Chen, Hongbin Ji, Pingyu Liu, Xiao-Long Zhou, Li Chen, Fuming Li.
      Taurine plays a crucial role in mitochondrial translation. Mammalian cells obtain taurine via exogenous uptake mediated by the plasma membrane transporter SLC6A6 or via cytosolic biosynthesis. However, it remains unclear how taurine enters mitochondria and impacts cellular metabolism. Here we show that SLC6A6, but not exogenous taurine, is essential for mitochondrial metabolism and cancer cell growth. We discover that SLC6A6 also localizes to mitochondria and imports taurine for mitochondrial transfer RNA modifications. SLC6A6 deficiency specifically reduces mitochondrial taurine abundance and abrogates mitochondrial translation and cell proliferation. We identify protein kinase A as a regulator of SLC6A6 subcellular localization, as it promotes SLC6A6 presence at the plasma membrane while inhibiting its mitochondrial localization. Furthermore, we identify NFAT5 as a key regulator of mitochondrial function through SLC6A6 and demonstrate that targeting the NFAT5-SLC6A6 axis markedly impairs mitochondrial translation and tumour growth. Together, these findings suggest that SLC6A6 is a mitochondrial taurine transporter and an exploitable metabolic dependency in cancer.
    DOI:  https://doi.org/10.1038/s42255-026-01455-6
  2. Cell Metab. 2026 Jan 29. pii: S1550-4131(26)00001-X. [Epub ahead of print]
    Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
    Ang Jia, Xiaowen Zhang, Ji-Hao Zhou, Yongcan Ma, Jing Wang, Yongbo Gong, Wenjie Song, Hangcheng Hu, Yufei Yu, Haixia Yang, Youli Lu, Linzhang Huang, Xingrong Du, Chunmei Chang, Shanshan Pei, Peng Li, Craig T Jordan, Tong-Jin Zhao, Haobin Ye.
      Acute myeloid leukemia (AML) arises from diverse mutations, yet its most aggressive drivers remain elusive. Here, we show that Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations drive hyperproliferative and therapy-/glucose stress-resistant AML, whereas existing inhibitors lack sufficient cytotoxicity. Dual physiological/glucose-deprived screening identified compound 615 selectively eliminating KRAS-mutant cells through concurrently inhibiting succinate dehydrogenase (SDH) and the cytosol-to-mitochondrial NAD+ transporter SLC25A51. Mechanistically, KRAS-mutant cells exhibit reduced 2-oxoglutarate dehydrogenase complex-mediated SLC25A51 K264 succinylation, a mitochondrial NAD+-dependent modification promoting protein stability. This creates a synthetic lethal vulnerability: low-dose 615 triggers a cascade failure by acutely inhibiting SLC25A51, followed by its destabilization, causing complete transporter suppression. Together with concurrent SDH inhibition, this drives catastrophic mitochondrial NAD+ depletion. Conversely, KRAS-wild-type cells preserve NAD+ influx via sufficient baseline succinyl-SLC25A51, which stabilizes SLC25A51 and enables sufficient succinate accumulation to drive hypoxia inducible factor 1 subunit alpha (HIF1α)-mediated compensatory NAD+ production during treatment. Our work reveals a KRAS-specific metabolic vulnerability and proposes a dual-inhibition therapy for KRAS-driven AML.
    Keywords:  NAD(+); OGDH complex; SLC25A51; leukemia; metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.001
  3. bioRxiv. 2026 Jan 15. pii: 2026.01.14.699555. [Epub ahead of print]
    LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
    Levi Ali, Avijit Mallick, Yunguang Du, Rui Li, Lihua Julie Zhu, Kuang Shen, Cole M Haynes.
      Mitochondrial homeostasis is maintained by multiple molecular chaperones and proteases located within the organelle. The mitochondrial matrix-localized protease LONP-1 degrades oxidatively damaged or misfolded proteins. Importantly, LONP-1 also regulates mitochondrial DNA replication. Here, we show that mutations in C. elegans that impair LONP-1 function cause dysregulation of mitochondrial DNA replication, mitochondrial RNA transcription and protein synthesis within the mitochondrial matrix. LONP-1 deficient worms had reduced levels of oxidative phosphorylation proteins despite increased mtDNA-encoded protein synthesis. Via a forward genetic screen, we identified three mutations that restored mitochondrial function and the rate of development in lonp-1 mutants to levels comparable to those in wildtype worms. Interestingly, all three suppressor mutations were found in genes encoding mitochondrial ribosome proteins. A point mutation in the mitochondrial ribosome protein MRPS-38 restored oxidative phosphorylation in lonp-1 mutant worms. Combined, our results suggest that LONP-1 regulates mitochondrial protein synthesis and that the suppressor mutations within MRPS-38 or MRPS-15 enhance oxidative phosphorylation complex assembly by slowing translation.
    DOI:  https://doi.org/10.64898/2026.01.14.699555
  4. Cell Metab. 2026 Feb 03. pii: S1550-4131(26)00002-1. [Epub ahead of print]38(2): 254-256
    Metastasis gets a little help from immune cell mitochondria.
    Michael V Berridge, Renata Zobalova, Jiri Neuzil.
      Although a role for mitochondrial transfer has been implicated in metastasis, the mechanisms are unclear. Using mouse metastatic models, Okwan-Duodu and colleagues1 report that mitochondrial transfer from non-cancer immune cells to cancer cells in the tumor facilitates lymph node metastasis via the cGAS/STING immune evasion pathway involving type I interferon.
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.002
  5. Cancer Res. 2026 Feb 04. OF1-OF14
    ZNF395 Is a Hypoxia-Responsive Regulator of Mitochondrial Glutaminolysis in Clear Cell Renal Cell Carcinoma.
    Joanna Koh, Chengheng Liao, Michelle Shu Wen Ng, Jing Han Hong, Hong Lee Heng, Dan Y Gui, Zhenxun Wang, Benjamin Yan-Jiang Chua, Zhimei Li, Radoslaw M Sobota, Lye Siang Lee, Jabed Iqbal, Kevin Junliang Lim, Divya Bezwada, Ralph J DeBerardinis, Gertrud Steger, Jianhong Ching, Patrick Tan, Bin Tean Teh, Qing Zhang, Xiaosai Yao.
      Hypoxia signaling induced by VHL deficiency fuels growth but also imposes metabolic stress on clear cell renal cell carcinomas (ccRCC). Many ccRCC cells depend on glutamine as the primary source of tricarboxylic acid (TCA) anaplerosis. Hypoxia-inducible factor α (HIFα) governs glycolysis but does not directly regulate glutamine metabolism; instead, the factor responsible for orchestrating glutamine metabolism and mitochondrial adaptations to hypoxia remains elusive. In this study, we showed that ZNF395 is a hypoxia-responsive factor that regulates glutamine metabolism in the mitochondria. When activated by a HIF2α-modulated superenhancer, ZNF395 facilitated the transcription of enzymes essential for glutaminolysis, including glutaminase (GLS) and isocitrate dehydrogenase 2. Functionally, ZNF395 depletion resulted in reduced TCA cycle intermediates and their derivatives, including amino acids, glutathione, and pyrimidine nucleotides, leading to impaired mitochondrial respiration. Restoration of mitochondrial complex I function and GLS expression partially rescued the effects of ZNF395 depletion on ccRCC tumor growth. Together, this study underscores the coordinated role of HIFα and ZNF395 in shaping metabolic adaptations in response to hypoxia in VHL-deficient ccRCCs.
    SIGNIFICANCE: ZNF395 and HIF are complementary mediators of hypoxia-induced metabolic reprogramming and therapeutic targets in VHL-deficient kidney cancer, with the former regulating glutamine metabolism and the latter regulating glucose metabolism.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4745
  6. bioRxiv. 2026 Jan 22. pii: 2026.01.19.700325. [Epub ahead of print]
    BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia.
    Laura López-Hernández, Stephanie J Crowley, Sara Cea-Sánchez, Ricardo de Arellano, Neetij Krishnan, Patrick Toolan-Kerr, Lynn White, Domenico Ignoti, Emily Soto-Hidalgo, Stefano Gustincich, Román González-Prieto, Luca Pandolfini, Isaia Barbieri, Patricia Altea-Manzano, Jeffrey A Magee, Jeffrey J Bednarski, Gonzalo Millán-Zambrano.
      Acute myeloid leukemia (AML) is driven by a combination of genetic alterations and non-mutational mechanisms that disrupt normal hematopoiesis and support leukemic cell survival. While the mutational landscape of AML is well characterized, the non-genetic processes that sustain leukemic maintenance remain comparatively less understood. Using human AML cell lines and murine models of AML, we identify BCL2-associated transcription factor 1 (BCLAF1) as a key regulator of leukemic progression through control of mRNA processing. BCLAF1 physically associates with core spliceosome components and regulates alternative splicing, with a predominant effect on intron retention. We demonstrate that BCLAF1 is required for the productive splicing of activating transcription factor 4 (ATF4) mRNA, thereby sustaining ATF4 protein expression. Loss of BCLAF1 reduces ATF4 protein levels, leading to downregulation of metabolic target genes and disruption of de novo amino acid biosynthesis. Furthermore, depletion of BCLAF1 sensitizes AML cells to venetoclax, a clinically relevant BCL-2 inhibitor. Together, these findings uncover a previously unrecognized role for BCLAF1 in coordinating mRNA splicing and metabolic adaptation in AML, highlighting its potential as a therapeutic target.
    Statement of significance: Aberrant RNA splicing and metabolic reprogramming are hallmarks of cancer, yet how these processes are mechanistically linked remains unclear. This study identifies BCLAF1 as a key regulator connecting splicing control to amino acid metabolism in acute myeloid leukemia, revealing a previously unrecognized functional vulnerability at the intersection of these pathways.
    DOI:  https://doi.org/10.64898/2026.01.19.700325
  7. Cell Death Dis. 2026 Jan 30. 17(1): 186
    Honokiol blocks tumor development and metastasis through mitochondrion-targeted effects.
    Martina Grandi, Francesco Boldrin, Giovanni Risato, Silvia Grillini, Natascia Tiso, Francesco Argenton, Emanuela Leonardi, Silvio Tosatto, Giancarlo Solaini, Alessandra Baracca, Valentina Giorgio.
      IF1 is the natural inhibitor of the mitochondrial ATP synthase during hydrolytic activity. It has been found to be overexpressed in many tumors, where it acts as a pro-oncogenic protein. During oxidative phosphorylation, IF1 binds to a novel site on the OSCP subunit of ATP synthase and promotes tumorigenesis by protecting cancer cells from permeability transition pore (PTP)-dependent apoptosis. In this work, honokiol, a biphenolic compound, showed binding affinity for two sites on the OSCP subunit, as predicted by molecular docking analysis. It was shown to be effective in disrupting the IF1-OSCP interaction and sensitizing cancer cells to apoptosis. In vivo, xenografts of zebrafish injected with IF1-expressing HeLa cells showed tumor development. The same xenografts, treated with honokiol, showed a significant reduction in tumor mass, similar to untreated fish injected with IF1 KO HeLa cells. In vitro, honokiol inhibits colony formation in soft agar of IF1-expressing HeLa cells by promoting the PTP opening and cell death, without any effect on cell proliferation. Interestingly, honokiol was shown to block metastasis in fish xenografts and migration in a wound healing assay, by promoting mitochondrial swelling in both control and IF1 KO cell lines, when cells are moving to close the scratch area. In conclusion, honokiol appears to be a promising anti-cancer compound, with pro-apoptotic properties through the displacement of IF1 from the OSCP subunit of ATP synthase, and anti-metastatic effects that are due to mitochondrial PTP opening.
    DOI:  https://doi.org/10.1038/s41419-026-08441-6
  8. Cell Rep Med. 2026 Feb 03. pii: S2666-3791(26)00003-0. [Epub ahead of print] 102586
    Proteomics landscape of early T-cell precursor acute lymphoblastic leukemia reveals deficient oxidative phosphorylation signatures.
    Miaomiao Liu, Tianyi Chen, Xiangjie Lin, Bowen Wu, Fujie Shi, Junya Liu, Yi Chen, Tao Zeng, Shangyu Hou, Qingfei Pan, Xuemei Wang, Yiyi Yao, Wenyu Yang, Yingchi Zhang, Jinyan Huang, Jie Jin, Yinghui Zhu, Huafeng Wang.
      Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) represents a therapeutically challenging, high-risk leukemia subtype whose comprehensive proteomic characterization remains limited. Our integrated 4D label-free proteomic analysis delineates a distinct molecular signature featuring profound oxidative phosphorylation (OxPhos) deficiency, characterized by compromised mitochondrial ATP synthesis and significant reductions in electron transport chain complexes I and IV. Single-cell RNA sequencing validation establishes that stem-like ETP-ALL populations exhibit substantially diminished ETC activity relative to T-lineage-differentiated counterparts. Pharmacological intervention using dichloroacetate to restore OxPhos functionality effectively suppresses leukemic proliferation and xenograft engraftment through ROS-mediated endoplasmic reticulum stress activation. Furthermore, we identify CD109 as an attractive immunophenotypic marker that not only distinguishes ETP-ALL from other hematologic malignancies but also defines a subset with enhanced ETC suppression and heightened metabolic vulnerability to dichloroacetate. These findings elucidate the mechanistic basis of mitochondrial dysregulation in ETP-ALL pathogenesis and nominate CD109 as a promising biomarker for targeted therapeutic strategies.
    Keywords:  CD109; early T-cell precursor acute lymphoblastic leukemia; mitochondrial dysfunction; oxidative phosphorylation; proteomics
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102586
  9. bioRxiv. 2026 Jan 23. pii: 2026.01.20.700677. [Epub ahead of print]
    PU.1 inhibition sensitizes stem-monocytic AML to BCL2 blockade.
    William M Yashar, Itallia V Pacentine, Akram Taherinasab, Thai Nguyen, Samantha Worme, Mitsuhiro Tsuchiya, Theresa Lusardi, Chelsea Hutchinson, Thomas L Fillmore, Camilo Posso, Sara Jc Gosline, Paul D Piehowski, Galip Gurkan Yardimci, Andrew C Adey, Julia E Maxson, Theodore P Braun.
      Acute myeloid leukemia (AML) exhibits substantial transcriptional heterogeneity across differentiation states that influences therapeutic response to BCL2 inhibition with venetoclax. While hematopoietic stem cell (HSC)-like AMLs show high sensitivity to venetoclax and monocytic-like AMLs demonstrate resistance, the therapeutic behavior of leukemias harboring both transcriptional programs remains poorly defined. Analysis of a large AML cohort reveals a distinct patient population exhibiting concurrent HSC- and monocyte-like transcriptional signatures, which we term stem-monocytic AML. Ex vivo drug sensitivity profiling demonstrates that stem-monocytic AMLs exhibit venetoclax resistance comparable to pure monocytic disease, despite expressing HSC-like transcriptional features. Using a leukemia cell line model that recapitulates stem-monocytic AML characteristics, we show through immunophenotyping and single-cell lineage tracing that venetoclax preferentially depletes immature blasts while sparing differentiated monocytic populations. Single-cell transcriptomic and chromatin accessibility analyses identify enrichment of myeloid differentiation transcription factors, particularly PU.1, in resistant populations. A targeted CRISPR knockout screen confirms that PU.1 disruption induces differentiation arrest and enhances venetoclax sensitivity primarily in the immature immunophenotypic compartments. Pharmacologic PU.1 inhibition with the small molecule DB2313 synergizes with venetoclax in both cell line models and primary patient samples. These findings establish stem-monocytic AML as a transcriptionally and functionally distinct subtype and nominate combined PU.1 and BCL2 inhibition as a rational therapeutic strategy for improving venetoclax response in this patient population.
    DOI:  https://doi.org/10.64898/2026.01.20.700677
  10. Genes Dev. 2026 Feb 04.
    Multiomic analysis of clonal development reveals new regulators of leukemic cell growth.
    Gracia Bonilla, Alexander Morris, Sharmistha Kundu, Anthony DuCasse, Grace Kirkpatrick, Jelena Milosevic, Nathan E Jeffries, Kashish Chetal, Emma E Yvanovich, Ting Zhao, Jun Xia, Rana Barghout, David Scadden, Michael K Mansour, Robert E Kingston, David B Sykes, Francois E Mercier, Ruslan I Sadreyev.
      Mechanisms driving the increase in cell growth in developing leukemia are not fully understood. We focused on epigenomic regulation of this process by analyzing the changes of chromatin marks and gene expression in leukemic cell clones as they progressed toward increased proliferation in a mouse model of acute myeloid leukemia (AML). This progression was characterized by gradual modulation of chromatin states and gene expression across the genome, with a surprising preferential trend of reversing the prior changes associated with the origins of leukemia. Our analyses of this modulation in independently developing clones predicted a small set of potential growth regulators whose transcriptomic and epigenomic progression was consistent between clones and maintained both in vivo and ex vivo. We selected three of these genes as candidates (Irx5 and Plag1 as growth suppressors and Smad1 as a driver) and successfully validated their causal growth effects by overexpression in mouse leukemic cells. Overexpression of the IRX5 gene in human MOLM13 leukemic cells suppressed cell growth both in vitro and in mouse xenografts. Public patient data confirmed expression levels of PLAG1 and SMAD1 as markers of AML status and survival, suggesting that multiomic analysis of evolving clones in a mouse model is a valuable predictive approach relevant to human AML.
    Keywords:  Polycomb group proteins; acute myeloid leukemia; cell growth regulation; chromatin modifications; clonal evolution; epigenetic factors; epigenome dynamics
    DOI:  https://doi.org/10.1101/gad.353186.125
  11. Curr Biol. 2026 Feb 03. pii: S0960-9822(26)00006-0. [Epub ahead of print]
    The mitochondrial intermembrane space nuclease Nuc1 (endonuclease G) prevents mitophagy-mediated mtDNA escape in yeast.
    Ryan R Cupo, Eunice Domínguez-Martín, Richard Youle.
      Mitochondria contain a genome (mtDNA) encoding a handful of proteins essential for cellular respiration. mtDNA can leak into the cytosol and drive fitness defects. The first genes associated with mtDNA escape were discovered in yeast and aptly named "yeast mitochondrial escape" (YME) genes. We identify the mechanism by which an intermembrane space nuclease, endonuclease G (human ENDOG; yeast Nuc1), prevents mtDNA escape to the cytosol in yeast. Nuc1 nuclease activity and mitochondrial localization are essential for preventing mtDNA escape and suggest a direct role of Nuc1 in degrading mtDNA bound for escape. We find that blocking autophagy via atg1 and atg8 mutants prevents mtDNA escape in the absence of Nuc1. We further demonstrate that blocking mitophagy via atg11 and atg32 mutants prevents mtDNA escape, whereas inducing mitophagy increases mtDNA escape in the absence of Nuc1. Finally, we demonstrate that Nuc1 degrades mtDNA bound for escape via the vacuole, as an atg15 mutant that prevents disassembly of autophagic bodies in the vacuole also prevents mtDNA escape. Overall, our results implicate vacuolar entry of mitochondria during mitophagy as an important mtDNA escape pathway in yeast, which is normally mitigated via the degradation of mtDNA by Nuc1.
    Keywords:  Atg1; Atg32; Drp1; NUMT; STING; autophagy; fission; lysosome; nucleoid; vacuole
    DOI:  https://doi.org/10.1016/j.cub.2026.01.006
  12. NPJ Precis Oncol. 2026 Jan 30.
    Mitochondrial complex I subunit NDUFS4 overexpression drives glioma progression by regulating mitochondrial function and COX5B.
    Jiang Wu, Juan Li, Li Xu, Yuanyuan Liu, Li Jiang.
      The current study explores the expression, functional significance, and underlying mechanisms of the mitochondrial protein NDUFS4 (NADH:ubiquinone oxidoreductase subunit S4) in glioma cells. TCGA shows that elevated NDUFS4 expression is consistently observed in glioma tissues, correlating with advanced tumor grade and diminished patient survival. Single-cell RNA sequencing further localizes this elevated expression primarily to glioma cells, where NDUFS4 co-expressed genes are integral to cellular respiration and mitochondrial ATP synthesis. These findings were corroborated in patient tissues and various primary and established glioma cell types, confirming consistent NDUFS4 overexpression. Genetic silencing (via shRNA) or CRISPR/Cas9-mediated knockout of NDUFS4 impaired mitochondrial function, evidenced by reduced oxygen consumption rate, inhibited mitochondrial complex I activity and ATP production and increased oxidative stress. NDUFS4 depletion also suppressed glioma cell proliferation, migration, and invasion, while promoting apoptosis. This inhibitory effect is specific to malignant cells, sparing non-cancerous astrocytes. Conversely, NDUFS4 overexpression enhanced mitochondrial activity and promoted aggressive malignant phenotypes in primary and immortalized glioma cells. Further multi-omics integration and experimental investigation established COX5B (cytochrome c oxidase subunit 5B) as an important downstream effector of NDUFS4. shRNA-induced silencing of COX5B replicated the outcomes of NDUFS4 depletion in primary glioma cells, and crucially, restoring COX5B in NDUFS4-silenced glioma cells abrogated the anti-glioma effects. In vivo studies demonstrated that NDUFS4 silencing effectively impeded intracranial growth of patient-derived glioma xenografts by compromising mitochondrial function, downregulating COX5B, inhibiting proliferation and inducing apoptosis. Collectively, these comprehensive data underscore NDUFS4's essential role in glioma progression and position it as a promising therapeutic target for this aggressive malignancy.
    DOI:  https://doi.org/10.1038/s41698-026-01281-9
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