bims-mibica 2026-09-13 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–09–13
fourteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Metabolic circuitry of NADH buffering reveals a vulnerability in redox-adaptive cancer cells.
Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity.
Mitochondrial DNA mutations are associated with impaired oxidative phosphorylation and enhanced imatinib response in chronic myeloid leukemia.
Linking cellular metabolism to mitochondrial outer membrane potential.
Targeting 3-mercaptopyruvate sulfurtransferase selectively eliminates colorectal cancer stem cells.
The stress-sensing MARCH5 axis governs blood cancer apoptotic resilience via tractable protein-protein interactions.
Mitochondrial Raf1 regulates glutamine catabolism.
Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.
CD84 expression stratifies venetoclax response and reveals a targetable vulnerability in resistant acute myeloid leukemia.
Transcription factor 12 promotes acute myeloid leukemia cell survival by regulating mitochondrial function and ROS.
Malic enzyme 1 senses L-lactate to determine tumor heterogeneity.
LPCAT3 is essential for leukemia progression and represents a therapeutic vulnerability in AML.
Acetyl-CoA-dependent processes are preferentially supported by local metabolite synthesis.
A novel approach to reverse Warburg metabolism in patients with recurrent glioblastoma: A phase II pharmacodynamic study of dichloroacetate.

Innovation (Camb). 2026 Sep 08. 7(9): 101365

Metabolic circuitry of NADH buffering reveals a vulnerability in redox-adaptive cancer cells.

Xuexue Li, Pengjiao Hou, Xuewei Zhai, Lifang Li, Zihao Guo, Luxin Qiao, Yanxia Fu, Jing Niu, Ping Chen, Ronghui Yang, Binghui Li.

  Mitochondrial dysfunction elevates cellular NADH/NAD+ ratios, inducing reductive stress that impairs biosynthesis and cell viability. However, the mechanisms by which cells buffer excess NADH to maintain redox homeostasis remain unclear. In this study, we identify a mitochondrial-cytosolic metabolic circuitry involving pyruvate carboxylase (PC), malate dehydrogenases (MDH1/2), and malic enzyme 1 (ME1) that mitigates NADH overload by coupling anaplerotic flux with NADH oxidation. Under reductive stress induced by electron transport chain (ETC) dysfunction, oxaloacetate derived from PC is converted to malate by MDH1/2, which is then oxidized by ME1, transforming both cytosolic and mitochondrial NADH into cytosolic NADPH. Although cellular NADPH is typically associated with antioxidant defense and biosynthesis, our experiments show that TPNOX, which can oxidase NADPH to NADP+, restores proliferation under ETC inhibition, and this rescue is entirely dependent on the mitochondrial-cytosolic metabolic circuitry. This finding highlights that the primary function of the circuit is to maintain NADH homeostasis rather than to generate NADPH. Notably, glucose-6-phosphate dehydrogenase (G6PD) enhances ME1 activity independently of its catalytic function by acting as a scaffold, thereby preventing net NADPH production while facilitating the conversion of NADH to NADPH. Disruption of the PC-MDH1/2-ME1 pathway through PC inhibition sensitizes cells to complex I inhibitors and/or glutaminase blockade, synergistically suppressing tumor growth both in vitro and in vivo. These findings uncover a redox-buffering strategy that redirects NADH into NADPH production, revealing a metabolic vulnerability in redox-adapted cancer cells.

Keywords:  glucose-6-phosphate dehydrogenase; malate dehydrogenases; malic enzyme 1; pyruvate carboxylase; redox homeostasis

DOI:  https://doi.org/10.1016/j.xinn.2026.101365
Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2537797123

Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity.

Sneha P Rath, Zhu Li, Arkajit Guha, Fangcong Dong, Ruma Banerjee, Vamsi K Mootha.

  Of the ~1,100 mitochondrial proteins, only a handful like PINK1 and ATFS-1 are known to stabilize and relocalize upon collapse of the proton motive force (PMF) to execute signaling roles. To systematically identify genes that increase exclusively at the protein level upon PMF collapse, we performed a joint proteomic and RNA-seq screen. The screen revealed 10 candidates (six mitochondrial), including two genes in vitamin B12 metabolism - the B12 chaperone MMADHC and cytosolic B12-dependent 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). MMADHC is short-lived across cell types and we show that its levels increase with PMF collapse. MMADHC stabilization precedes PINK1 activation in a time course of increasing mtDNA depletion, suggesting greater sensitivity to PMF collapse. MMADHC accumulates in mitochondria with LONP1 inhibition but in the cytosol upon PMF collapse, likely due to mitochondrial import failure. Cytosol-stabilized MMADHC increases MTR levels and activity. Altogether, the mitochondrial PMF regulates the cytosolic B12-dependent MTR, integral to one-carbon metabolism, by controlling the stability and compartmentalization of the B12 chaperone MMADHC.

Keywords:  MMADHC; methionine synthase; mitochondria; proton motive force; vitamin B12

DOI:  https://doi.org/10.1073/pnas.2537797123
Hemasphere. 2026 Sep;10(9): e70429

Mitochondrial DNA mutations are associated with impaired oxidative phosphorylation and enhanced imatinib response in chronic myeloid leukemia.

Ilaria S Pagani, Vaidehi Krishnan, John F Ouyang, Chung H Kok, BeiJun Chen, Kian Leong Lee, Cong M Pham, Paul Wang, Elyse Page, Phuong Dang, Verity A Saunders, Jane James, Kelly Lim, Stefano Mangiola, Yingnan Gao, Naranie Shanmuganathan, Agnes Yong, Susan Branford, Charles Chuah, David T Yeung, Deborah L White, Vignir G Helgason, Daniel Thomas, S Tiong Ong, Timothy P Hughes, David M Ross.

Mitochondrial DNA (mtDNA) mutations are frequently observed in cancer, but their clinical and functional significance in chronic myeloid leukemia (CML) remains incompletely defined. Here, we show that a distinct mtDNA mutational landscape is associated with mitochondrial metabolic programs and response to imatinib therapy in CML. We performed comprehensive profiling of somatic mtDNA mutations in 120 patients with chronic-phase CML. At diagnosis, 241 somatic mtDNA mutations were identified in 92 patients, including 29 homoplasmic mutations. In a clinically annotated cohort of 79 imatinib-treated patients, a higher number of mtDNA mutations (≥3 mutations) and higher variant allele frequency were associated with superior molecular responses, and remained significant in multivariable analyses. mtDNA mutational patterns were associated with distinct metabolic phenotypes in CD34+ leukemic stem/progenitor cells. Suboptimal responders exhibited increased mitochondrial respiration, spare respiratory capacity, mitochondrial content, and enrichment of mitochondrial biogenesis and lipid metabolic programs, consistent with enhanced oxidative phosphorylation dependence. In contrast, favorable responders displayed higher mtDNA mutational burden together with reduced respiratory reserve and increased mitophagy-related programs. Pharmacologic Complex I inhibition reduced clonogenic potential and enhanced imatinib sensitivity. Collectively, these findings identify mtDNA mutational states as a biomarker of metabolic fitness and therapeutic response in CML, while supporting further investigation of mitochondrial metabolism as a potential therapeutic vulnerability in CML.

DOI: https://doi.org/10.1002/hem3.70429
Mitochondrion. 2026 Sep 10. pii: S1567-7249(26)00108-X. [Epub ahead of print] 102218

Linking cellular metabolism to mitochondrial outer membrane potential.

Kaitlin Abrantes, Bethel G Beyene, Nina A Bautista, Wendy Fitzgerald, Tatiana K Rostovtseva, Sergey M Bezrukov, Megha Rajendran.

  The voltage-dependent anion channel (VDAC) of the mitochondrial outer membrane (MOM) responds to transmembrane voltage through intrinsic gating and voltage-dependent interactions with cytosolic proteins, such as α-synuclein and β-tubulin. Despite this characteristic voltage sensitivity found in vitro, the existence of a substantial MOM potential (ΔΨMOM) in vivo remains controversial. Using pH sensors targeted to the cytosol and the intermembrane space (IMS), we measured the difference in proton concentration across the MOM and calculated a ΔΨMOM of ~33 mV, positive from the IMS side in HeLa cells; in contrast, HEK-293 cells lacked substantial ΔΨMOM. Hexokinase 2 (HK2) is known to be overexpressed in cancer cells. Consistent with the previously proposed role of VDAC- HK complexation in ΔΨMOM generation, we observed lower HK2 expression in HEK-293 cells than in HeLa cells. In addition, by studying pH changes in the IMS and cytosol in response to changes in glucose and glucose-6-phosphate concentrations in HeLa cells, we establish a relationship between ΔΨMOM and metabolic activity in cancer cells. Thus, our results demonstrate the metabolism-dependent generation of ΔΨMOM and provide strong evidence that VDAC regulation by voltage, observed in in vitro studies, is highly relevant to cell physiology.

Keywords:  Hexokinase; VDAC; Voltage-dependent anion channel; pH sensors

DOI:  https://doi.org/10.1016/j.mito.2026.102218
Redox Biol. 2026 Sep 02. pii: S2213-2317(26)00375-7. [Epub ahead of print]97 104376

Targeting 3-mercaptopyruvate sulfurtransferase selectively eliminates colorectal cancer stem cells.

Kelly Ascenção, Olivia Oravecz, Csaba Szabo.

  Cancer stem cells (CSCs) contribute to therapeutic resistance, metastatic progression, and tumor recurrence, yet the metabolic pathways that sustain their survival remain incompletely understood. Here, we identify 3-mercaptopyruvate sulfurtransferase (3-MST), a hydrogen sulfide-producing enzyme encoded by MPST, as a metabolic dependency of colorectal CSCs. 3-MST expression was increased in human colorectal tumors and cancer cell lines and strongly correlated with proliferative capacity. HCT116-derived CSCs exhibited elevated 3-MST expression, increased hydrogen sulfide and reactive sulfur species production, altered membrane rigidity, and a metabolically restrained phenotype characterized by low basal oxidative phosphorylation and glycolysis. Genetic depletion of 3-MST preferentially impaired CSC proliferation, spheroid formation, stem-like properties, and migration, with less pronounced effects in differentiated parental cells. Pharmacological inhibition of 3-MST reproduced these effects across CSCs derived from several colorectal cancer cell lines and induced near-complete suppression of mitochondrial respiration and glycolytic activity. 3-MST inhibition also increased membrane fluidity, promoted cell death, and reduced CSC-derived tumor growth in mice. Integrated transcriptomic, proteomic, metabolomic, and lipidomic analyses demonstrated coordinated disruption of mitochondrial carbon metabolism, respiratory-chain maintenance, lipid desaturation, and membrane phospholipid homeostasis. These changes were accompanied by accumulation of free fatty acids and diacylglycerols and activation of antioxidants, integrated stress-response, endoplasmic-reticulum-stress, apoptotic, and p53-associated pathways. Ferroptosis-related molecular signatures were also enriched. These findings identify 3-MST as a critical regulator of colorectal CSC bioenergetics and membrane homeostasis and reveal a therapeutically exploitable metabolic vulnerability in treatment-resistant colorectal cancer.

Keywords:  3-Mercaptopyruvate sulfurtransferase; Bioenergetics; Colon cancer; Gasotransmitters; Hydrogen sulfide; Mitochondria

DOI:  https://doi.org/10.1016/j.redox.2026.104376
Blood. 2026 Sep 09. pii: blood.2026033874. [Epub ahead of print]

The stress-sensing MARCH5 axis governs blood cancer apoptotic resilience via tractable protein-protein interactions.

Thomas E Lew, Mark F van Delft, Luuk Heitink, Simon A Cobbold, Christine Anne White, Jason Alfredo Randall Bong, Philip Hittmeyer, Amelia H Zhu, Vineet Vaibhav, Jumana Yousef, Laura F Dagley, Christopher D Riffkin, Angela Georgiou, Adrienne Hilton, Allan Shuai Huang, Yin Yuan, Miles B Horton, Mark A Dawson, Andrew W Roberts, David Ching Siang Huang.

The mitochondrial E3 ligase MARCH5 has consistently emerged as a dependency in unbiased screens in acute myeloid leukemia and myeloma, yet the underpinning mechanism remains ill-defined. Here, we show that MARCH5 cooperates with UBE2J2 and MFN2, forming a stress-sensing complex at mitochondria-ER contact sites (MERCS) that restrains apoptosis in response to diverse organellar damage signals. Loss of MARCH5 potently sensitizes diverse blood cancer cell lines to BCL-2 and BCL-XL inhibition and compromises stress tolerance. By contrast, non-hematopoietic cell lines exhibit a phenotype largely restricted to BCL-XL dependence, permitting tissue-selective therapeutic synergy with venetoclax and other agents. Mechanistically, spatial organization underpins this specificity. The complex assembles at MERCS, where it co-localizes with BCL-2 and BCL-XL but not MCL-1. Upon organellar damage, it dissociates prior to BAX/BAK activation, lowering the apoptotic threshold and enforcing reliance on neighboring BCL-2 and BCL-XL. Consistent with its distribution, MARCH5 loss minimally alters MCL-1 dependence, revealing a spatially encoded mechanism integrating diverse stress signals into cell-death decisions. To guide future therapeutics, we demonstrate that disrupting key protein-protein interactions within this complex is sufficient to sensitize blood cancer cell lines, restoring venetoclax responsiveness and prolonging survival in a murine model of refractory lymphoma. Genetic deletion of MARCH5 or UBE2J2 restored BH3-mimetic sensitivity to primary chronic lymphocytic leukemia cells rendered resistant by cytokine stimulation. These findings establish the MERCS-resident MARCH5 complex as a central regulator of malignant cell stress tolerance and highlight tractable protein interfaces for therapeutic targeting.

DOI: https://doi.org/10.1182/blood.2026033874
Cell Rep. 2026 Sep 09. pii: S2211-1247(26)01053-3. [Epub ahead of print]45(9): 117975

Mitochondrial Raf1 regulates glutamine catabolism.

Ronald L Shanderson, Ian D Ferguson, Luca Ducoli, Weili Miao, Suhas Srinivasan, Zurab Siprashvili, Albert M Li, Mary Grace Velasco, Yang Li, Christine N Hoang, Jiangbin Ye, Paul A Khavari.

  Raf kinases are central to mitogenic signaling and cancer, yet the full complement of functionally important Raf-proximal proteins across subcellular compartments remains undefined. Here, proximity-dependent biotinylation (BioID) of Raf1 in Raf1-dependent cancer cells recovered proteins localized to the mitochondrial matrix. Mitochondrial purification and super-resolution microscopy confirmed that a pool of Raf1 resides within mitochondria. There, Raf1 associated with glutaminase (GLS) across diverse human cancers and enabled glutaminolysis, a major source of biosynthetic precursors in tumor cells. These effects required Raf1 kinase activity but were independent of canonical MAP kinase pathway signaling, and matrix-targeted kinase-dead Raf1 impaired both glutaminolysis and in vivo tumorigenesis. Raf1 therefore acts inside mitochondria, where it engages GLS to drive glutamine catabolism and support tumor growth, revealing a non-canonical, metabolic arm of Raf signaling.

Keywords:  CP: metabolism; MAPK; Raf1; glutaminase; metabolic reprograming

DOI:  https://doi.org/10.1016/j.celrep.2026.117975
Cell. 2026 Sep 11. pii: S0092-8674(26)00996-7. [Epub ahead of print]

Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.

Charles Ng, Tak Shun Fung, Dayi Li, Korbinian N Kropp, Luis F Somarribas Patterson, Alexandria Markovitz, Daniel N Weinberg, Olivia Jones, Ji-Young Kim, Guoan Zhang, Richard Koche, Mara Monetti, Huayuan Tang, Yun He, Zhengshuang Xu, Xin Cai, Ziqi Yu, Geetha Bhagavatula, Sean P Colgan, Ya-Hui Lin, Zhuoning Li, Elizabeth M Steinert, Christopher A Klebanoff, Santosha A Vardhana, Navdeep S Chandel, Lin Wu, Craig B Thompson.

  Immune elimination of chronic infection or cancer requires cytotoxic CD8+ T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process. Here, we report the ability of D-α-hydroxybutyrate (DAHB) to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation. This conversion elevates the level of a phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induced CD8 effector gene transcription was coupled to bioenergetics by BAF-complex-dependent remodeling of chromatin at effector loci. DAHB-enhanced CD8+ T cell antitumor activity both in vitro and in vivo. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.

Keywords:  BAF; CD8 T cell effector function; D-alpha-hydroxybutyrate; OXPHOS; chromatin remodeling; creatine; phosphocreatine; tumor immunology

DOI:  https://doi.org/10.1016/j.cell.2026.08.023
Exp Hematol Oncol. 2026 Sep 07. pii: 90. [Epub ahead of print]15(1):

CD84 expression stratifies venetoclax response and reveals a targetable vulnerability in resistant acute myeloid leukemia.

Xuemei Wang, Xiangjie Lin, Tianyi Chen, Yi Chen, Huafeng Wang, Yinghui Zhu.

  Venetoclax-based regimens have become increasingly integrated into the therapeutic landscape of acute myeloid leukemia (AML), yet primary resistance and relapses remain major barriers to durable benefits. Building on our previous discovery of CD84 as a critical survivor and redox regulator in AML, we here demonstrate that CD84 expression contributes to venetoclax sensitivity. Low CD84 expression is associated with favorable clinical response, whereas high CD84 expression correlates with primary resistance and is up-regulated at relapse in two of three paired samples. Functional perturbation of CD84 through genetic knockdown or CD84-targeted CAR-T cells sensitized AML cells to venetoclax in vitro and in vivo cell-derived xenograft models. Mechanistically, CD84 coordinates a pro-survival program with upregulating the antioxidant stress sensor SESN2, which suppresses mitochondrial reactive oxygen species and antagonizes venetoclax-induced apoptosis. SESN2 knockdown phenocopied CD84 depletion, while SESN2 overexpression partially restored venetoclax resistance in CD84-deficient cells. Our findings suggest that CD84-mediated upregulation of SESN2 contributes to venetoclax resistance and may represent a potential therapeutic target to enhance treatment efficacy in AML.

Keywords:  Acute myeloid leukemia; CAR-T cell therapy; CD84; Redox homeostasis; Venetoclax resistance

DOI:  https://doi.org/10.1186/s40164-026-00830-z
Autoimmunity. 2026 Dec 31. 59(1): 2722938

Transcription factor 12 promotes acute myeloid leukemia cell survival by regulating mitochondrial function and ROS.

Nianxue Wang, Jianhong Xie, Ruya Zhang, Can Yang, Wei Ren, Liping Shu.

  Acute myeloid leukemia (AML) cells rely heavily on mitochondrial oxidative phosphorylation (OXPHOS) for energy, making mitochondrial function a promising therapeutic target. TCF12, a transcription factor belonging to the basic helix-loop-helix (bHLH) family, has been implicated in various cancers and is highly expressed in AML, where it may contribute to disease progression. However, the effects of TCF12 on AML progression and the underlying mechanisms remain unclear. This study aimed to elucidate the role of TCF12 in promoting AML cell survival and uncover the underlying mechanism. We found that TCF12 was highly expressed in AML and was associated with poor patient prognosis. Knockdown of TCF12 significantly inhibited AML cell growth, suppressed glycolysis, increased ROS accumulation, and induced mitochondrial dysfunction. Additionally, TCF12 was shown to promote EZH2 transcription, whereas its knockdown increased TXNIP expression, thereby inhibiting AML progression. In summary, TCF12 promotes AML progression by regulating EZH2-mediated suppression of TXNIP, thereby enhancing glycolysis, maintaining mitochondrial function, regulating ROS levels, and promoting cell survival, which underscores its potential as a therapeutic target.

Keywords:  EZH2; TCF12; TXNIP; acute myeloid leukemia (AML); mitochondrial dysfunction

DOI:  https://doi.org/10.1080/08916934.2026.2722938
Signal Transduct Target Ther. 2026 Sep 11. pii: 386. [Epub ahead of print]11(1):

Malic enzyme 1 senses L-lactate to determine tumor heterogeneity.

Si-Yi Cao, Kewen Hu, Shijing Huang, Xiao-Lin Guan, Jian Wang, Yuan Shen, Hui Ming, Aihong Gu, Chao Wang, Xiao Shen, Qing Wu, Zhengjun Chen, Miao Yin, Wenyu Wen, Qun-Ying Lei.

L-lactate is generally elevated in tumors and acts as a signaling molecule that promotes tumor progression. Here, we reveal that malic enzyme 1 (ME1) functions as a previously unrecognized sensor of L-lactate through direct binding at arginine 155 (R155), thereby potentiating malignancy. Mechanistically, L-lactate binding promotes the nuclear translocation of ME1, a process involving reduced acetylation at lysine 362 (K362) and facilitated by nuclear import of karyopherin-α 4 (KPNA4). Nuclear accumulation of ME1 enhances metastatic potential, which is correlated with increased interaction with hepatoma-derived growth factor (HDGF) and acquisition of an epithelial‒mesenchymal transition (EMT)-related phenotype. Under nutrient-deficient conditions, L-lactate promotes the assembly of a ME1-lactate dehydrogenase B (LDHB) complex, which enhances oxidative phosphorylation (OXPHOS) and increases ATP production, suggesting a metabolic adaptive mechanism that supports tumor cell survival. Notably, the ME1R155A mutation, which disrupts L-lactate binding, abolishes the protumorigenic effect of the L-lactate-ME1 axis on tumor progression in vivo. In conclusion, our findings identify ME1 as a direct sensor of L-lactate and support a model in which lactate-mediated signaling and metabolic adaptation converge on ME1 to regulate tumor cell plasticity in a context-dependent manner under heterogeneous metabolic conditions. These insights advance our understanding of the spatiotemporal control of metabolic adaptation in cancer and reveal a potential therapeutic target.

DOI: https://doi.org/10.1038/s41392-026-02839-6
Blood Sci. 2026 Sep;8(3): e00296

LPCAT3 is essential for leukemia progression and represents a therapeutic vulnerability in AML.

Mutian Cao, Lizhen Cong, Yifei He, Mingyue Hao, Yuanyi Ling, Wanting Li, Mingyue Zhang, Weiping Yuan, Yajing Chu.

  Acute myeloid leukemia (AML) is a group of genetically and clinically heterogeneous malignancies characterized by clonal expansion of immature myeloid progenitors and profound disruption of normal hematopoiesis. Emerging evidence suggests that alterations in cellular homeostasis shape cancer progression. However, the mechanisms underlying AML progression remain largely unclear. Here, we identify lysophosphatidylcholine acyltransferase 3 (LPCAT3), a key enzyme of the Lands' cycle, as a critical regulator of AML progression. Analysis of public transcriptomic datasets and patient-derived CD34+ cells revealed robust LPCAT3 overexpression in AML and an association between high LPCAT3 levels and inferior overall AML patient survival. Suppression of LPCAT3 by shRNA or CRISPR-Cas9 in MOLM-13 and THP-1 cells markedly impaired proliferation, induced apoptosis, and caused G0/G1 cell-cycle arrest. Conversely, enforced overexpression promoted cell survival. In xenograft murine models, LPCAT3 depletion reduced leukemic burden. RNA-seq following LPCAT3 loss showed that genes differentially expressed were significantly enriched in granulocyte chemotaxis-related pathways, suggesting a role of LPCAT3 in modulation of leukemic differentiation programs and microenvironmental interactions. Collectively, these data established that LPCAT3 as a previously unrecognized mediator of AML cell fitness and as a potential therapeutic target.

Keywords:  Acute myeloid leukemia; Apoptosis; Cell proliferation; Chemotaxis; Immune microenvironment; LPCAT3

DOI:  https://doi.org/10.1097/BS9.0000000000000296
Sci Adv. 2026 Sep 11. 12(37): eaee4935

Acetyl-CoA-dependent processes are preferentially supported by local metabolite synthesis.

Julianna G Supplee, Pedro Costa-Pinheiro, Karl Wessendorf-Rodriguez, Stephanie Stransky, Qihua Yang, Christina Demetriadou, Nivitha Murali, Joy Li, Jennifer L Pennise, Mariola M Marcinkiewicz, Simone Sidoli, Nathaniel W Snyder, Christian M Metallo, Ronen Marmorstein, Kathryn E Wellen.

The cell nucleus is an active metabolic site. Numerous enzymes best known for their roles in cytosolic or mitochondrial pathways also function in the nucleus, where they contribute to gene regulation and DNA replication and repair. Although metabolites can diffuse through nuclear pores, it remains unclear the extent to which the nucleus and cytosol operate as continuous versus distinct metabolic spaces. Both compartments require acetyl-CoA-for example, for histone acetylation and lipid synthesis-and the acetyl-CoA generating enzyme ATP-citrate lyase (ACLY) resides in both locations, but the significance of its dual localization is incompletely understood. Using cell lines in which ACLY is localized to either compartment, we find that ACLY in either location supports fatty acid synthesis and histone acetylation, yet compartment-localized ACLY enables finer control. Nuclear ACLY preserves histone H3K23 acetylation under glucose limitation and modulates specific transcriptional programs, whereas cytosolic ACLY most efficiently supports lipid biosynthetic fluxes. Thus, local synthesis defines a preferential metabolic fate, providing more precise regulation.

DOI: https://doi.org/10.1126/sciadv.aee4935
Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag223

A novel approach to reverse Warburg metabolism in patients with recurrent glioblastoma: A phase II pharmacodynamic study of dichloroacetate.

Carolyn O Dirain, Stuart A Grossman, Xiaobu Ye, Priya Sambasivan, Puranjay Shori, Himashi Liyanarachchi, Thomas D Franklin, Joy Fisher, Trisha Surakus, Michaella Iacoboni, Matthias Holdhoff, Karisa C Schreck, Stephen B Tatter, Richard E Wagner, Roy Strowd, Chetan Bettegowda, Peter W Stacpoole.

   Background: Glioblastomas are characterized by the Warburg effect, driven by upregulation of pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase complex (PDC), leading to lactate accumulation. Dichloroacetate (DCA) is a potent and safe PDK inhibitor that crosses the blood-brain barrier, reverses Warburg metabolism, and reduces lactate levels.
Methods: This trial (RO1FD007271) evaluated the pharmacodynamics and pharmacokinetics of oral DCA in recurrent glioblastoma patients requiring surgical debulking. The primary endpoint was decreased PDC phosphorylation (p-PDHA1) in resected tumors. Patients received either 1 week of DCA or no DCA prior to surgery. All patients received DCA postoperatively. Enhancing and non-enhancing tumor tissue, and serial plasma DCA and lactate levels were analyzed.
Results: 37 patients were enrolled (median age = 60 years). In DCA-treated patients, the contrast-enhancing tumor had lower p-PDHA1, PDK4, HIF1-α, VEGF-α, and PGK1 expression (all P < .05) than non-DCA-treated patients. In non-enhancing tumors, p-PDHA1 and PDK 1-3 expression were not different, but PDK4, PCNA, and PGK1 levels were reduced, and ERK1/2 was increased in DCA-treated patients (all P ≤ .01). At surgery, DCA-treated patients had lower plasma lactate (P = .004) than untreated patients. Postoperatively when all patients received DCA, plasma lactate fell dramatically (P < .001). DCA was well-tolerated but did not delay tumor recurrence.
Conclusions: In recurrent glioblastomas, DCA was safe, well-tolerated, and promoted aerobic respiration. It reduced markers of tumor cell proliferation and lowered plasma lactate. Although no clinical benefit was noted, further studies of combination therapy are indicated, given the known association between poor cancer outcomes and elevated PDK expression and lactate levels.

Keywords:  Warburg metabolism; dichloroacetate (DCA); glioblastoma (GBM); lactate; pyruvate dehydrogenase complex (PDC); pyruvate dehydrogenase kinase (PDK)

DOI:  https://doi.org/10.1093/noajnl/vdag223