bims-medica 2026-09-13 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–09–13
twenty-one papers selected by
Brett Chrest, Wake Forest University

Acetyl-CoA-dependent processes are preferentially supported by local metabolite synthesis.
Differential activation of TCA cycle activity and PDH flux by dichloroacetate in skeletal muscle measured by hyperpolarized [2-13C,3-2H3]pyruvate.
A simple, anesthesia-free infusion technique for in vivo metabolic tracing.
Linking cellular metabolism to mitochondrial outer membrane potential.
A novel approach to reverse Warburg metabolism in patients with recurrent glioblastoma: A phase II pharmacodynamic study of dichloroacetate.
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.
Malic enzyme 1 senses L-lactate to determine tumor heterogeneity.
Pentose phosphate pathway-derived NADPH facilitates physiological hypertrophy and alleviates ischemia-reperfusion injury in the heart.
Dimethylmalonate suppresses white adipocyte differentiation and ameliorates diet-induced obesity.
Distinct Urea Cycle Dysfunction Profiles Differentiate Acute Metabolic Decompensation in TMEM70 and MT-ATP6-Related Mitochondrial ATP Synthase Defects.
Recent Progress in the Synthesis of Succinate Dehydrogenase Inhibitors: From Pyrazole-Coupled Carboxamides and Beyond.
Mitochondrial DNA mutations are associated with impaired oxidative phosphorylation and enhanced imatinib response in chronic myeloid leukemia.
FASN-mediated de novo lipogenesis promotes ceramide accumulation and myocardial damage in arrhythmogenic cardiomyopathy.
Enhanced SIRT3 activity potentiates germinal center epigenetic modulation through α-ketoglutarate.
Scaling temporal resolution from mice to humans: Challenges and innovations in preclinical imaging of translational models.
Adipocyte-derived β-hydroxybutyrate confers metabolic resilience in multiple myeloma.
Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.
Milestones in the Elucidation of Heme Biosynthesis.
Propionyl-CoA catabolism is a metabolic gatekeeper for fatty acid oxidation in pancreatic cancer.
Lactate Metabolism: Separating Correlation From Causation.

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
iScience. 2026 Sep 18. 29(9): 117325

Differential activation of TCA cycle activity and PDH flux by dichloroacetate in skeletal muscle measured by hyperpolarized [2-13C,3-2H3]pyruvate.

Sung-Han Lin, Andrew Cho, Mai T Huynh, Zohreh Erfani, Blanka Kucejova, Sasanka Wathukara Dewage, Thomas Jue, Xiaorong Fu, Zoltán Kovács, Shawn C Burgess, Jae Mo Park.

  Despite the central role of skeletal muscle bioenergetics in whole-body metabolic health, assessing mitochondrial oxidative phosphorylation and tricarboxylic acid (TCA) cycle activity in vivo remains a major challenge. While hyperpolarized [1-13C]pyruvate has been used to probe pyruvate dehydrogenase (PDH) flux to approximate TCA cycle activity, this approach relies on the unreliable assumption that PDH and TCA cycle fluxes are tightly coupled. Here, we demonstrate that hyperpolarized [2-13C,3-2H3]pyruvate can track label-incorporation into TCA cycle-derived glutamate in rat skeletal muscle. Following intravenous dichloroacetate administration, we observed a greater increase in hyperpolarized [1-13C]acetyl-L-carnitine relative to [5-13C]glutamate, suggesting disproportionately increased PDH flux relative to TCA cycle flux. A similar trend was also observed in ex vivo GC-MS analysis of skeletal muscle tissue collected from rats injected with [U-13C3]pyruvate. Together, these findings highlight the complex interplay between PDH and TCA cycle fluxes and establish hyperpolarized [2-13C,3-2H3]pyruvate as a robust agent for assessing mitochondrial metabolism in skeletal muscle.

Keywords:  TCA cycle; acetyl-L-carnitine; dichloroacetate; hyperpolarized; oxidative phosphorylation; pyruvate; pyruvate dehydrogenase; skeletal muscle

DOI:  https://doi.org/10.1016/j.isci.2026.117325
Sci Adv. 2026 Sep 11. 12(37): eaeg1157

A simple, anesthesia-free infusion technique for in vivo metabolic tracing.

Yumi Kim, Samantha Caldwell, Meredith Long, Dominique Abrahams, Margi Baldwin, Gina M DeNicola.

Accurate metabolic flux analysis requires tracer delivery that preserves physiological metabolism. Current methods may distort metabolism through isoflurane anesthesia, surgical stress, or complex procedures. We demonstrate that isoflurane anesthesia profoundly alters serum and tissue metabolism across multiple pathways. In serum, acylcarnitines and fatty acids were broadly decreased, whereas amino acid metabolites and select nucleotide species were increased. Across multiple organs, isoflurane induced coordinated metabolic remodeling and distinct tissue-specific responses, including glycolytic remodeling in the brain and amino acid accumulation in the pancreas. To address these metabolic disturbances, we established a nonsurgical tail vein catheterization method completed in minutes under brief isoflurane anesthesia that enables multihour tracer infusion in awake, freely moving mice. Using U-13C6-cystine infusion, this method achieved robust cysteine labeling and downstream labeling comparable to jugular infusion while maintaining circulating cystine pools closer to physiological levels. This platform provides a practical approach for in vivo stable isotope tracing under more physiological conditions.

DOI: https://doi.org/10.1126/sciadv.aeg1157
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
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
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
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
Nat Metab. 2026 Sep 08.

Pentose phosphate pathway-derived NADPH facilitates physiological hypertrophy and alleviates ischemia-reperfusion injury in the heart.

Dan Wu, Tao Chen, Xin Dong, Haoqi Li, Zijie Cheng, Huimin Li, Yufan Chao, Fangling Li, Yun Yin, Fujun Guo, Xinran Xu, Yuxuan Zhang, Kun Ning, Xiaoqing Fu, Yuemin Bian, Fenfen Ma, Julia Ritterhoff, Wang Wang, Qingxun Hu.

Exercise promotes physiological cardiomyocyte growth and protects against ischaemia-reperfusion (IR) injury in the heart. The molecular mechanism by which exercise benefits cardiac metabolism and function remains largely unknown. Here, using a genetically encoded fluorescent sensor, we show that exercise increases cytosolic, but not mitochondrial, NADPH levels in cardiomyocytes. This effect is mediated by activation of the pentose phosphate pathway (PPP). Inhibition of PPP activity or depletion of cytosolic NADPH attenuates exercise-induced heart hypertrophy in mice. We observe that NADPH promotes cardiomyocyte growth by inhibiting HDAC3/C/EBPβ pathways. Moreover, exercise-activated PPP/NADPH pathway suppresses acute IR injury and preserves heart function 4 weeks after IR. Among 310 tested Tibetan compounds, the spermidine derivative lyciumspermidine-0527 directly activates the rate-limiting PPP enzyme glucose-6-phosphate dehydrogenase, elevates intracellular NADPH levels and alleviates IR injury. Altogether, these results show that PPP-derived NADPH is a critical metabolic checkpoint that regulates exercise-induced physiological cardiomyocyte growth and protects against IR-induced heart injury.

DOI: https://doi.org/10.1038/s42255-026-01587-9
Biochem Biophys Res Commun. 2026 Sep 10. pii: S0006-291X(26)01343-4. [Epub ahead of print]836 154577

Dimethylmalonate suppresses white adipocyte differentiation and ameliorates diet-induced obesity.

Yusei Sato, Yuki Morioka, Miharu Amano, Takushi Namba.

  Obesity is driven by pathological expansion of white adipose tissue (WAT), reflecting both adipocyte hypertrophy and the differentiation of preadipocytes into mature white adipocytes. Arresting adipogenic differentiation is therefore a logical anti-obesity strategy. Because adipogenesis relies on extensive metabolic rewiring, blocking it by targeting mitochondrial enzymes-without collapsing cellular bioenergetics-remains an attractive but unresolved objective. Here, we investigated dimethylmalonate (DMM), a membrane-permeable diester that undergoes intracellular cleavage to yield malonate, a classic competitive inhibitor of succinate dehydrogenase (SDH). During the induced differentiation of 3T3-L1 preadipocytes, DMM treatment concentration-dependently restrained intracellular lipid accumulation. Furthermore, it markedly blunted the differentiation-induced induction of Pparg, which encodes the master transcriptional regulator of the white adipocyte lineage. Importantly, this occurred without bioenergetic collapse: viability remained near 90% at 10 mM, oxygen consumption was sustained and modestly increased, and intracellular ATP content rose. Concurrently, elevated cellular succinate confirmed robust on-target SDH inhibition. In a murine model of high-fat diet (HFD)-induced obesity, daily oral administration of DMM at 600 mg/kg, but not at 200 mg/kg, attenuated body weight gain and reduced both subcutaneous and visceral WAT mass. These morphological improvements were accompanied by improved glucose tolerance and insulin sensitivity, with no significant alteration in daily food intake or in the mass of the liver, heart, and skeletal muscle. Collectively, our findings demonstrate that DMM suppresses white adipocyte differentiation and ameliorates diet-induced obesity while sustaining mitochondrial respiration and ATP content, highlighting targeted SDH modulation as a viable anti-obesity therapeutic strategy.

Keywords:  Adipogenesis; Dimethylmalonate; Mitochondria; Obesity; Succinate dehydrogenase; White adipocyte differentiation

DOI:  https://doi.org/10.1016/j.bbrc.2026.154577
J Inherit Metab Dis. 2026 Sep;49(5): e70244

Distinct Urea Cycle Dysfunction Profiles Differentiate Acute Metabolic Decompensation in TMEM70 and MT-ATP6-Related Mitochondrial ATP Synthase Defects.

Barbara Siri, Diego Martinelli, Rosalba Carrozzo, Sara Boenzi, Sara Cairoli, Cristiano Rizzo, Teresa Giovanniello, Johannes Häberle, Carlo Dionisi-Vici.

  ATP synthase defects, including TMEM70 and MT-ATP6 deficiencies, cause severe mitochondrial encephalo-(cardio)-myopathies complicated by acute metabolic decompensations (AMDs) often associated with hyperammonaemia. However, detailed biochemical characterisation of these events remains limited. The aim of the study was to evaluate the metabolic profiles associated with TMEM70 and MT-ATP6 deficiencies during AMDs in comparison to stable metabolic conditions, assessing frequency and severity of hyperammonaemia, and exploring the mechanisms linking impaired mitochondrial ATP production to the urea cycle by in vivo ureagenesis studies, using [15N] ammonium chloride as stable isotope and assessed by high-resolution mass-spectrometry coupled with liquid chromatography. We retrospectively analysed clinical and biochemical profiles from two genetically confirmed cohorts. Patients with TMEM70 deficiency experienced more frequent AMDs, often with hyperammonaemia and requiring extracorporeal detoxification, while the MT-ATP6 cohort had more prominent neurological symptoms and a lower incidence of hyperammonaemia. Biochemically, both groups showed elevated lactate, alanine and glutamine, with orotic aciduria and abnormalities in purine/pyrimidine metabolism. Plasma citrulline levels were divergent in the two cohorts, with a consistent reduction in patients with MT-ATP6 deficiency and normal or borderline elevated levels in the TMEM70 cohort. In vivo stable isotope studies pointed to the differential impact of TMEM70 and MT-ATP6 deficiency on ureagenesis and on the enrichment of individual urea cycle-related amino acids. This study reveals that TMEM70 and MT-ATP6 deficiencies share features of mitochondrial dysfunction but present distinct metabolic profiles, highlighting a different impact on the urea cycle and its related metabolites, and providing novel insights on our understanding of mitochondrial pathophysiology.

Keywords:  ATP synthase defects; MT‐ATP6; TMEM70‐related encephalo‐(cardio)‐myopathy; acute metabolic decompensation; urea cycle

DOI:  https://doi.org/10.1002/jimd.70244
Mini Rev Med Chem. 2026 Sep 07.

Recent Progress in the Synthesis of Succinate Dehydrogenase Inhibitors: From Pyrazole-Coupled Carboxamides and Beyond.

Pedro Alves Bezerra Morais, Lucas Inacio Dos Santos Ferreira, Jéssica Adalgisa Barbosa Silva, Gabriel Scudino Freitas, Lara Chaves de Freitas Ferreira, Elziane Favoreto Alves Firmino, Adilson Vidal Costa, Vagner Tebaldi de Queiroz, Heberth de Paula, Valdemar Lacerda Júnior.

  A growing global population and increasingly stringent food-security demands, together with evolving challenges such as crop diseases, resistant weeds, and agrochemical-resistant pathogenic microorganisms, require new strategies to safeguard agricultural productivity. Succinate dehydrogenase (SDH, also known as complex II) participates in both the tricarboxylic acid cycle and the mitochondrial respiratory chain in pathogenic fungi, thereby affecting fungal metabolism and mitochondrial respiration. This enzyme has therefore been widely explored as a target in the search for new fungicides. Currently, 25 commercially available succinate dehydrogenase inhibitors (SDHIs) are used to protect economically important crops. The discovery of new agrochemicals is driven by the need to mitigate annual losses in agricultural productivity, estimated at approximately US$220 billion per year. This review summarizes advances in the synthesis of potent SDHIs over the last decade, including semisynthetic approaches and strategies combining carboxamide scaffolds with heterocyclic moieties based on bioisosterism, scaffold hopping, and molecular hybridization. The studies summarized here show that numerous hit compounds have recently been synthesized with EC50 values against several fungal strains and IC50 values for SDH inhibition that compare favorably with those of reference agrochemicals such as boscalid, thifluzamide, fluxapyroxad, fenfuram, and fluopyram. Finally, both established and emerging synthetic methods aimed at accelerating the generation of large compound libraries are increasingly supported by robust computational approaches, including 3D-QSAR and molecular dynamics simulations, to predict binding modes and provide structural insights for future investigations.

Keywords:  Antifungal agents; agrochemicals.; carboxamides; enzymatic inhibition; heterocycles; rational design; semisynthesis; succinate dehydrogenase

DOI:  https://doi.org/10.2174/0113895575446683260811054954
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
iScience. 2026 Sep 18. 29(9): 117251

FASN-mediated de novo lipogenesis promotes ceramide accumulation and myocardial damage in arrhythmogenic cardiomyopathy.

Zirui Liu, Hao Cui, Tianshuo Yang, Songren Shu, Zhice Chen, Jing Han, Mingming Su, Jian Huang, Xiao Chen, Jiangping Song, Shengshou Hu.

  Arrhythmogenic cardiomyopathy (ACM) is a heritable disease caused by desmosomal gene mutations and marked by progressive myocardial loss and fibrofatty replacement. Here, we show that fatty acid synthase (FASN), the rate-limiting enzyme of de novo lipogenesis, is upregulated in cardiomyocytes of ACM patients and of a cardiomyocyte-specific Dsg2-mutant mouse model. Desmosomal dysfunction drives nuclear translocation of junction plakoglobin (JUP), which cooperates with SREBP1 to activate FASN transcription. The resulting de novo lipogenesis diverts glucose toward synthesis of lipotoxic ceramides, promoting cardiomyocyte apoptosis, as shown by isotope tracing, lipidomics, and RNA sequencing (RNA-seq). Pharmacological FASN inhibition with orlistat reduced myocardial lipid accumulation, apoptosis, inflammation, and fibrosis, improving cardiac function and survival. These findings define a JUP/SREBP1/FASN axis linking desmosomal dysfunction to myocardial lipotoxicity and identify FASN as a candidate therapeutic target in ACM.

Keywords:  arrhythmogenic cardiomyopathy; de novo lipogenesis; fatty acid synthase; lipotoxicity; myocardial injury

DOI:  https://doi.org/10.1016/j.isci.2026.117251
J Biol Chem. 2026 Sep 11. pii: S0021-9258(26)02424-5. [Epub ahead of print] 113552

Enhanced SIRT3 activity potentiates germinal center epigenetic modulation through α-ketoglutarate.

Xinyu Yang, Guoyuan Peng, Qian Hao, Kexin Liu, Zhengcao Xin, Mingming Zhang, Innocent Agida, Yong Zuo, Leng-Siew Yeap, Tianshi Wang, Jianli He, Hongsheng Tan, Jinke Cheng.

  Germinal center (GC) B cells depend on sustained epigenetic modulation to maintain transcriptional identity and support affinity maturation; however, whether mitochondrial metabolism directly enhances this chromatin state remains unclear. Here, we show that enhanced SIRT3 activity promotes glutamine-derived α-ketoglutarate (αKG) accumulation and is associated with reduced H3K27me3 enrichment at the Bcl6 locus. Using SIRT3 K223R gain-of-function mice, metabolomic profiling, and stable isotope tracing, we show that SIRT3 activation increases glutamine-derived αKG accumulation without a uniform increase in downstream tricarboxylic acid (TCA) cycle labeling. Elevated αKG was associated with reduced H3K27me3 at tested Bcl6 regulatory regions, reinforced BCL6 and AID expression, sustained B cell proliferation, and qualitatively enhanced antibody affinity maturation. Glutamine supplementation partially phenocopied these effects, whereas inhibition of glutamine metabolism attenuated them. Importantly, sustained activation of this metabolic-epigenetic axis was associated with enhanced GC expansion accompanied by increased autoantibody levels and renal IgG deposition in a pristane-induced lupus model. Collectively, our findings indicate that enhanced SIRT3 activity potentiates a glutamine-αKG-chromatin axis that links mitochondrial glutamine metabolism to germinal center epigenetic modulation and humoral immune output.

Keywords:  Antibody affinity maturation; B cells; Epigenetic regulation; Germinal center; Glutaminolysis; SIRT3; α-Ketoglutarate

DOI:  https://doi.org/10.1016/j.jbc.2026.113552
J Physiol. 2026 Sep 10.

Scaling temporal resolution from mice to humans: Challenges and innovations in preclinical imaging of translational models.

Sara Gargiulo, Matteo Gramanzini.

  Temporal scaling physiology differs significantly between mice and humans, essentially because, in mice, several biological processes occur at a much faster time scale. Mice have faster metabolism, heart and respiratory rate, blood flow rates, brain activity, and disease progression dynamics. By combining three-dimensional spatial data with time, four-dimensional imaging enables to capture rapid, transient physiological events and long-term pathogenetic changes in living mouse models, enhancing the translation of biological insights to human disease processes. In preclinical imaging, technical trade-offs among spatial and temporal resolution and field of view coexist with the need for anaesthesia or restraints to prevent motion, as well as invasive procedures to access and visualize target structures, potentially affecting physiology and animal welfare. These issues are addressed by developing specialized and advanced imaging technologies, applicable to awake or freely moving rodents, and through careful animal management using a multidisciplinary approach, opening new horizons in the study of human diseases in mouse models. Combining different techniques or using advanced algorithms can further help overcome the limitations of individual imaging modalities and improve both spatial and temporal resolution. We provide an overview of emerging preclinical imaging techniques that improve the translation of findings from mouse models, advancing our understanding of human disease physiology and pathogenesis through enhanced spatiotemporal resolution. It aims to help researchers critically select complementary experimental methods across diverse scientific fields, at the same time as summarizing recent technological advances in preclinical imaging and key considerations in animal care and use.

Keywords:  biological scaling; mouse models; preclinical imaging; temporal resolution

DOI:  https://doi.org/10.1113/JP290409
Nat Commun. 2026 Aug 11. pii: 9611. [Epub ahead of print]17(1):

Adipocyte-derived β-hydroxybutyrate confers metabolic resilience in multiple myeloma.

Chen Song, Peng Yang, Yu Li, Tao Xia, Rui Li, Mengmeng Guo, Wenjun Li, Chenfeng Liu, Tiantian Jia, Yansheng Wang, Xunxia Bao, Qi Wang, Yuan Yao, Qian Dai, Huan Liu, Zongwei Li.

Multiple myeloma (MM) remains an incurable blood cancer. Obesity is a known risk factor, but how adipocytes promote MM progression is not fully understood. Here, we uncover a metabolic crosstalk between adipocytes and MM cells that promotes MM cell survival under glucose deprivation. We show that glucose restriction activates AMPK, disrupting HSP90-IRF4 binding and rendering IRF4 susceptible to TRIM21-mediated proteasomal degradation. Paradoxically, the same stress stimulates adipocytes to produce β-hydroxybutyrate (β-OHB). MM cells utilize β-OHB through OXCT1-mediated ketolysis, fueling NAT10-dependent acetylation of IRF4 at K87, which restores IRF4-HSP90 binding and sustains tumor cell survival. Genetic ablation of the rate-limiting ketogenic enzyme Hmgcs2 in adipocytes abrogates this protective effect. Importantly, combining an AMPK activator (metformin) with an OXCT1 inhibitor (pimozide) or a NAT10 inhibitor (remodelin) shows synergistic anti-tumor activity in vivo. Our findings position adipocyte-derived β-OHB as a critical metabolic adaptor and highlight a potential combination therapy for MM.

DOI: https://doi.org/10.1038/s41467-026-76595-0
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
Chem Rev. 2026 Sep 09. 126(17): 10107-10144

Milestones in the Elucidation of Heme Biosynthesis.

Harry A Dailey.

Heme (protoheme IX) is an essential cofactor in biology, serving diverse roles including, but not limited to, one-electron reactions, oxygen transport, catalysis, and signaling. The elucidation of its biosynthetic pathway represents one of the more remarkable scientific accomplishments of the past century. Early 19th-century chemists first isolated, named and characterized porphyrins, while their structural determination by Fischer in the 1920s earned a Nobel Prize. The mid-20th century ushered in isotopic tracer studies which revealed glycine and succinyl-CoA as the starting substrates for the pathway to heme. Identification of porphobilinogen (PBG) as an early pathway intermediate led to the identification of 5-aminolevulinic acid (ALA) as the first committed pathway precursor. Subsequent decades brought the recognition of porphyrinogens as true pathway intermediates, the sequence of decarboxylation and oxidation steps, the identification of the glutamate-based pathway to ALA in plants and most bacteria, the characterization of all pathway enzymes, the discovery of alternate bacterial pathways, and identification of multiprotein complexes. This review traces the historical progression of discoveries, highlighting both the breakthroughs and missteps that shape the current view of heme biosynthesis, and underscores the interplay of chemistry, physiology, and molecular biology in unraveling this ancient metabolic pathway.

DOI: https://doi.org/10.1021/acs.chemrev.6c00368
Oncogene. 2026 Sep 11.

Propionyl-CoA catabolism is a metabolic gatekeeper for fatty acid oxidation in pancreatic cancer.

Weidong Yu, Bo Wang, Fanhao Meng, Xiaojun Ren, Danyi Zhou, Huanxin Wei, Zhengquan Yang, Hongwei Sun, Minghua Jiang, Tao Xia, Wei Cui, Hezhi Fang.

Pancreatic ductal adenocarcinoma (PDAC) cells rely on fatty acid oxidation (FAO) for proliferation; however, the regulatory mechanisms governing this dependency and their clinical implications remain unclear. Here, we report that PDAC patients exhibit decreased plasma levels of propionyl-CoA intermediates, alongside accelerated propionyl-CoA catabolic activity within both human PDAC tumors and Pdx1-Cre/KrasG12D/+/Trp53R172H/+ (KPC) mouse tumors. Specifically, PDAC cells upregulate propionyl-CoA carboxylase (PCC) to accelerate propionyl-CoA catabolism, thereby establishing a metabolic signature distinct from that of healthy tissues. Mechanistically, PCC is essential for PDAC growth, not by fueling the TCA cycle, but by preventing toxic propionyl-CoA accumulation. We further demonstrate that elevated propionyl-CoA leads to the propionylation-induced inactivation of the mitochondrial fatty acid oxidation (FAO) enzyme ACAA2 at Lysine 137, thereby blocking the FAO flux required for tumor proliferation. Moreover, high PCCA expression in patient PDAC tumors is significantly associated with decreased lipid accumulation, and PDAC cells with high PCC levels are more sensitive to etomoxir-induced cell proliferation arrest. These findings establish the PCC-ACAA2 axis as a critical metabolic vulnerability and a promising target for diagnostic and therapeutic interventions in PDAC.

DOI: https://doi.org/10.1038/s41388-026-03979-3
Bioessays. 2026 Sep;48(9): e70181

Lactate Metabolism: Separating Correlation From Causation.

Bhavya Blaze, Ahmad A Cluntun.

  Lactate is among the most frequently measured metabolites in physiology and medicine, yet it remains one of the most persistently misunderstood. Long regarded as a metabolic waste product, a marker of anaerobic metabolism, or a direct cause of acidosis and fatigue, lactate remains burdened by misconceptions that obscure its true biological roles. Recent advances in metabolic flux analysis, isotope tracing, hyperpolarized magnetic resonance spectroscopy, and cellular imaging have revised this view and established lactate as a central intermediary in energy metabolism, redox homeostasis, and interorgan metabolic communication. Here, we re-examine common myths surrounding lactate biology and clarify the distinction between correlation and causation in its interpretation. By reframing lactate as a dynamic indicator and, in some contexts, a regulator, of metabolic state rather than a toxic by-product, this review improves experimental reasoning and clinical interpretation across diverse physiological and pathological contexts.

Keywords:  aerobic glycolysis; clinical biomarkers; correlation versus causation; lactate metabolism; metabolic flux; mitochondrial metabolism; redox homeostasis

DOI:  https://doi.org/10.1002/bies.70181