bims-medica 2026-06-07 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–06–07
29 papers selected by
Brett Chrest, Wake Forest University

Adaptive plasticity of aspartate metabolism in succinate dehydrogenase-deficient cancer cells.
Surface Complex V couples proton gradient across the plasma membrane to ATP production in cancer.
Cells Engage Endogenous Malonate Synthesis to Drive Mitochondrial Metabolism.
Extracellular lactate reprograms mitochondrial metabolism and NAD+/NADH redox balance in blood-brain barrier endothelial cells via an LDHB-MPC-NAD+ axis.
β-Hydroxybutyrate elicits divergent metabolic responses between MCF-7 and T47D ER+ breast cancer cells under glucose restriction.
Mitochondrial copper stabilizes lipoylated TCA cycle proteins to sustain metabolism and proliferation.
Glycolysis and glycolytic enzymes in acute myeloid leukemia: Warburg and beyond.
Functional specialization within the mitochondrial network: Are all mitochondria created equal?
Cancer as a window into mitochondrial biology.
Management and risk mitigation strategies for FLT3-ITD+ acute myeloid leukemia: clinical utilization of quizartinib.
The significance of the ketolytic gene OXCT1 in metabolism, intracellular signaling and disease development.
The KDM-family inhibitor JIB-04 sensitizes AML cells to venetoclax by inducing a ferroptosis-like phenotype.
Cristae Architecture as a Metabolic Checkpoint in Effector T Cells - Implications for Cancer Immunity.
Skeletal muscle carnitine-acylcarnitine translocase deletion reveals vulnerability of oxidative muscle to fatty acid oxidation deficiency.
Intestinal mitochondrial complex I inhibition essential for clinical benefits of metformin.
A liquid chromatography-mass spectrometry method to quantify total Coenzyme A concentration and isotopic labeling.
Mitochondrial RNA degradation regulates differentiation, stemness, and immune sensitivity in acute myeloid leukemia.
HSPA6 maintains IMPDH2 phosphorylation to regulate GTP synthesis for driving radioresistance of glioblastoma stem cells.
Direct pharmacological targeting of asparagine synthetase to overcome resistance to L-asparaginase in ALL therapy.
Ketone bodies as guardians of leukemic stemness through ferroptosis suppression.
Pan-cancer molecular signatures connecting aspartate transaminase to cancer prognosis, metabolic and immune signatures.
A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage.
Design, synthesis, and mechanistic study of novel isoflavone derivatives as mitochondrial complex I inhibitors for non-small cell lung cancer treatment.
Reductive death is averted by a conserved de novo lipogenic switch.
Effect of six weeks ubiquinol supplementation on mitochondrial respiratory function and exercise capacity in healthy males.
Next-generation genetically encoded biosensors for spatiotemporal intracellular pH monitoring, mapping, and profiling.
Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors.
Marked changes in one-carbon metabolism on a low-carbohydrate high-fat diet: a randomized controlled trial (CARBFUNC).
Excess glucose shapes mitochondrial metabolism and redox state in human primary white adipocytes.

bioRxiv. 2026 May 21. pii: 2026.05.18.726122. [Epub ahead of print]

Adaptive plasticity of aspartate metabolism in succinate dehydrogenase-deficient cancer cells.

David Sokolov, Eric Zheng, Serwah Danquah, Madeleine L Hart, Lucas B Sullivan.

Succinate dehydrogenase (SDH) supports cancer cell proliferation by enabling oxidative biosynthesis of the amino acid aspartate, yet SDH loss can also drive tumorigenesis. To cope with SDH loss, cancer cells can engage alternative aspartate synthesis pathways; however, the variables dictating pathway usage and adaptive mechanisms involved are incompletely understood. Here, we systematically profile the adaptation of SDH-knockout cancer cells and find that cells can adapt to SDH loss via at least two distinct mechanisms: suppression of respiratory complex I or upregulation of pyruvate carboxylase. Each route gives rise to distinct metabolic states with both shared and unique dependencies, but either route allows cells to overcome aspartate limitation, improve proliferative fitness, and mitigate pyrimidine-dependent replication stress. Overall, this work provides a comprehensive view of adaptive aspartate synthesis in SDH-deficient cancer cells, highlights a remarkable redox-constrained metabolic plasticity, and nominates potential metabolic vulnerabilities likely to be shared among SDH-deficient cancer cells.

DOI: https://doi.org/10.64898/2026.05.18.726122
bioRxiv. 2026 May 21. pii: 2026.05.19.726308. [Epub ahead of print]

Surface Complex V couples proton gradient across the plasma membrane to ATP production in cancer.

Samantha A McLaughlin, Kendall W Knechtel, Zelia M Correa, J William Harbour, Daniel Pelaez.

Cancer cells alter their metabolism to support growth and survival, most notably by fermenting glucose to lactate even in the presence of oxygen, a phenomenon known as the Warburg effect. Although this metabolic state has been recognized for decades, its bioenergetic advantages remain unclear, as fermentation produces less net ATP than mitochondrial respiration. How aerobic fermentation contributes to cellular energy balance therefore remains unresolved. Here, we show that extracellular acidification generated by lactate export creates a proton gradient across the plasma membrane that is harnessed by ectopic ATP synthases to drive intracellular ATP production. We find that ATP synthase and proton-shuttling components of the mitochondrial respiratory chain translocate to the plasma membrane in cancer cells and are preferentially oriented to exploit this gradient, linking a hallmark of aerobic fermentation directly to energy supplementation. This work provides a mechanistic resolution to the apparent energetic inefficiency of the Warburg paradigm and identifies a previously unrecognized pathway for energy complementation in cancer.

DOI: https://doi.org/10.64898/2026.05.19.726308
bioRxiv. 2026 May 29. pii: 2026.05.22.727248. [Epub ahead of print]

Cells Engage Endogenous Malonate Synthesis to Drive Mitochondrial Metabolism.

Riley J Wedan, Pieter R Norden, Morgan T Canfield, Abigail E Ellis, Sanskriti Saxena, Jacob Z Longenecker, Michelle Dykstra, Ryan D Sheldon, Sara M Nowinski.

Malonate is often described as an endogenous inhibitor of complex II of the electron transport chain. However, the cellular source of malonate is unclear, and current knowledge concerning its metabolism is limited to the action of a single enzyme, Acyl-CoA Synthetase Family Member 3 (ACSF3), which converts malonate to malonyl-CoA in the mitochondrial matrix. One potential route of malonate metabolism downstream of ACSF3 is its consumption by the mitochondrial fatty acid synthesis (mtFAS) pathway. However, studies examining the link between ACSF3 and mtFAS have yielded conflicting results. We developed a novel mass spectrometry approach to perform stable isotope tracing into products of mtFAS, and found that while malonate is in fact a carbon source for mtFAS, ACSF3 is not required for malonate incorporation into mtFAS products. Using this method to trace other nutrients into mtFAS, we also found evidence of acetyl-CoA carboxylase 1 (ACC1)-dependent malonate synthesis from glucose. We further show that ACC1 is required for optimal mtFAS activity, with downstream effects on oxidative phosphorylation. Together these findings establish the malonate as a regulated endogenous intermediate that supports mtFAS activity and mitochondrial oxidative function.

DOI: https://doi.org/10.64898/2026.05.22.727248
Free Radic Biol Med. 2026 May 29. pii: S0891-5849(26)00839-7. [Epub ahead of print]253 377-392

Extracellular lactate reprograms mitochondrial metabolism and NAD+/NADH redox balance in blood-brain barrier endothelial cells via an LDHB-MPC-NAD+ axis.

Charul Jain, Helgi Kuzmychova, Akaljot Grewal, Ujala Chawla, Revanti Mukherjee, Versha Banerji, Christopher M Anderson, Emma Martell, Tanveer Sharif.

Brain endothelial cells (BECs) form the structural foundation of the blood-brain barrier (BBB) and exhibit a paradoxical metabolic phenotype, converting approximately 90% of consumed glucose to lactate despite residing in an oxygen-rich vascular environment. Whether the extracellular lactate that BECs continuously produce and export feeds back to regulate their own metabolism and redox state has not been directly investigated. Here, using validated BBB model, we demonstrate that exogenous lactate drives a concentration- and time-dependent biphasic growth response, with 10 mM lactate maximally promoting BEC proliferation at 48 h. Mechanistically, lactate suppresses canonical glycolysis evidenced by downregulation of GLUT1 and key glycolytic enzymes and reduced glucose uptake while simultaneously driving a coordinated shift toward mitochondrial oxidative metabolism. This shift is mediated by upregulation of LDHB, MPC1, MPC2, and PDH activation, enabling lactate-derived pyruvate to enter mitochondria and fuel comprehensive TCA cycle engagement, mitochondrial biogenesis, and enhanced oxidative phosphorylation capacity as measured by high-resolution respirometry. At the redox level, lactate oxidation imposes reductive pressure on the NAD+/NADH pool, which is counterbalanced by activation of the NAMPT-dependent NAD+ salvage pathway, resulting in expansion of the total NAD pool. Genetic silencing of LDHB or MPC1 and pharmacological inhibition of NAMPT each independently abolish lactate-driven BEC proliferation, establishing the LDHB-MPC-NAD+ axis as mechanistically essential. These findings identify the cerebrovascular endothelium as an active participant in brain lactate mitochondrial function and introduce the LDHB-MPC-NAD+ axis as a novel redox-metabolic regulatory circuit at the BBB.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.05.335
bioRxiv. 2026 May 18. pii: 2026.05.14.725288. [Epub ahead of print]

β-Hydroxybutyrate elicits divergent metabolic responses between MCF-7 and T47D ER+ breast cancer cells under glucose restriction.

Cynthia Cheung, Natalija Glibetic, Rylee Maldonado, Scott Bowman, Tia Skaggs, Louise Torres, Katelynn A Perrault Uptmor, Michael Weichhaus.

Background: The ketogenic diet is being explored as an adjuvant intervention in breast cancer because it lowers circulating glucose and elevates ketone bodies such as β-hydroxybutyrate (BHB), but how individual ER+ breast cancer subtypes adapt to these conditions remains poorly characterized. We examined metabolic responses to BHB supplementation under glucose restriction in two ER+ breast cancer cell lines, asking whether metabolic adaptation patterns differ between models.
Methods: MCF-7 and T47D cells were cultured under high glucose, glucose-restricted (5% of standard), or glucose-restricted with 10 mM BHB conditions and profiled by comprehensive two-dimensional gas chromatography-mass spectrometry (GC×GC-MS). Pairwise Welch's t-tests with Benjamini-Hochberg false discovery rate (FDR) correction were applied to identify treatment-responsive metabolites. Targeted assays quantified intracellular glycine, SHMT1 protein, and total branched-chain amino acid (BCAA) concentrations across a BHB dose range (2.5-15 mM). Patient tumor transcriptomic data from TCGA (n=1,084) and paired tumor-normal samples from GSE58135 (n=20) were analyzed for genes involved in one-carbon, ketone body, and BCAA metabolism.
Results: MCF-7 and T47D cells exhibited markedly divergent metabolic responses to BHB. In MCF-7 cells, BHB supplementation produced a broad pattern-level metabolic shift: 75% of detected metabolites trended upward when BHB was added to glucose-restricted cultures (C vs. B comparison), with 1,4-butanediol reaching nominal significance (FC=2.35, p=0.016) and a 4.1-fold trend increase in lactic acid (p=0.11), although no individual metabolite survived FDR correction. T47D cells showed essentially no metabolic response to BHB at the global level. Targeted assays detected an elevation in glycine at 5 mM BHB in both cell lines that did not follow a monotonic dose response and was not accompanied by changes in SHMT1 protein expression. Total BCAA levels were elevated by BHB in T47D cells but remained unchanged in MCF-7 cells. In paired patient samples, OXCT1 (log2FC = -1.41), SHMT1 (log2FC = -1.31), and ACAT1 (log2FC = -1.07) were significantly downregulated in ER+ tumors relative to matched normal tissue (adjusted p < 0.001 for all three).
Conclusions: ER+ breast cancer cell lines show heterogeneous metabolic responses to BHB supplementation under glucose restriction. The broad pattern of metabolite elevation in MCF-7 but not T47D cells suggests that capacity to utilize ketone bodies as metabolic substrate varies between ER+ models. The downregulation of OXCT1, ACAT1, and SHMT1 in ER+ tumors compared to normal tissue identifies these enzymes as candidate biomarkers that may help stratify which patients are likely to benefit from ketogenic interventions. Findings related to individual metabolites should be regarded as exploratory and require validation in larger, adequately powered cohorts.

DOI: https://doi.org/10.64898/2026.05.14.725288
bioRxiv. 2026 May 22. pii: 2026.05.20.726656. [Epub ahead of print]

Mitochondrial copper stabilizes lipoylated TCA cycle proteins to sustain metabolism and proliferation.

Santanu Ghosh, Andrew F Jarvis, Jordi C J Hintzen, Nate R McKnight, Pedro Costa-Pinheiro, Noelle H Noughton, Yumi Kim, Alison Jaccard, Scot C Leary, Paul A Cobine, Caroline R Bartman, Gina M DeNicola, Nathaniel W Snyder, Kathryn E Wellen, George M Burslem, Donita C Brady.

Copper (Cu) is an essential cofactor for mitochondrial cytochrome c oxidase, yet whether it directly regulates mitochondrial metabolism beyond respiration remains unclear. Here we show that mitochondrial Cu, delivered by SLC25A3, is required to maintain the stability of lipoylated TCA cycle proteins. Loss of Slc25a3 or pharmacological Cu depletion selectively destabilized the lipoylated E2 subunits of mitochondrial dehydrogenases and the lipoylation enzymes LIPT1 and LIPT2, an effect not reproduced by acute electron transport chain inhibition. Mechanistically, we find that Cu directly engages the reduced lipoyl moiety using chemical probes and synthetic peptide approaches. Cu depletion impaired PDH and OGDH activity, rewired TCA cycle metabolism, and imposed a dependence on pyruvate carboxylase for anaplerosis. This metabolic defect depleted aspartate, suppressed mTORC1 signaling, and limited proliferation. Conversely, selective delivery of Cu to the mitochondria restored lipoylation, TCA cycle function, and cell growth. Together, these findings identify mitochondrial Cu as a structural regulator of the lipoylation machinery and reveal a direct link between Cu homeostasis and central carbon metabolism.

DOI: https://doi.org/10.64898/2026.05.20.726656
Front Pharmacol. 2026 ;17 1823211

Glycolysis and glycolytic enzymes in acute myeloid leukemia: Warburg and beyond.

Kristina Seiler, Yasmeen H Mady, Bruce E Torbett, Jean-Emmanuel Sarry, Mario P Tschan.

  The ability to generate and regulate energy, maintain metabolic flux, and preserve redox homeostasis is the basis of all cellular processes in both healthy and diseased tissues. While the importance of glycolytic metabolism in cancer biology is well established, the clinical translation of metabolic targeting strategies remains limited. A deeper understanding of how energy flux is regulated and how metabolic enzymes contribute to cell survival, proliferation, differentiation, and therapy response will help identify cancer-specific metabolic dependencies and drive novel therapeutic approaches. Recent advances in molecular and metabolic profiling have highlighted the multifaceted roles of glycolytic enzymes beyond their canonical functions. In this review, we summarize current knowledge on glycolytic enzymes and their involvement in normal and malignant myelopoiesis, with a particular focus on acute myeloid leukemia (AML). AML cells exhibit high glycolytic activity and frequently overexpress key glycolytic enzymes. Beyond their metabolic functions, these enzymes also exert regulatory roles in signaling, transcriptional control, and redox balance. Here, we discuss both the canonical and non-canonical functions of glycolytic enzymes and evaluate their potential as therapeutic targets in AML.

Keywords:  AML; OxPhos; Warburg effect; glycolysis; metabolic inhibitors; metabolic reprogramming; non-canonical functions

DOI:  https://doi.org/10.3389/fphar.2026.1823211
Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00184-1. [Epub ahead of print]38(6): 1089-1092

Functional specialization within the mitochondrial network: Are all mitochondria created equal?

Jessica B Spinelli.

Mitochondria are classically viewed as a uniform ATP-producing network; however, a growing body of evidence suggests distinct subpopulations exist within tissues and even single cells. Here, I highlight evidence supporting the presence of functionally distinct mitochondria and propose mechanisms by which these subpopulations are formed and regulated.

DOI: https://doi.org/10.1016/j.cmet.2026.04.019
Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00188-9. [Epub ahead of print]38(6): 1085-1088

Cancer as a window into mitochondrial biology.

Thomas MacVicar, Laura C Greaves, Payam A Gammage, Stephen W G Tait, Kelsey H Fisher-Wellman, Gordon Freedman.

Cancer has revealed that the mitochondrion is not a static organelle but a system of extraordinary plasticity. Here, we introduce fundamental mitochondrial behaviors that have been illuminated by cancer research and propose that further investigation in mitochondrial biology holds promise for oncology and beyond.

DOI: https://doi.org/10.1016/j.cmet.2026.05.003
Leuk Lymphoma. 2026 May 30. 1-8

Management and risk mitigation strategies for FLT3-ITD+ acute myeloid leukemia: clinical utilization of quizartinib.

Laurie Horsch, Jeffrey Baron, Pamela J Sung, Eunice S Wang.

  Acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutations represent a clinically aggressive subtype of AML characterized by a poor prognosis and high frequency of relapse. Although several FLT3 inhibitors exist, they differ in their side effects, potency and clinical use. Quizartinib is a potent next generation FLT3 inhibitor with a risk of QTc-prolongation necessitating a Risk Evaluation and Mitigation Strategies (REMS) program as well as potential drug-drug interactions with strong CYP3A4 inhibitors. Here we detail two patient cases illustrating the real-world use of quizartinib in combination with anthracycline and cytarabine-based chemotherapy and maintenance monotherapy for the management of FLT3-ITD+ AML. These cases highlight the practical recommendations on management of quizartinib-based chemotherapy in accordance with the Food and Drug Administration (FDA)-mandated REMS requirements. Adopting these strategies to optimize the safe treatment of FLT3-ITD+ AML with quizartinib may ultimately improve patient outcomes in this highly challenging malignancy.

Keywords:  Acute myeloid leukemia; FLT3-ITD mutation; QTc prolongation; quizartinib; safety profile

DOI:  https://doi.org/10.1080/10428194.2026.2676107
Cell Mol Life Sci. 2026 Jun 06.

The significance of the ketolytic gene OXCT1 in metabolism, intracellular signaling and disease development.

Karolina Górecka, Kamila Soboska, Marcin Pacholczyk, Luciano Pirola, Aneta Balcerczyk.

  OXCT1 (3-oxoacid CoA-transferase 1), encoding the mitochondrial enzyme SCOT (succinyl-CoA:3-ketoacid CoA transferase), is a key enzyme in ketone body utilization. It catalyzes the reversible transfer of CoA from succinyl-CoA to acetoacetate, generating acetoacetyl-CoA, which is subsequently converted into acetyl-CoA for entry into the tricarboxylic acid (TCA) cycle and mitochondrial energy production. Although classically regarded as a metabolic enzyme, emerging evidence indicates that OXCT1 participates in broader regulatory networks. In addition to its protein-coding transcript, the OXCT1 locus produces regulatory non-coding RNAs, including circ-OXCT1 and lncRNA OXCT1-AS1, which provides additional levels of regulation, as for now reported in various types of cancer. Moreover, the review summarizes current knowledge on OXCT1 biochemical function, regulation, and tissue distribution, with emphasis on transcriptional control, post-translational modifications such as lysine succinylation and redox-dependent regulation, and integration with nutrient-sensing and stress-response pathways. By combining recent literature with bioinformatics analysis, we demonstrate that OXCT1 displays highly dynamic expression across diverse cancer types and metabolic states, consistent with a role in metabolic plasticity and disease progression. Furthermore, we discuss here the OXCT1 role in other pathological conditions including metabolic disorders, neurological disease, and cardiomyopathy, implicating both metabolic dysfunction and aberrant protein modification in disease mechanisms. Collectively, these findings establish OXCT1 as a central regulator of metabolic adaptation and a potential therapeutic target.

Keywords:  Cancer; Ketogenic diet; Ketone bodies; OXCT1; Succinylation; β-hydroxybutyrate

DOI:  https://doi.org/10.1007/s00018-026-06264-4
Blood Neoplasia. 2026 Aug;3(3): 100236

The KDM-family inhibitor JIB-04 sensitizes AML cells to venetoclax by inducing a ferroptosis-like phenotype.

Katharina Wohlan, Dandan Fan, Anna G Guzman, Alexis Quezada, Hyunji Park, Elmira Khabusheva, Farzane Sivandzade, Matthew Wither, Amber Alcorn, Tamara Thevarajah, Steven M Kornblau, Courtney D DiNardo, Jianzhong Su, Margaret A Goodell, Rachel E Rau.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with various molecular and cytogenetic subtypes. Treatment options for older adult patients are limited due to high toxicity of conventional chemotherapy. The B-cell leukemia/lymphoma 2 inhibitor venetoclax is effective in combination with hypomethylating agents or low-dose cytarabine, but ∼30% of patients do not respond to the initial combination treatment. Thus, alternative combinations are needed to sensitize AML cells to venetoclax and overcome resistance mechanisms. Here, we report that targeting histone lysine-specific demethylases induces a ferroptosis-like phenotype driven by oxidative stress in various AML subtypes. In both patient samples and cell lines, JIB-04 increases the level of reactive oxygen species, ferrous iron, and lipid peroxidation, all signs of ferroptosis. The combination of JIB-04 and venetoclax proved to be highly synergistic. Blocking the JIB-04-induced phenotype by using the antioxidant N-acetyl-l-cysteine reverses the synergistic killing. At the molecular level, the ferroptosis inducers HMOX1, SAT1, and PTGS2 were found to be upregulated by JIB-04. Collectively, these findings identify JIB-04 as a potential new ferroptosis inducer in AML and highlight the potential of oxidative stress induction as a valuable strategy in combination with venetoclax to treat AML.

DOI: https://doi.org/10.1016/j.bneo.2026.100236
J Cancer Immunol (Wilmington). 2026 ;8(1): 17-22

Cristae Architecture as a Metabolic Checkpoint in Effector T Cells - Implications for Cancer Immunity.

Prakash Jeysankar, Sonal Srikanth, Beibei Wu, Yousang Gwack.

  Effector T cells rely on tightly coordinated metabolic and epigenetic programs to sustain immune function. Emerging evidence highlights a central role for mitochondria in integrating these programs through nutrient utilization and regulation of metabolite flux. The electron transport chain (ETC), localized to the inner mitochondrial membrane, directs cellular metabolism toward oxidative phosphorylation. The efficiency of ETC activity is governed by the highly folded architecture of the inner mitochondrial membrane into cristae. Although mitochondrial metabolism is well recognized as a key determinant of cellular metabolic states, the regulatory roles of cristae-organizing structural proteins, particularly in T cells, remain poorly defined. Our recent study identifies the inner mitochondrial membrane protein TMEM11 as a critical structural determinant of cristae organization and demonstrates how cristae integrity governs effector T cell function by controlling oxidative phosphorylation and metabolite flux. TMEM11 deficiency disrupts cristae architecture in T cells without affecting mitochondrial biogenesis or cell viability. Mechanistically, loss of TMEM11 impairs ETC function, leading to elevated mitochondrial reactive oxygen species (mtROS), which diverts acetyl-CoA away from histone acetylation toward fatty acid synthesis, thereby suppressing cytokine production. Collectively, these findings reveal a structural-metabolic-epigenetic axis that is essential for effector T cell immunity and suggest potential relevance for T cell-mediated cancer therapy.

Keywords:  Cristae; Effector T cells; Mitochondria; Reactive oxygen species

DOI:  https://doi.org/10.33696/cancerimmunol.8.120
Am J Physiol Endocrinol Metab. 2026 Jun 01.

Skeletal muscle carnitine-acylcarnitine translocase deletion reveals vulnerability of oxidative muscle to fatty acid oxidation deficiency.

Filip Jevtovic, Nicholas C Williamson, Andrea S Pereyra, Molly Alexander, Espen E Spangenburg, Jessica M Ellis.

  Fatty acid oxidation (FAO) is a critical bioenergetic source for skeletal muscle with FAO impairments being linked to metabolic and contractile dysfunction. FAO is regulated by the carnitine shuttle in which FAO eligible fatty acids, in the form of acylcarnitines, are transported into the mitochondrial matrix by carnitine‑acylcarnitine translocase (CACT), yet the role of CACT in muscle in vivo has remained unexplored. To determine the requirement of CACT in muscle FAO and its influence on muscle mitochondrial bioenergetics, lipid profile, and muscle contractility, a novel conditional skeletal muscle-specific CACT knockout mouse (CactSk-/-) was generated. The requirement of CACT for long-chain FAO was confirmed by the complete abrogation of FAO flux in CactSk-/- muscle mitochondria. CACT was also required for the oxidative flux of medium-chain octanoyl-carnitine and acetyl-carnitine. CACT loss disrupted the lipid profile of skeletal muscle with long-chain acylcarnitine accumulation and shifted saturation profile of phospholipids away from saturated and highly unsaturated and towards di- and tri-saturated phospholipids. Elevated mitochondrial content was demonstrated by increased phospholipid content and mitochondrial staining in CactSk-/- muscles, occurring to a greater extent in oxidative muscles. Loss of CACT reduced muscle specific force production by ~70% in oxidative soleus muscle despite increased fiber size, and compensatory mitochondrial accumulation that preserved muscle metabolic capacity. These findings demonstrate the crucial role of CACT in muscle FAO and that oxidative muscles, in particular, undergo extensive lipid compositional, metabolic, and structural remodeling that coincides with impaired contractile function.

Keywords:  Skeletal muscle; carnitine-acylcarnitine translocase; fatty acid metabolism; muscle contraction

DOI:  https://doi.org/10.1152/ajpendo.00117.2026
Nat Rev Endocrinol. 2026 Jun 03.

Intestinal mitochondrial complex I inhibition essential for clinical benefits of metformin.

Olivia Tysoe.

DOI: https://doi.org/10.1038/s41574-026-01269-2
bioRxiv. 2026 May 20. pii: 2026.05.19.726225. [Epub ahead of print]

A liquid chromatography-mass spectrometry method to quantify total Coenzyme A concentration and isotopic labeling.

Amelia L Taylor, Nathaniel W Snyder, Caroline R Bartman.

Coenzyme A is an essential cofactor synthesized from pantothenate, cysteine, and ATP, and is involved in numerous processes of cellular metabolism through its ability to carry activated acyl groups. Coenzyme A participates in catabolism of carbohydrate, fat and amino acids; biosynthesis of fatty acids, cholesterol and heme; and protein modification including acetylation and 4-phosphopantetheinylation. Despite CoA's critical functions, the regulation of CoA levels and the rate of CoA synthesis in different cell types and disease states are not well understood. One reason for this gap is that many acyl-CoA species are analytically challenging to measure due to factors including instability, poor ionization, and the wide range of biochemical properties conferred by different acyl chain lengths. In addition, most current methods do not support analysis of CoA isotopic labeling, which is required to quantify CoA synthesis rate or to measure absolute concentration using isotope-labeled internal standards. Here, we describe a method to quantify the concentration and isotopic labeling of total CoA, defined as the sum of CoASH plus all acyl-CoA species. Acyl-CoA species are hydrolyzed using sodium hydroxide to remove acyl chains, then CoA is derivatized on the thiol with N-ethylmaleimide (NEM). Following protein precipitation and solid phase extraction, samples are analyzed by liquid chromatography-mass spectrometry. This method is linear in a wide range that captures mouse tissue CoA levels, with accuracy within 15% error and precision below 15% relative standard deviation for both pure standards and tissue samples. We applied this method to measure total CoA concentration in five tissues from male and female mice, and total CoA synthesis rate in mouse liver via infusion of 13 C- 15 N-pantothenate. Overall, this method offers a tractable approach to measure total CoA concentration and isotopic labeling to enable study of total CoA synthesis rates and concentrations in health and disease.

DOI: https://doi.org/10.64898/2026.05.19.726225
Nat Commun. 2026 May 30.

Mitochondrial RNA degradation regulates differentiation, stemness, and immune sensitivity in acute myeloid leukemia.

Geethu Emily Thomas, Veronique Voisin, Kazem Nouri, Rose Hurren, Karen Kai-Lin Fang, Ali Chegini, Marcela Gronda, Yongran Yan, Neil MacLean, Yulia Jitkova, Dakai Ling, Mary Ma, Xiao Ming Wang, Andrea Arruda, Vito Spadavecchio, Mark D Minden, Li Zhang, Jong Bok Lee, Aaron D Schimmer.

Eukaryotic cells have separate genomes in the nucleus and mitochondria. Mitochondrial DNA is transcribed bi-directionally to generate mitochondrial RNA (mtRNA) and dsRNA as a by-product of this transcription. We demonstrate that mtRNA transcription and degradation are increased in AML (Acute Myeloid Leukemia) cells and stem cells resulting in higher rates of mtRNA turnover. We discover that the mitochondrial degradosome, SUV3 and PNPase, is upregulated in AML cells and stem cells and functionally important for degradation of mtRNA and mitochondrial dsRNA (double stranded RNA) in AML. Depleting SUV3 or PNPase impairs mtRNA degradation and promotes the accumulation of dsRNA. dsRNA that accumulates after depleting SUV3 or PNPase, stimulates IFN-I signaling that induces AML differentiation, decreases stemness and increases sensitivity to immune-mediating cytotoxicity. Thus, this work highlights mitochondrial RNA regulation in AML and identifies a mechanism by which mtRNA turnover influences AML differentiation, stem cell function, and immune sensitization.

DOI: https://doi.org/10.1038/s41467-026-73558-3
Cell Rep. 2026 Jun 02. pii: S2211-1247(26)00568-1. [Epub ahead of print]45(6): 117490

HSPA6 maintains IMPDH2 phosphorylation to regulate GTP synthesis for driving radioresistance of glioblastoma stem cells.

Junlei Yang, Qiankun Lin, Danling Gu, Jiancheng Gao, Yang Liu, Kailin Yang, Zhe Zhu, Chenfei Lu, Daqi Li, Shusheng Ci, Fan Lin, Qianghu Wang, Xu Qian, Yongping You, Qigang Zhou, Xiuxing Wang, Ming Lu, Qian Zhang, Yun Chen, Weiwei Tao, Junxia Zhang.

  Glioblastoma (GBM) is the most common and malignant primary brain tumor. Glioblastoma stem cells (GSCs) promote radioresistance and therapeutic failure, yet the underlying mechanisms remain unclear. Here, we show that heat shock protein HSPA6 promotes GSC radioresistance by enhancing GTP synthesis. HSPA6 is induced by irradiation and reduces GSC sensitivity to radiotherapy. HSPA6 interacts with and activates IMPDH2, a key rate-limiting enzyme in purine biosynthesis, thereby promoting GTP synthesis, reducing DNA damage, and enhancing radioresistance. Mechanistically, HSPA6 recruits ROCK2 to phosphorylate and activate IMPDH2 at S416. Pharmacological inhibition of HSPA6 and IMPDH2 combined with irradiation significantly improves survival in mice bearing GBM. Our study uncovers the crucial role of HSPA6/IMPDH2-mediated GTP synthesis in GSC radioresistance and suggests that targeting this axis may improve radiotherapy efficacy for GBM.

Keywords:  CP: Cancer; CP: Genomics; GTP synthesis; glioblastoma; glioblastoma stem cells; heat shock protein family A member 6; radioresistance

DOI:  https://doi.org/10.1016/j.celrep.2026.117490
JCI Insight. 2026 Jun 04. pii: e203777. [Epub ahead of print]

Direct pharmacological targeting of asparagine synthetase to overcome resistance to L-asparaginase in ALL therapy.

Rodney Claude, Sankalp Srivastava, Kirk A Staschke, Carlos A Mellado Fritz, Shaoxiong Chen, Lei Liu, Minghua Zhong, Harish Kothandaraman, Nadia A Lanman, Utpal P Davé, Sandeep Batra, Jiehao Zhou, Yue Fang, Chi Zhang, Reuben Kapur, Jing Fan, Ronald C Wek, Ji Zhang.

  Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from both B- and T-cell lineages. Current therapy exploits ALL cells' low expression of asparagine synthetase (ASNS) by using L-asparaginase, a bacterial enzyme that depletes circulating asparagine. However, resistance can emerge through induction of ASNS, mediated in part by the amino acid stress sensor GCN2. In this study, we addressed the efficacy of L-asparaginase in combination with genetic or pharmacological inhibition of GCN2 and a novel ASNS inhibitor designated ASX-173. Using a KrasG12D-driven mouse model of T-ALL, we found that GCN2 is dispensable for leukemogenesis. However, genetic inactivation or pharmacologic inhibition of GCN2 sensitized ALL cells to asparagine depletion, correlating with impaired ASNS induction. While GCN2 targeting enhanced sensitivity to asparagine depletion, a subset of Gcn2-/- T-ALL cells retained high ASNS expression and remained resistant to L-asparaginase. Likewise, some human T-ALL cells with elevated ASNS levels were refractory to GCN2 inhibition even under asparagine-depleted conditions. When combined with L-asparaginase, ASX-173 effectively eliminated ASNS-high leukemic cells in vitro and in vivo. These findings suggest that direct targeting of ASNS provides therapeutic benefit in leukemias that express high ASNS and are resistant to GCN2 inhibition under asparagine-depleted conditions.

Keywords:  Amino acid metabolism; Cell stress; Hematology; Leukemias; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.203777
Cell Stem Cell. 2026 Jun 04. pii: S1934-5909(26)00162-1. [Epub ahead of print]33(6): 901-903

Ketone bodies as guardians of leukemic stemness through ferroptosis suppression.

Xi Zhao, Li Zhuang, Boyi Gan.

Leukemia stem cells exploit cell-intrinsic ketogenesis to suppress ferroptosis and sustain disease propagation. In this issue, Han et al.1 uncover a β-hydroxybutyrate-epigenetic-lipid remodeling axis that protects stemness by restraining ferroptosis, revealing a metabolic vulnerability with therapeutic potential.

DOI: https://doi.org/10.1016/j.stem.2026.04.022
Front Oncol. 2026 ;16 1727389

Pan-cancer molecular signatures connecting aspartate transaminase to cancer prognosis, metabolic and immune signatures.

Geoffrey H Siwo, Amit G Singal, Akbar K Waljee.

  Serum aspartate transaminase (sAST) level is used routinely in conjunction with other clinical assays to assess liver health and disease. Increasing evidence suggests that sAST is associated with all-cause mortality and has prognostic value in several cancers, including gastrointestinal and urothelial cancers. Here, we undertake a systems approach to unravel molecular connections between AST and cancer prognosis, metabolism, and immune signatures at the transcriptomic and proteomic levels. We find that GOT1 and GOT2 expression is reversed in tumors relative to normal tissues whereby tumors residing in tissues that normally have low expression tend to have high GOT1/GOT2 expression and vice versa. Expression of GOT1 and GOT2 is associated with overall survival in several tumors across distinct tissues. At the proteomic level, expression of AST is associated with distinct pan-cancer molecular subtypes with an enrichment of specific metabolic and immune signatures. The GOT1 interactome is enriched with the targets of cancer-associated miRNAs, specifically mir34a - a promising cancer therapeutic, while the GOT2 interactome is enriched with proteins that interact with cancer-associated transcription factors. Our findings suggest that perturbations in the levels of GOT1/GOT2 within specific tissues reflect pathophysiological changes beyond tissue damage and have implications for cancer metabolism, immune infiltration, prognosis, and treatment personalization.

Keywords:  AST - aspartate transaminase; GOT1; GOT2; cancer; miRNA; proteome; transcriptome

DOI:  https://doi.org/10.3389/fonc.2026.1727389
J Cell Biol. 2026 Aug 03. pii: e202511088. [Epub ahead of print]225(8):

A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage.

Erqing Gao, Liwei Guan, Kehang Zhang, Shuze Qi, Jingxiu Xu, Jie Zhang, Tianyi Zhu, Bing Yang, Chonglin Yang, Eric Miska, Mao Zhang, Suhong Xu.

Maintenance of mitochondrial integrity is fundamental for cellular survival, yet how cells recognize catastrophic mitochondrial membrane damage remains unknown. Here, we identify MAI-1 as the first genetically encoded reporter of severe mitochondrial membrane damage. MAI-1 is a Caenorhabditis elegans homolog of the ATP synthase inhibitor IF1 that lacks a mitochondrial targeting sequence, resides in the cytosol under basal conditions, but rapidly and irreversibly translocates to severely damaged mitochondria within milliseconds. We validate MAI-1 across diverse injury paradigms and demonstrate that cytosolic IF1 variants from other species exhibit conserved damage-induced recruitment. Mechanistically, MAI-1 recruitment requires the presence of an intact ATP synthase complex. Using MAI-1 as a sensor, we uncover that these severely damaged mitochondria are cleared through the LGG-1-mediated, PINK1/PARKIN-independent lysosomal pathway. Together, our findings establish a powerful tool for visualizing severe mitochondrial membrane damage and reveal a surveillance mechanism dedicated to structural integrity control.

DOI: https://doi.org/10.1083/jcb.202511088
Bioorg Chem. 2026 May 25. pii: S0045-2068(26)00572-9. [Epub ahead of print]179 110036

Design, synthesis, and mechanistic study of novel isoflavone derivatives as mitochondrial complex I inhibitors for non-small cell lung cancer treatment.

Jiawei Liu, Ni Meng, Rulan Li, Mengru Liu, Yueshan Ma, Xifu Liu, Jing Chen, Yu Cheng.

  Non-small cell lung cancer (NSCLC) remains the most prevalent and lethal form of lung cancer, highlighting an urgent need for novel therapeutic agents. Given its status as a critical hub for tumor bioenergetics, mitochondrial complex I has emerged as a promising therapeutic target. In this study, to optimize the efficacy of our previously identified mitochondrial complex I inhibitor DBI-2, we designed and synthesized 27 novel isoflavone derivatives. Among them, compound IV-16 exhibited the most potent antiproliferative activity against human NSCLC A549 cells (IC50 = 0.43 μM), demonstrating a 2.7-fold increase in potency compared to the lead compound DBI-2, while maintaining low cytotoxicity against normal cells. Mechanistically, compound IV-16 suppressed the cellular oxygen consumption rate, which could be reversed by the complex II substrate succinate, confirming its specific inhibition of mitochondrial complex I. This binding mode was further elucidated by molecular dynamics simulations, highlighting dominant interactions with key residues GLU204 and PHE86. Furthermore, compound IV-16 significantly inhibited cell migration and induced apoptosis in vitro. Notably, compound IV-16 triggered autophagy by activating the AMPK signaling pathway and subsequently inhibiting the downstream mTOR/S6 axis. In silico ADMET prediction further indicated that compound IV-16 possesses favorable pharmacokinetic profiles and low toxicity risks. Collectively, this study elucidates the structure-activity relationships of these novel isoflavone derivatives and identifies compound IV-16 as a promising mitochondrial complex I inhibitor with therapeutic potential for the treatment of NSCLC.

Keywords:  Isoflavone; Mitochondrial complex I; Molecular dynamics simulation; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.bioorg.2026.110036
Mol Cell. 2026 Jun 02. pii: S1097-2765(26)00317-5. [Epub ahead of print]

Reductive death is averted by a conserved de novo lipogenic switch.

Fasih M Ahsan, Jen F Rotti, Armen I Yerevanian, Sinclair W Emans, Nicole L Stuhr, Jose A Aceves-Salvador, Wei Wang, Daniel J Baker, Dimitra Pouli, Owen S Skinner, Michael D Blower, Alexander A Soukas.

  Biguanides, including metformin, the world's most prescribed oral hypoglycemic, extend health span and lifespan in vertebrates and invertebrates. Given the widespread use and apparent safety of metformin, it is assumed that its effects are not associated with toxicity, except when in marked excess. Here, we determine that accumulation of damaging reducing equivalents is an unanticipated toxicity associated with biguanides, defense against which requires post-transcriptional protection of de novo lipogenesis. We demonstrate that biguanide treatment during impaired lipogenesis drives NADPH toxicity, leading to catastrophic elevation of NADH/GSH reducing equivalents and accelerated death across metazoans. Multiple NADPH-generating interventions require de novo lipogenesis to prevent markedly shortened survival, indicating that this defense mechanism is broadly leveraged. We propose that fatty acid biosynthesis is a tunable rheostat that can minimize biguanide-induced reductive stress while maximizing its pro-longevity outcomes and can serve as an exploitable vulnerability in reductive stress-sensitive cancers.

Keywords:  Caenorhabditis elegans; cancer; de novo lipogenesis; eukaryotic initiation factor 3; lifespan; mRNA translation; metformin; phenformin; protein synthesis; reductive stress

DOI:  https://doi.org/10.1016/j.molcel.2026.05.011
Eur J Appl Physiol. 2026 Jun 06.

Effect of six weeks ubiquinol supplementation on mitochondrial respiratory function and exercise capacity in healthy males.

Jarred P Acton, Nehal S Alsharif, Jack W Bond, Stuart P Cocksedge, Abbie G Mclellan, Donald L Peden, Mark P Funnell, Hannah F Dugdale, Lewis J James, Richard A Ferguson, Tom Clifford, Stephen J Bailey.

  Coenzyme Q10 (CoQ10) is an integral component of the mitochondrial electron transfer system. Most studies have administered the oxidised form of CoQ10 (ubiquinone) and observed no effects on mitochondrial respiratory function or endurance exercise performance. The reduced form of CoQ10, ubiquinol (UQH2), has greater bioavailability than ubiquinone, but the effects of UQH2 supplementation on mitochondrial respiratory function and exercise capacity are unclear. Fifty-four healthy, recreationally active males were randomised to receive either 300 mg·day- 1 UQH2 or placebo (PLA) for 6 weeks in a double-blind independent-group design. Before and after the supplementation period, skeletal muscle mitochondrial respiration variables and protein content of the mitochondrial leak proteins, adenine nucleotide translocase1 + 2 (ANT1 + 2) and uncoupling protein-3 (UCP-3), were assessed. In addition, participants completed a severe-intensity cycle test to exhaustion to assess time to the limit of tolerance (TLim) and oxygen uptake (V̇O2) kinetics. Compared to pre-supplementation and PLA, UQH2 supplementation increased plasma [CoQ10] (P < 0.05), and lowered inverse respiratory control ratio (Pre-PLA: 0.064 ± 0.034 vs. Post-PLA: 0.072 ± 0.026; Pre- UQH2: 0.073 ± 0.039 vs. Post-UQH2: 0.044 ± 0.019; P < 0.05), suggestive of improved oxidative phosphorylation coupling efficiency. There were no differences in ANT1 + 2 or UCP-3 protein content post-supplementation compared to pre-supplementation between groups (P > 0.05). End-exercise V̇O2, change in V̇O2 between 2 min and end-exercise, and TLim were not different between groups post-supplementation (P > 0.05). Six-weeks UQH2 supplementation increased plasma [CoQ10] and oxidative phosphorylation coupling efficiency, but did not alter mitochondrial leak proteins, TLim or V̇O2 kinetics during severe-intensity exercise in healthy, active males.

Keywords:  Coenzyme Q10; Dietary supplement; Exercise performance; Mitochondrial respiratory efficiency; V̇O2 kinetics

DOI:  https://doi.org/10.1007/s00421-026-06275-w
bioRxiv. 2026 May 22. pii: 2026.05.19.726343. [Epub ahead of print]

Next-generation genetically encoded biosensors for spatiotemporal intracellular pH monitoring, mapping, and profiling.

Sam Taylor, Bruno Colon, Kyutae D Lee, Jennifer Arcuri, Shraddha Chandthakuri, Daniel G Isom.

Bioluminescence resonance energy transfer (BRET) systems are widely used for live-cell spectroscopy and biosensor engineering, yet the intrinsic pH sensitivity of commonly used BRET components has not been systematically examined. Here, we show that major BRET luciferase donors, fluorescent acceptors, and donor-acceptor assay pairs exhibit pronounced pH-dependent spectroscopic behavior across physiologically relevant conditions, identifying environmental pH responsiveness as a fundamental property of widely used BRET systems and a potential source of previously underappreciated assay artifacts. Leveraging these principles, we engineered ORION (ratiOmetRIc prOton seNsor), a genetically encoded ratiometric BRET pH sensor based on the NanoLuc-mVenus fusion. ORION exhibited strong brightness, an approximately 9-fold dynamic range, and robust responsiveness across a substantially broader pH range than that of existing genetically encoded sensors. Compared to pHluorin2, ORION maintained substantially improved quantitative performance at acidic pH values below 6.0. To demonstrate its utility in a biological application, we applied ORION across diverse cancer cell models and identified heterogeneous acid imprinting states, suggesting that tumor cells can retain persistent physiological memory of adaptation to acidic microenvironments even after prolonged ex vivo culture. Together, these findings establish pH responsiveness as a fundamental property of BRET systems and position ORION as a best-in-class platform for interrogating and quantifying pH regulation of biology in living systems.

DOI: https://doi.org/10.64898/2026.05.19.726343
Leukemia. 2026 Jun 02.

Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors.

Aditi Chatterjee, Moaath K Mustafa Ali, Christopher M Bailey, Yuchen Liu, Donald Small, Catherine C Smith, Elie Traer, Yin Wang, Giovannino Silvestri, Maria R Baer.

FLT3 inhibitor efficacy in AML with FLT3-ITD is short-lived, frequently due to new mutations, most commonly in NRAS. Sphingosine kinase 1 (SPHK1), which phosphorylates sphingosine to generate sphingosine-1-phosphate (S1P), is upregulated and localized to the plasma membrane in RAS-mutated cells. We studied S1P and FLT3 co-targeting to overcome FLT3 inhibitor resistance in NRAS-mutated FLT3-ITD AML cells. NRAS-mutated FLT3-ITD AML cell lines and patient blasts were treated with FLT3 inhibitors and/or S1P receptor (S1PR) modulators. FLT3 inhibitor sensitivity was assessed by immunoblotting, cytotoxicity, apoptosis and colony formation. Co-treatment was also assessed in vivo in an orthotopic mouse model. Downstream RAS and SPHK1 effectors were measured by immunoblotting and qRT-PCR. The S1PR modulators fingolimod (FTY720) and mocravimod (KRP-203) resensitized FLT3-ITD-expressing MOLM-14 and MV4-11 human AML cells with G12D, G12S, Q61K or Q61H, but not G12C, and patient blasts with G13D, G13V or G12D NRAS mutations to FLT3 inhibitors. Moreover, FTY720 co-treatment resensitized G12D NRAS-mutated M14(R)701 cells to gilteritinib in vivo. Co-treatment inactivated ERK, transcriptionally downregulated SPHK1, and inactivated downstream AKT, p70 S6K and BAD, with inactivation abrogated by constitutive SPHK1 expression. The clinically applicable S1PR modulators fingolimod and mocravimod resensitize NRAS-mutated FLT3-ITD AML cells to FLT3 inhibitors, supporting potential clinical efficacy.

DOI: https://doi.org/10.1038/s41375-026-02982-7
J Nutr. 2026 Jun 02. pii: S0022-3166(26)00274-9. [Epub ahead of print] 101625

Marked changes in one-carbon metabolism on a low-carbohydrate high-fat diet: a randomized controlled trial (CARBFUNC).

Marianne Bråtveit, Johnny Laupsa Borge, Tonje Bjørnstad, Cathrine Sommersten, Adrian McCann, Gülen Arslan Lied, Ottar Nygård, Gunnar Mellgren, Jutta Dierkes, Simon Nitter Dankel.

   BACKGROUND: Studying the impact of dietary carbohydrates and fat on markers of one-carbon metabolism could provide important insight into distinct metabolic adaptations and how diets affects disease risk.
OBJECTIVE: To determine changes in plasma one-carbon metabolites and B-vitamers on isocaloric diets differing in carbohydrate processing or amount.
METHODS: 193 individuals with obesity were randomized to equal energy- and protein diets either with more processed, acellular carbohydrates (A-HCLF, comparator arm), minimally processed cellular carbohydrates (C-HCLF) (both designed with 45 energy percent (E%) carbohydrates and 38 E% fat), or a low-carbohydrate, high-fat diet (LCHF) designed with 8 E% carbohydrate and ∼75 E% fat including 30 E% saturated fat. Addressing secondary outcomes of the trial, we analyzed changes in plasma one-carbon metabolites and B-vitamers, and dietary B-vitamin intakes after 3, 6, 9 and 12 months, using constrained linear mixed effect modelling (cLMM).
RESULTS: After 3 months, the relative change score following the LCHF diet was significantly different from the A-HCLF comparator for plasma α-hydroxybutyrate (LCHF/A-HCLF: +41.3%*/-1.56%, p<0.001; *: significant within-group change), methylmalonic acid (MMA) (-5.69%*/+8.64%*, p<0.001), methionine (-7.81%*/+1.44%, p=0.001), nicotinamide (-19.7%*/+14.0%, p=0.007), 1-Methylnicotinamide (mNAM) (-14.1%*/+14.1%, p=0.003), pyridoxal (-2.42%/+18.9%*), 4-pyridoxic acid (-12.4%*/+21.4%*, p<0.001), and cysteine (-3.00%*/+1.10%). Between-group differences for most of these metabolites remained significant after 6 and 9 months. Comparing C-HCLF to A-HCLF, significant differences in relative change scores were found for mNAM after 3 (C-HCLF/A-HCLF: -11.5%/+14.1%, p=0.012) and 9 (-14.9%*/+18.6%, p=0.001) months. Plasma changes in one-carbon metabolites and B-vitamers showed weak correlations with dietary B-vitamins.
CONCLUSION: Compared with A-HCLF, the LCHF diet was followed by significantly different changes in plasma α-hydroxybutyrate, MMA, methionine, nicotinamide, mNAM, pyridoxal, 4-pyridoxic acid and cysteine. These shifts were largely independent of vitamin consumption, and may rather reflect ketoadaptive mechanisms, including enhanced fatty acid oxidation and upregulated antioxidant defense. Carbohydrate quality had less impact on the one-carbon metabolites.
CLINICAL TRIAL REGISTRY NUMBER: NCT03401970 (https://clinicaltrials.gov/study/NCT03401970).

Keywords:  B-vitamers; Humans; dietary carbohydrates; ketosis; low-carbohydrate diet; metabolomics; obesity; one-carbon metabolism; randomized controlled trial; saturated fat

DOI:  https://doi.org/10.1016/j.tjnut.2026.101625
Free Radic Biol Med. 2026 Jun 03. pii: S0891-5849(26)00825-7. [Epub ahead of print]

Excess glucose shapes mitochondrial metabolism and redox state in human primary white adipocytes.

Elena Herbers, Kari Moisio, Ruben Torregrosa-Muñumer, Jari E Karppinen, Sini Heinonen, Birgitta W van der Kolk, Antti Hassinen, Hilkka Peltoniemi, Reetta Tuominen, Eija Pirinen, Ville Hietakangas, Liliya Euro, Kirsi H Pietiläinen.

  Mitochondrial dysfunction in white adipose tissue (WAT) is a hallmark of obesity, yet nutrient-driven responses in adipocytes remain poorly defined, partly due to widespread use of supra-physiological glucose-rich media in in vitro adipocyte models. We used integrated transcriptomics, fluxomics, and functional analyses to assess how glucose availability shapes mitochondrial metabolism and redox status during human adipocyte differentiation. Primary human adipocytes (n = 6 donors) were differentiated in commonly used media containing high glucose (DMEM/F12, 17.6 mM; DMEM/HG, 25 mM), physiological glucose (LG, 5.5 mM), or galactose (Gal, 25 mM). High-glucose conditions were associated with a shift from oxidative phosphorylation toward glycolysis, reduced mitochondrial biogenesis, NADH accumulation, and elevated mitochondrial reactive oxygen species, accompanied by impaired insulin sensitivity, reduced adiponectin secretion, together with transcriptional signatures of inflammatory and stress-associated responses. Fluxomics revealed altered pyruvate flux, enhanced anaplerotic pathways, and upregulated anabolic programs. In contrast, LG and Gal conditions preserved mitochondrial and redox features, more closely resembling characteristics of healthy WAT. Collectively, these data define a metabolic phenotype, in which supra-physiological glucose is associated with redox imbalance and metabolic reprogramming in human adipocytes under defined in vitro conditions. Our results highlight the importance of physiological glucose for adipocyte metabolism modeling and provide a framework for interpreting nutrient effects on mitochondrial and redox phenotypes.

Keywords:  adipocyte; glycolysis; high glucose; metabolic reprogramming; mitochondrial dysfunction; redox stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.321