bims-medica 2025-11-02 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–11–02
eighteen papers selected by
Brett Chrest, Wake Forest University

Ketone Catabolism Is Essential for Maintaining Normal Heart Function During Aging.
Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.
The Warburg Effect Redefined: A Kinetic and Regulatory Perspective.
Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer.
Minimum Dietary Fat Threshold for Effective Ketogenesis and Obesity Control in Mice.
Heterogenous mitochondrial ultrastructure and metabolism of human glioblastoma cells: differences between stem-like and differentiated cancer cells in response to chemotherapy.
Targeting serine metabolism vulnerability in omipalisib-resistant acute myeloid leukemia with phosphoglycerate dehydrogenase inhibitors.
VDAC1 inhibitor DIDS uncouples respiration in isolated tissue mitochondria and induces mitochondrial hyperfusion in mammalian cells.
Metformin induces ferroptosis associated with lipidomic remodeling in AML.
Insulinemic and Inflammatory Dietary Patterns and Colorectal Cancer Risk: A Dietary Data Harmonization Study of One Million Participants in the COMETS Consortium.
A carbon trail to follow: unveiling itaconate's metabolism in vivo.
In C57BL/6J mice, weight loss in previously obese mice reduced bone mass and shifted the cortical bone metabolome.
Nicotinamide nucleotide transhydrogenase dysfunction transcriptionally impacts mitochondrial β-oxidation and neuromuscular junction in M. Gastrocnemius of 24-day-old mice.
Atorvastatin Induces Bioenergetic Impairment and Oxidative Stress Through Reverse Electron Transport.
13C-metabolic flux analysis of K562 cells before and after differentiation into erythroid reveals a metabolic shift toward oxidative metabolism.
Venetoclax and new BCL-2 inhibitors in acute myeloid leukemia.
A red fluorescent genetically encoded biosensor for in vivo imaging of extracellular L-lactate dynamics.
A generalized strategy to kill leukemic cells by targeting the regulatory systems governing mitochondrial membrane potential.

J Am Heart Assoc. 2025 Oct 28. e042508

Ketone Catabolism Is Essential for Maintaining Normal Heart Function During Aging.

Mariko Aoyagi Keller, Michinari Nakamura.

   BACKGROUND: The heart uses various nutrient sources for energy production, primarily favoring fatty acid oxidation. Although ketones can be fuel substrates, ketolysis has been shown to be dispensable for heart development and function in mice. However, the long-term consequences of ketolysis downregulation in the heart remain unknown. Here we demonstrate that ketone catabolism is essential for preserving cardiac function during aging.
METHODS: To investigate the functional significance of ketone use in the heart, we employed a mouse model with impaired ketolysis in the heart. In addition, we administered a ketogenic diet to evaluate the effects of exogenous ketone supplementation on cardiac ketone metabolism and function in this model.
RESULTS: The cardiac expression of SCOT (succinyl-CoA:3-ketoacid CoA transferase), a rate-limiting enzyme in ketolysis, decreases with age in mice. SCOT cardiomyocyte-specific knockout mice exhibit normal heart function at 10 weeks of age but progressively develop cardiac dysfunction and remodeling as they age, without overt hypertrophy in both sexes. Notably, ketone supplementation via a ketogenic diet partially rescues contractile dysfunction in SCOT cardiomyocyte-specific knockout mice, suggesting ketone oxidation-independent mechanisms contribute to the development of cardiomyopathy caused by SCOT downregulation.
CONCLUSIONS: These findings indicate that ketone catabolism is crucial for maintaining heart function during aging, and that ketones confer cardioprotection independently of ketone oxidation.

Keywords:  cardiac remodeling; heart failure; hypertrophy; ketogenic diet; ketolysis; ketone; ketone oxidation

DOI:  https://doi.org/10.1161/JAHA.125.042508
Mol Cell. 2025 Oct 28. pii: S1097-2765(25)00819-6. [Epub ahead of print]

Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.

Mushtaq A Nengroo, Austin T Klein, Heather S Carr, Olivia Vidal-Cruchez, Umakant Sahu, Daniel J McGrail, Nidhi Sahni, Niklas B Thompson, Peter A Faull, Peng Gao, John M Asara, Hardik Shah, Marc L Mendillo, Issam Ben-Sahra.

  The de novo purine synthesis pathway is fundamental for nucleotide production, yet the role of mitochondrial metabolism in modulating this process remains underexplored. Here, we identify that succinate dehydrogenase (SDH) is essential for maintaining de novo purine synthesis. Genetic or pharmacological inhibition of SDH suppresses purine synthesis, contributing to a decrease in cell proliferation. Mechanistically, SDH inhibition elevates succinate, which in turn promotes the succinylation of serine hydroxymethyltransferase 2 (SHMT2) within the mitochondrial tetrahydrofolate (THF) cycle. This post-translational modification lowers formate output, depriving cells of one-carbon units needed for purine assembly. In turn, cancer cells activate the purine salvage pathway, a metabolic compensatory adaptation that represents a therapeutic vulnerability. Notably, co-inhibition of SDH and purine salvage induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings reveal a signaling role for mitochondrial succinate in tuning nucleotide metabolism and highlight a dual-targeted strategy to exploit metabolic dependencies in cancer.

Keywords:  TCA cycle; cancer; formate; mitochondrial metabolism; nucleotide metabolism; succinate

DOI:  https://doi.org/10.1016/j.molcel.2025.10.002
Cureus. 2025 Sep;17(9): e93331

The Warburg Effect Redefined: A Kinetic and Regulatory Perspective.

Amal Bhanu Vayakkattil, Aiswarya S Pazhanchery, Shibu Andrews, Udayabhanu Vayakkattil.

  The Warburg effect, characterized by the preferential conversion of glucose to lactate despite adequate oxygen availability, constitutes a regulated metabolic adaptation rather than a mere dysfunctional response to hypoxia. This metabolic shift arises because lactate dehydrogenase (LDH) exhibits a significantly higher catalytic capacity compared to pyruvate dehydrogenase (PDH), resulting in a substantial reduction of pyruvate to lactate once PDH becomes saturated. In cancer cells, this kinetic preference is further amplified by the upregulation of glucose and monocarboxylate transporters (GLUT1, MCT1, and MCT4) and alterations to the plasma membrane, which enhance transport efficiency. These adaptations maintain a high glycolytic flux, facilitate continuous lactate efflux, and circumvent traditional feedback inhibition. The accumulation of glycolytic intermediates supports the biosynthesis of nucleotides, lipids, and proteins, thereby promoting tumorigenesis. Over time, metabolite-induced DNA methylation and chromatin remodeling reinforce this metabolic state, stabilizing the oxygen-independent proliferative phenotype. Consequently, the Warburg effect is best conceptualized as a primary metabolic strategy initiated by membrane remodeling, sustained by kinetic flux imbalances, and perpetuated by epigenetic feedback, collectively enabling tumor growth and survival in adverse microenvironments.

Keywords:  atp; cancer; cell proliferation; epigenetic; glucose transporter; glycolysis; lactate; lactate dehydrogenase; monocarboxylate transporters; warburg effect

DOI:  https://doi.org/10.7759/cureus.93331
Cell Metab. 2025 Oct 24. pii: S1550-4131(25)00435-8. [Epub ahead of print]

Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer.

Zhengwei Wu, Zhenxun Wang, Seow Qi Ng, Jessica Alice Lidster, Paul Schwerd-Kleine, Zi Jin Cheryl Phua, Kai Lay Esther Peh, Yin Ying Ho, Ju Yuan, S Shathishwaran, Xun Hui Yeo, Ying Zhang, Yui Hei Jasper Chiu, Li Yieng Eunice Lau, Tony Kiat Hon Lim, Angela Takano, Eng Huat Tan, Anders Jacobsen Skanderup, Vinay Tergaonkar, Weiping Han, Ying Swan Ho, Daniel Shao Weng Tan, Wai Leong Tam.

  Tumor-initiating cells (TICs) preferentially reside in poorly vascularized, nutrient-stressed tumor regions, yet how they adapt to glucose limitation is unclear. We show that lung TICs, unlike bulk tumor cells, can switch from glucose to ketone utilization under glucose deprivation. Ex vivo ketone supplementation or a prolonged ketogenic diet supports TIC growth and tumor-initiating capacity. Integrated metabolomics, genomics, and flux analyses reveal that ketones fuel ketolysis, fatty acid synthesis, and de novo lipogenesis. Paradoxically, ketogenic diet intervention creates metabolic vulnerabilities in TICs, sensitizing them toward inhibition of the ketone transporter monocarboxylate transporter 1 (MCT1), regulated by its chaperone protein CD147, as well as toward pharmacological blockade of fatty acid synthase (FASN). Loss of CD147 ablates TICs under glucose limitation conditions in vitro and in vivo. These findings uncover a nutrient-responsive metabolic switch in lung TICs and provide mechanistic insight into how dietary manipulation can influence cancer progression and enhance the efficacy of targeted therapies.

Keywords:  CD147; MCT1; glucose stress; ketogenic diet; ketone metabolism; lung cancer; metabolic reprogramming; monocarboxylate transporter; tumor-initiating cells

DOI:  https://doi.org/10.1016/j.cmet.2025.10.001
Nutrients. 2025 Oct 12. pii: 3203. [Epub ahead of print]17(20):

Minimum Dietary Fat Threshold for Effective Ketogenesis and Obesity Control in Mice.

Jiawen Shou, Xingchen Dong, Fei Sun, Jia Li, Huiren Wang, Qing Ai, Michael Pellizzon, Ting Fu.

  Background/Objectives: Ketogenic diets (KDs), defined by very low carbohydrate and high fat content, are widely studied for obesity and metabolic disease. However, KD formulations vary from 60-95% fat, leading to inconsistent induction of ketogenesis and variable outcomes. The fat threshold required for sustained ketosis, and the tissue-specific programs that mediate KD efficacy, remain unclear. Methods: We evaluated multiple KD formulations (80-95% fat) in C57BL/6J wild-type (WT) and diet-induced obese (DIO) mice. Plasma, hepatic, and intestinal β-hydroxybutyrate (BHB) were measured together with expression of ketogenesis and fatty acid oxidation genes. Body weight, adipose distribution, and liver morphology were assessed under both direct feeding and therapeutic settings. Results: In WT mice, only diets exceeding 85% fat induced robust ketogenesis, reflected by elevated BHB and hepatic upregulation of Cd36, Cpt1a, Acat1, and Hmgcs2. Moderate KDs (80-85%) failed to trigger ketosis and resembled high-fat feeding. In obese mice, an 80% KD lowered fasting glucose without reducing body weight, whereas a 90% KD promoted systemic ketosis, weight loss, and adipose reduction. Interestingly, hepatic transcriptional programs for fatty acid oxidation and ketogenesis were suppressed under 90% KD despite elevated BHB, suggesting reliance on substrate availability and peripheral utilization. In contrast, intestinal Hmgcs2 was strongly induced in both WT and DIO mice, with Oxct1 upregulated only in obesity, indicating local ketone production and consumption. Conclusions: These findings identify > 85% dietary fat as a threshold for sustained ketosis and highlight distinct liver-intestine contributions, underscoring ketogenesis as the central driver of KD's anti-obesity benefits.

Keywords:  hepatic and intestinal ketogenesis; ketogenic diet; obesity

DOI:  https://doi.org/10.3390/nu17203203
Radiol Oncol. 2025 Oct 27.

Heterogenous mitochondrial ultrastructure and metabolism of human glioblastoma cells: differences between stem-like and differentiated cancer cells in response to chemotherapy.

Urban Bogataj, Metka Novak, Simona Katrin Galun, Klementina Fon Tacer, Milos Vittori, Cornelis J F Van Noorden, Barbara Breznik.

   BACKGROUND: Glioblastoma stem-like cells (GSCs) contribute to the resistance of glioblastoma (GBM) tumors to standard therapies. The background of the resistance of GSCs to the chemotherapeutic agent temozolomide is not yet fully understood in the context of cellular metabolism and the role of mitochondria. The aim of this study was to perform a detailed ultrastructural characterization of the mitochondria of GSCs prior and post temozolomide exposure and to compare it to differentiated GBM cells.
MATERIALS AND METHODS: Patient-derived and established GBM cell lines were used for the study. The ultrastructure of the mitochondria of the examined cell lines was assessed by transmission electron microscopy. The microscopic analysis was complemented and compared by an analysis of cell metabolism using Seahorse extracellular flux analysis.
RESULTS: We found that the metabolic profile of GSCs is quiescent and aerobic. Their elongated mitochondria with highly organized cristae are indicating increased biogenesis and mitochondrial fusion and corresponds to a more oxidative phosphorylation (OXPHOS)-dependent metabolism. The metabolism of GSCs is dependent on OXPHOS and there are no changes in defective mitochondria fraction after the treatment with temozolomide. In contrast, differentiated GBM cells with fragmented mitochondria, which have less organized cristae, are more energetic and glycolytic. Temozolomide treatment induced ultrastructural mitochondrial damage in differentiated GBM cells.
CONCLUSIONS: We demonstrated differences in mitochondrial ultrastructure and cellular metabolism between GSCs and differentiated GBM cells in response to temozolomide, suggesting that mitochondria play an important role in the resistance of GSCs to temozolomide. This study provides a basis for further studies addressing GSC chemotherapy resistance in the context of mitochondrial structure and function.

Keywords:  chemotherapy resistance; glioblastoma; metabolism; mitochondria ultrastructure; stem cells

DOI:  https://doi.org/10.2478/raon-2025-0056
Biomed Pharmacother. 2025 Oct 27. pii: S0753-3322(25)00883-2. [Epub ahead of print]192 118689

Targeting serine metabolism vulnerability in omipalisib-resistant acute myeloid leukemia with phosphoglycerate dehydrogenase inhibitors.

Chi-Yang Tseng, Yu-Hsuan Fu, Da-Liang Ou, Hsin-An Hou, Hsiung-Fei Chien, Liang-In Lin.

  Acute myeloid leukemia (AML) is the most common acute leukemia that primarily affects older adults. Dysregulated PI3K/AKT/mTOR signaling pathway is a common abnormality in AML. Our previous study demonstrated the excellent cytotoxicity of dual PI3K/mTOR inhibitor omipalisib against AML cells. However, its clinical application remains challenging because of potential resistance mechanisms following kinase inhibitor administration. In this study, OCI-AML3-OR, an OCI-AML3 subline that is resistant to omipalisib, was established. Transcriptomics analysis revealed that the significant differentially expressed genes (DEGs) between parental and omipalisib-resistant AML cells were dominantly associated with cell cycle-related and nucleotide metabolism pathways. Metabolomic analysis in conjunction with metabolite enrichment analysis revealed a shift in glucose metabolism toward the pentose phosphate pathway (PPP) and serine synthesis pathway (SSP) in OCI-AML3-OR cells. OCI-AML3-OR cells exhibited enhanced proliferation by increasing purine synthesis dominated by SSP and PPP. Targeting phosphoglycerate dehydrogenase (PHGDH), a SSP rate-limiting enzyme, with NCT-503 and WQ-2101 resulted in increased reactive oxygen species levels and the induction of apoptosis in OCI-AML3-OR cells and another omipalisib-insensitive SKNO-1 cell in vitro. Furthermore, we found that, like OCI-AML cells, the exportin 1 (XPO1) inhibitors selinexor and eltanexor significantly induced cell cycle arrest and reduced PHGDH expression in OCI-AML3-OR cells. Finally, in vivo experiments demonstrated that both NCT-503 and selinexor significantly inhibited tumor growth and prolonged mouse survival without causing weight loss of OCI-AML3-OR xenografts. Therefore, treatment with PHGDH inhibitors could be a therapeutic strategy for refractory AML to PI3K/mTOR inhibitors. Relevant clinical trials are warranted.

Keywords:  Acute myeloid leukemia; Drug resistance; Omipalisib; Phosphoglycerate dehydrogenase inhibitor

DOI:  https://doi.org/10.1016/j.biopha.2025.118689
BBA Adv. 2025 ;8 100171

VDAC1 inhibitor DIDS uncouples respiration in isolated tissue mitochondria and induces mitochondrial hyperfusion in mammalian cells.

Surajit Das, Arpita Dutta, Minakshi Bedi, Arumay Pal, Shubhra Majumder, Alok Ghosh.

  Mitochondrial outer membrane protein, voltage-dependent anion channel 1 (VDAC1), is a gatekeeper of transport, metabolism, and cellular apoptosis. Ablation of VDAC1 or treatment with small molecular VDAC1 inhibitors often causes metabolic reprogramming in cells. However, the mechanism of VDAC1-mediated reprogramming of mitochondrial oxidative phosphorylation (OXPHOS) is still unclear. To address this problem, we tested how the high-affinity VDAC1 inhibitor, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), changes cell viability and mitochondrial functions. The IC50 value of DIDS was found 508 µM and 580 µM after 24 h of treatment on human osteosarcoma U2OS and mouse NIH-3T3 fibroblast cells. Moreover, when we inhibited mitochondrial OXPHOS by oligomycin A, 500 µM DIDS was found to uncouple the respiration like the conventional uncoupler CCCP in both the cells. Additionally, we observed that 50-200 µM DIDS, even after 2 h of treatment, depolarizes mitochondrial membrane potential. Also, brief DIDS treatment leads to an increase in cell population with hyperfused mitochondria and attenuation of DRP1 recruitment to mitochondria in U2OS cells. However, no significant alteration in the steady-state level of mitochondrial respiratory chain complex I and complex V subunits was noticed after DIDS treatment. Similar to cell lines, DIDS treatment also showed significant respiratory uncoupling in isolated mitochondria prepared from the normal muscle, liver, and sarcoma tumor tissues of mice. Finally, in silico modeling using AutoDock Vina and AlphaFold3 identified that DIDS binds inside the beta-barrel structure of VDAC1. Together, our findings directly demonstrate that DIDS binds to the VDAC1 inner pocket, uncouples OXPHOS, and promotes mitochondrial hyperfusion.

Keywords:  DIDS; Mitochondrial dynamics; OXPHOS; Uncoupling; VDAC1; mitochondria

DOI:  https://doi.org/10.1016/j.bbadva.2025.100171
Blood Adv. 2025 Oct 31. pii: bloodadvances.2025016155. [Epub ahead of print]

Metformin induces ferroptosis associated with lipidomic remodeling in AML.

Dominique Sternadt, Diego A Pereira-Martins, Prodromos Chatzikyriakou, Luise Albuquerque-Simões, Ming Yang, Douglas R Silveira, Albertus Tj Wierenga, Isabel Weinhäuser, Shanna M Hogeling, Lieve Oudejans, Pilar Casares-Alaez, Jean-Emmanuel Sarry, Christian Frezza, Gerwin A Huls, Lynn Quek, Jan Jacob Schuringa.

Metabolic reprogramming is a hallmark of cancer, essential for sustaining leukemogenesis. In acute myeloid leukemia (AML), high dependency on oxidative phosphorylation (OXPHOS) is often linked to poor outcomes and inhibiting this pathway has shown to be highly effective. However, most OXPHOS inhibitors are not clinically translatable due to significant side effects. Thus, repurposing safe FDA-approved drugs that can target OXPHOS is of great interest. Here, we evaluated metformin, an antidiabetic drug that inhibits OXPHOS, in a genetically diverse panel of primary AML samples to identify metabolic profiles predicting treatment susceptibility. Using label-free quantitative proteome analysis on sorted CD34+/CD117+ AML, we performed single-sample gene set enrichment analysis focused on metabolic terms and correlated enrichment scores with metformin sensitivity, followed by functional studies. Ex vivo treatment of AML samples with metformin showed a significant increase in ROS levels and ferroptosis induction, especially in samples with disturbed lipid metabolism, such as IDH2- and FLT3-mutant AMLs. In IDH2-mutant cells, co-treatment with palmitate, a saturated fatty acid (FA), increased metformin sensitivity, which could be rescued by CD36 knockdown, rendering these cells more resistant to treatment. Lipidomic analysis revealed profound alterations upon metformin treatment, including increased production of triglycerides and polyunsaturated FAs, further supporting a metabolic shift. We observed upregulation of genes related to lipid droplet formation, including DGAT1, a key enzyme in this process. DGAT1 inhibition was strongly synergistic with metformin, while iron chelators acted antagonistically. Our results underscore the potential of leveraging metabolic vulnerabilities in AML to identify more effective and personalized therapeutic strategies.

DOI: https://doi.org/10.1182/bloodadvances.2025016155
Am J Clin Nutr. 2025 Oct 28. pii: S0002-9165(25)00620-3. [Epub ahead of print]

Insulinemic and Inflammatory Dietary Patterns and Colorectal Cancer Risk: A Dietary Data Harmonization Study of One Million Participants in the COMETS Consortium.

Ni Shi, Rachel Hoobler, Rhea Harewood, Amanda E Toland, Demetrius Albanes, Emmanouil Bouras, Marc J Gunter, Linda M Liao, Steven C Moore, Fulvio Ricceri, Jerome I Rotter, Rashmi Sinha, Rachael Stolzenberg-Solomon, Anne Tjønneland, Alexis C Wood, Danxia Yu, Mary C Playdon, Fred K Tabung.

   BACKGROUND: Inflammatory and insulinemic dietary patterns have been associated with colorectal cancer (CRC) risk, but generalizability across diverse populations with heterogeneous food supplies and dietary behaviors has not been established.
OBJECTIVE: We harmonized disparate dietary and covariate data on a large scale to compute the reverse Empirical Dietary Index for Hyperinsulinemia-rEDIH, reverse Empirical Dietary Inflammatory Pattern-rEDIP, and Healthy Eating Index (HEI)-2015 scores, and tested their associations with CRC risk.
METHODS: We leveraged data among 501,892 women and 407,390 men from six cohorts across the U.S. (NIH-AARP, MESA, PLCO, SCCS) and Europe (EPIC, ATBC) with varying sociodemographic characteristics, participating in the Consortium of Metabolomics Studies. We harmonized nomenclature and nutritional information for more than 800 unique food items across cohorts. We used multivariable-adjusted Cox regression, adjusting for demographic, clinical, and lifestyle factors, to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations between the dietary indices and CRC risk per cohort, then meta-analyzed the estimates.
RESULTS: During a median follow-up of 14.9 years, 16,525 incident CRC cases were diagnosed. Participants in the highest quintile of rEDIH (low-insulinemic diet) had an 18% reduced risk of CRC (HR 0.82; 95% CI: 0.78, 0.86) compared to those in the lowest quintile. For the same comparison, similar risk reductions were observed for rEDIP (anti-inflammatory diet) (HR 0.84; 95% CI: 0.80, 0.89) and HEI-2015 (overall dietary quality) (HR 0.80; 95% CI: 0.76, 0.85). Heterogeneity between cohorts in the meta-analyzed estimates was low for rEDIH (I2=22.3%) compared to rEDIP (I2=62.5%) and HEI-2015 (I2=83.9%).
CONCLUSION: Using carefully harmonized data from nearly one million individuals in the U.S. and Europe, we observed significant CRC risk reduction with habitual intake of low-insulinemic and anti-inflammatory dietary patterns, comparable to higher overall dietary quality. Study findings underscore the utility of these dietary patterns for global cancer prevention efforts.

Keywords:  COMETS consortium; Dietary data harmonization; colorectal cancer prevention; metabolic dietary patterns; multi-continental populations

DOI:  https://doi.org/10.1016/j.ajcnut.2025.10.016
Immunometabolism (Cobham). 2025 Oct;7(4): e00072

A carbon trail to follow: unveiling itaconate's metabolism in vivo.

Denis E Anisov, Sally A Clayton, Maxim A Nosenko.

  The discovery of itaconate as an immunoregulatory metabolite has transformed the field of immunometabolism and opened multiple therapeutic avenues over the past decade. While the immunological functions of itaconic acid have been extensively studied, several aspects of its biochemistry-particularly in vivo utilization pathways-have remained unclear. In a recent study published in Nature Metabolism, Willenbockel et al apply carbon tracing to uncover the metabolic fate of itaconate within the organism. Insights from this work have important implications for understanding the physiological roles of itaconate and for advancing itaconate-based therapeutic strategies.

Keywords:  itaconate metabolism; stable isotope tracing; succinate dehydrogenase

DOI:  https://doi.org/10.1097/IN9.0000000000000072
Bone. 2025 Oct 27. pii: S8756-3282(25)00302-3. [Epub ahead of print]202 117690

In C57BL/6J mice, weight loss in previously obese mice reduced bone mass and shifted the cortical bone metabolome.

Carolyn Chlebek, Casey McAndrews, Benjamin Aaronson, Hope D Welhaven, Kanglun Yu, Samantha N Costa, Joseph Shaver, Sophia Silvia, Victoria E DeMambro, Ronald K June, Meghan E McGee-Lawrence, Clifford J Rosen.

  Obesity is linked to increased fracture risk. Despite the negative effects of weight loss on the skeleton, patients with obesity are advised to lose weight via calorie restriction. Obesity and weight loss individually alter both whole-body and local metabolism. Little is known about changes to bone mass and metabolome following calorie restriction in obese preclinical models. We hypothesized that caloric restriction would reduce bone mass in obese mice and would alter the cortical bone metabolome. To induce obesity, 8-week-old male and female C57BL/6J mice received 60 % kCal high-fat diet for 12 weeks. From 20 to 30 weeks of age, mice either remained obese or lost weight through 30 % caloric restriction. Controls consumed 10 % kCal low-fat diet. Compared to obesity, calorie restriction elicited cortical bone loss and trabecular thinning. Weight loss also reduced bone formation. Both obesity and subsequent calorie restriction altered the cortical bone metabolome in a sex-dependent manner. Metabolic pathways altered with diet generally mapped to amino acid or fatty acid metabolism. In males, weight loss was associated with a downregulation of pathways related to tryptophan, tyrosine, ubiquinone, and fatty acids. In females, calorie restriction downregulated taurine and hypotaurine metabolism but upregulated pyrimidine metabolism, nicotinate and nicotinamide metabolism, and pantothenate and CoA biosynthesis. In summary, despite improvements in components of systemic metabolism, caloric restriction in obese preclinical models reduced bone mass and did not restore the cortical metabolome to control conditions.

Keywords:  Bone QCT/microCT; Bone-fat interactions; DXA; Molecular pathways - remodeling; Nutrition; Other – diseases and disorders of/related to bone; Preclinical studies

DOI:  https://doi.org/10.1016/j.bone.2025.117690
Int J Biol Macromol. 2025 Oct 28. pii: S0141-8130(25)09166-4. [Epub ahead of print]332(Pt 1): 148609

Nicotinamide nucleotide transhydrogenase dysfunction transcriptionally impacts mitochondrial β-oxidation and neuromuscular junction in M. Gastrocnemius of 24-day-old mice.

Jingyi Song, Jaap Keijer, Melissa Bekkenkamp-Grovenstein, Melanie Humphry, Claudia Carmone, Sander Grefte.

  Nicotinamide nucleotide transhydrogenase (NNT) is a key mitochondrial enzyme generating NADPH by utilizing the proton gradient produced by oxidative phosphorylation (OXPHOS), thereby linking redox homeostasis to mitochondrial energy metabolism. The commonly used C57BL/6 J mouse strain lacks functional NNT, yet its impact during early development remains unclear. This study aimed to characterize adaptive molecular responses in the gastrocnemius muscle of young mice with NNT deficiency. Congenic Nnt deficient (NntΔ; BL6JRcc.BL6J-NntC57BL/6J/Wuhap) and wild-type (Nntwt; B6JRcc(B6J)-Nnt+/Wuhap) mouse lines were newly created. Transcriptome profiling was performed on gastrocnemius muscles of 24-day-old male mice, followed by validation of key findings. Energy metabolism emerged as the most affected process, and NntΔ mice exhibited significant reduced OXPHOS-related genes, particularly within complex I and complex V showing a downregulation of 42.2 % and 50 % of their subunits, respectively. Additionally, expression of Cpt1b, Cpt2, and Slc25a20, involved in fatty acid transport, was reduced by 33 %, 19 % and 23 %, respectively. These results may explain the trend toward decreased oxygen consumption rates using palmitoylcarnitine (29 %; P-value = 0.068) and octanoylcarnitine (18 %; P-value = 0.081). CHRNA1, a protein critical for neuromuscular junction (NMJ) function, was also downregulated by 31 %. These results suggest that functional loss of NNT impairs mitochondrial energy pathways and β-oxidation, potentially influencing NMJ in the gastrocnemius muscle during development.

Keywords:  Mitochondria; NNT; OXPHOS

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148609
Antioxidants (Basel). 2025 Sep 23. pii: 1147. [Epub ahead of print]14(10):

Atorvastatin Induces Bioenergetic Impairment and Oxidative Stress Through Reverse Electron Transport.

Francesca Valenti, Luca Pincigher, Nicola Rizzardi, Francesca Orsini, Christian Bergamini, Romana Fato.

  Statins are the first-line therapy for managing elevated cholesterol levels that represent a risk of acute cardiovascular events. However, the use of statins is associated with several side effects, likely due to the depletion of Coenzyme Q10 (CoQ10), a key component of the mitochondrial electron transport chain and a membrane antioxidant. In our study, we present evidence of the cytotoxic effects of Atorvastatin on human dermal fibroblasts in terms of oxidative stress and mitochondrial impairment. Interestingly, CoQ10 supplementation in statin-treated cells significantly reduced ROS levels and restored mitochondrial oxygen consumption rate and the intracellular ATP/ADP ratio. Moreover, our data suggest that the mechanism for Atorvastatin off-target effects at high concentrations involves the inhibition of respiratory complexes I and III, leading to reverse electron transport and ROS production by Complex I. These findings highlight the potential benefits of CoQ10 supplementation in mitigating statin-induced cytotoxicity and propose a mechanistic basis for the adverse effects associated with Atorvastatin therapy.

Keywords:  Coenzyme Q10; RET; Ubiqsome; mitochondria; statin

DOI:  https://doi.org/10.3390/antiox14101147
J Biosci Bioeng. 2025 Oct 30. pii: S1389-1723(25)00266-X. [Epub ahead of print]

13C-metabolic flux analysis of K562 cells before and after differentiation into erythroid reveals a metabolic shift toward oxidative metabolism.

Eisuke Mochizuki, Nobuyuki Okahashi, Takeo Taniguchi, Fumio Matsuda.

  In regenerative medicine, it is crucial to discover the key factors associated with erythroid differentiation for efficient production of artificial red blood cells. One such factor is erythroid metabolism as erythroid cells dynamically coordinate their metabolic processes to obtain energy for proper differentiation. However, the details of these metabolic changes are not well understood. In this study, we aimed to analyze the metabolism of K562, a cell line that differentiates into erythroid cells using 13C-metabolic flux analysis. The results showed that differentiated cells decreased glycolytic flux and increased TCA cycle flux compared with undifferentiated cells, indicating a shift to oxidative metabolism via differentiation. Based on the finding, the inhibition of ATP synthase by oligomycin treatment significantly suppressed differentiation of K562 cells, suggesting that the activation of oxidative metabolism is required for proper differentiation of K562 cells.

Keywords:  (13)C-metabolic flux analysis; Erythropoiesis; Glycolysis; K562; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.jbiosc.2025.10.002
Expert Opin Pharmacother. 2025 Oct 27.

Venetoclax and new BCL-2 inhibitors in acute myeloid leukemia.

Pasquale Niscola, Gianfranco Catalano, Gloria Pasqualini, Daniela Piccioni, Marco Giovannini, Nelida Inés Noguera.

   INTRODUCTION: The development of B-cell lymphoma-2 (BCL-2) inhibitors has totally revolutionized the management of acute myeloid leukemia (AML). These highly effective, small molecules trigger apoptosis in leukemia cells by specifically targeting the BCL-2 protein. Notably, venetoclax, an extremely high-affinity BCL-2 inhibitor, stands out particularly for its high therapeutic index, especially when combined with hypomethylating agents like azacytidine and decitabine, among older patients and even young patients with comorbidities that preclude intensive chemotherapy regimens. Once more, because the new AML model is evolving, venetoclax is being used more with high-intensity chemotherapy even in young patients, at any age. Areas covered. This review summarizes the progress in AML targeting the intrinsic apoptosis pathway with current and developing BCL-2 inhibitors, as well as their clinical applications in combination therapies.
EXPERT OPINION: While venetoclax has made significant progress in treating AML, ongoing clinical research is moving this agent into first-line combination treatments. Notably, the lack of response to this agent and the development of acquired resistance remain significant concerns. Although specific gene mutations strongly predict clinical response, research is ongoing into predictive biomarkers and new drug combinations that work synergistically. Emerging therapies targeting BCL-2 also aim to maximize treatment benefits and address issues related to venetoclax resistance.

Keywords:  BH3 mimetics; acute myeloid leukemia; hypomethylating agents; intensive chemotherapy; targeted therapies; venetoclax

DOI:  https://doi.org/10.1080/14656566.2025.2582022
Nat Commun. 2025 Oct 29. 16(1): 9531

A red fluorescent genetically encoded biosensor for in vivo imaging of extracellular L-lactate dynamics.

Yuki Kamijo, Philipp Mächler, Natalie Ness, Cong Quang Vu, Tsukasa Kusakizako, Jamsad Mannuthodikayil, Zaneta Ku, Marc Boisvert, Ekaterina Grebenik, Ikumi Miyazaki, Rina Hashizume, Haruaki Sato, Rui Liu, Yukiko Hori, Taisuke Tomita, Tetsuro Katayama, Akihiro Furube, Gabriela Caraveo, Marie-Eve Paquet, Mikhail Drobizhev, Osamu Nureki, Satoshi Arai, Marco Brancaccio, Robert E Campbell, David Kleinfeld, Yusuke Nasu.

L-Lactate is increasingly recognized as an intercellular energy currency in mammals, but mysteries remain regarding the spatial and temporal dynamics of its release and uptake between cells via the extracellular environment. Here we introduce R-eLACCO2.1, a red fluorescent extracellular L-lactate biosensor that is superior to previously reported green fluorescent biosensors in in vivo sensitivity to increases in extracellular L-lactate and spectral orthogonality. R-eLACCO2.1 exhibits excellent fluorescence response in cultured cells, mouse brain slices, and live mice. R-eLACCO2.1 also serves as an effective fluorescence lifetime-based biosensor. Using R-eLACCO2.1, we monitor whisker stimulation and locomotion-induced changes in endogenous extracellular L-lactate in the somatosensory cortex of awake mice. To highlight the potential insights gained from in vivo measurements with R-eLACCO2.1, we perform dual-color imaging from the somatosensory cortex of actively locomoting mice. This enables us to simultaneously observe the neural activity, reported by a green fluorescent GCaMP calcium ion biosensor, and extracellular L-lactate. As the high-performance tool in the suite of extracellular L-lactate biosensors, R-eLACCO2.1 is ideally suited to delimit the emerging roles of L-lactate in mammalian metabolism.

DOI: https://doi.org/10.1038/s41467-025-64484-x
Cell Rep. 2025 Oct 29. pii: S2211-1247(25)01267-7. [Epub ahead of print]44(11): 116496

A generalized strategy to kill leukemic cells by targeting the regulatory systems governing mitochondrial membrane potential.

Ting Liu, Ji-Hao Zhou, Yongbo Gong, Ying Zhang, Yongcan Ma, Xiaowen Zhang, Mohammad Minhajuddin, Wenjie Song, Zixuan Zhuang, Ana Vujovic, Youli Lu, Ang Jia, Rongqun Guo, Ruobing Ren, Lu Zhou, Yu Xiong, Linzhang Huang, Xingrong Du, Tong-Jin Zhao, Peng Li, Craig T Jordan, Haobin Ye.

  Targeting mitochondria emerges as a promising anti-leukemia strategy, yet selective mitochondrial disruption remains challenging. Here, we identified elevated mitochondrial membrane potential (MMP) as a hallmark of leukemic transformation and chemotherapy-resistant cells, prompting screening for MMP-targeting agents. Alexidine (AD), an MMP-depleting compound, demonstrated potent anti-leukemic activity with low toxicity. Mechanistically, AD binds unsaturated cardiolipin to destabilize the inner membrane localization of mitochondrial ribosome, suppressing cardiolipin-dependent mitochondrial translation, a process validated as an independent prognostic marker in leukemia. Interestingly, intercellular heterogeneity in mitochondrial translation drives heterogeneous MMP states within the population, which is associated with stemness and chemoresistance. Intriguingly, this intra-population MMP difference stems not from cardiolipin-mediated translation but from asparagine-driven mitochondrial protein synthesis-a mechanism leukemia cells selectively activate to evade chemotherapy. Critically, pharmacological asparagine depletion synergistically enhances chemosensitivity by disrupting this resistance pathway. Our findings establish that MMP regulation through cardiolipin-maintained homeostasis and asparagine-fueled adaptation represents therapeutic vulnerabilities, advocating co-targeting strategies to overcome resistance.

Keywords:  CP: cancer; alexidine; asparagine; leukemia stem cells; mitochondrial membrane potential; mitochondrial translation

DOI:  https://doi.org/10.1016/j.celrep.2025.116496