bims-medica 2025-04-06 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–04–06
25 papers selected by
Brett Chrest, Wake Forest University

Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.
Diet-induced obesity dampens the temporal oscillation of hepatic mitochondrial lipids.
Ketone Catabolism is Essential for Maintaining Normal Heart Function During Aging.
Detection of liver mitochondrial oxaloacetate by NMR spectroscopy and membrane potential-dependent accumulation.
Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation.
Oral decitabine in acute myeloid leukemia: assessing efficacy, safety, and future implications for older patients.
Hyperpolarized 13C-MRS can Quantify Lactate Production and Oxidative PDH Flux in Murine Skeletal Muscle During Exercise.
Method for Detecting Mitochondrial ATP by Hybridization Chain Reaction.
FLT3 inhibition upregulates OCT4/NANOG to promote maintenance and TKI resistance of FLT3-ITD+ acute myeloid leukemia.
Advancing Obesity Management: the Very Low-Energy Ketogenic therapy (VLEKT) as an Evolution of the "Traditional" Ketogenic Diet.
Oncogene-induced senescence mitochondrial metabolism and bioenergetics drive the secretory phenotype: further characterization and comparison with other senescence-inducing stimuli.
What can ATP content tell us about Barth syndrome muscle phenotypes?
LDHB silencing enhances the effects of radiotherapy by impairing nucleotide metabolism and promoting persistent DNA damage.
Protein succinylome analysis identifies citrate synthase as a central regulator of osteoclast metabolic activity.
Dietary Glycemic Index, Glycemic Load, Sugar, and Fiber Intake in Association With Breast Cancer Risk: An Updated Meta-analysis.
In vivo validation of the palmitoylation cycle as a therapeutic target in NRAS -mutant cancer.
Integrative insights into the role of CAV1 in ketogenic diet and ferroptosis in pancreatic cancer.
HDAC6 and USP9X Control Glutamine Metabolism by Stabilizing GS to Promote Glioblastoma Tumorigenesis.
Sweet beverages and the risk of colorectal cancer: the Norwegian Women and Cancer Study.
The association between ultra-processed foods intake and the odds of prostate cancer: a case-control study.
Immune checkpoints regulate acute myeloid leukemia stem cells.
A three-week Ketogenic Diet increases Global Cerebral Blood Flow and Brain-Derived Neurotrophic Factor.
Association of overweight/obesity and digestive system cancers: A meta-analysis and trial sequential analysis of prospective cohort studies.
Effects of One-Month Very-Low-Calorie Ketogenic Diet on 24 h Energy Metabolism and Body Composition in Women with Obesity.
Characterization of a new mutation of mitochondrial ND6 gene in hepatocellular carcinoma and its effects on respiratory complex I.

bioRxiv. 2025 Mar 13. pii: 2025.03.10.642426. [Epub ahead of print]

Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.

Patrick B Jonker, Mumina Sadullozoda, Guillaume Cognet, Juan J Apiz Saab, Kelly H Sokol, Violet X Wu, Deepa Kumari, Colin Sheehan, Mete E Ozgurses, Darby Agovino, Grace Croley, Smit A Patel, Althea Bock-Hughes, Kay F Macleod, Hardik Shah, Jonathan L Coloff, Evan C Lien, Alexander Muir.

Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors perturb cellular metabolic activity, which imposes metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising antineoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we challenged pancreatic cancer cells with microenvironmental nutrient levels and analyzed changes in cell metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1. Synthesis of these fatty acids is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids in cellular membranes. As a consequence of microenvironmental constraints on fatty acid synthesis, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to polyunsaturated fatty acids, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to polyunsaturated-enriched fat sources.

DOI: https://doi.org/10.1101/2025.03.10.642426
J Lipid Res. 2025 Apr 01. pii: S0022-2275(25)00050-1. [Epub ahead of print] 100790

Diet-induced obesity dampens the temporal oscillation of hepatic mitochondrial lipids.

Rashi Jain, Rajprabu Rajendran, Sona Rajakumari.

  Mitochondria play a pivotal role in energy homeostasis and regulate several metabolic pathways. The inner and outer membrane of mitochondria comprises unique lipid composition and proteins that are essential to form electron transport chain complexes, orchestrate oxidative phosphorylation, β-oxidation, ATP synthesis, etc. As known diet-induced obesity affects mitochondrial function, dynamics, and mitophagy, which are governed by circadian clock machinery. Though DIO impairs the interplay between circadian oscillation and lipid metabolism, the impact of DIO on mitochondrial membrane lipid composition and their temporal oscillation is unknown. Thus, we investigated the diurnal oscillation of liver mitochondrial lipidome at various Zeitgeber times using quantitative lipidomics. Our data suggested that obesity disrupted lipid accumulation profiles and diminished the oscillating lipid species in the hepatic mitochondria. Strikingly, HFD manifested a more homogenous temporal oscillation pattern in phospholipids regardless of possessing different fatty acyl-chain lengths and degrees of unsaturation. In particular, DIO impaired the circadian rhythmicity of phosphatidyl ethanolamine, phosphatidyl choline, phosphatidyl serine and ether-linked phosphatidyl ethanolamine. Also, DIO altered the rhythmic profile of PE/PC, ePE/PC, PS/PC ratio and key proteins related to mitochondrial function, dynamics, and quality control. Since HFD dampened lipid oscillation, we examined whether the diurnal oscillation of mitochondrial lipids synchronized with mitochondrial function. Also, our data emphasized that acrophase of mitochondrial lipids synchronized with increased oxygen consumption rate and Parkin levels at ZT16 in chow-fed mice. Our study revealed that obesity altered the mitochondrial lipid composition and hampered the rhythmicity of mitochondrial lipids, oxygen consumption rate and Parkin levels in the liver.

Keywords:  Circadian rhythm; Diet-induced obesity; High-fat diet; MASLD; Membrane lipids; Mitochondrial lipidome; OXPHOS; Temporal oscillation

DOI:  https://doi.org/10.1016/j.jlr.2025.100790
bioRxiv. 2025 Mar 19. pii: 2025.03.18.643760. [Epub ahead of print]

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

Mariko Aoyagi Keller, Michinari Nakamura.

The heart utilizes various nutrient sources for energy production, primarily favoring fatty acid oxidation. While 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. The cardiac expression of succinyl-CoA:3-ketoacid CoA transferase (SCOT), a rate-limiting enzyme in ketolysis, decreases with aging in female mice. SCOT cardiomyocyte-specific knockout (cKO) 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 cKO mice, suggesting ketone oxidation-independent mechanisms contribute to the development of cardiomyopathy caused by SCOT downregulation. These findings indicate that ketone catabolism is crucial for maintaining heart function during aging, and that ketones confer cardioprotection independently of ketone oxidation.

DOI: https://doi.org/10.1101/2025.03.18.643760
FASEB J. 2025 Apr 15. 39(7): e70490

Detection of liver mitochondrial oxaloacetate by NMR spectroscopy and membrane potential-dependent accumulation.

Liping Yu, Brian D Fink, William I Sivitz.

  Oxaloacetate (OAA) is a central liver metabolite fundamental to critical metabolic pathways. However, understanding OAA metabolism in the liver has been limited because the compound is very difficult to measure by mass spectroscopy and not abundant enough for detection by other methods. Here we describe a novel approach to quantifying OAA in liver mitochondria. Moreover, we provide evidence for membrane potential-dependent OAA accumulation in mitochondria during complex II-energized respiration consistent with OAA inhibition of succinate dehydrogenase.

Keywords:  inner membrane potential; liver; metabolites; mitochondria; oxaloacetate; respiration

DOI:  https://doi.org/10.1096/fj.202500039R
Cancer Metab. 2025 Mar 31. 13(1): 16

Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation.

Anna Solta, Büsra Ernhofer, Kristiina Boettiger, Christian Lang, Zsolt Megyesfalvi, Theresa Mendrina, Dominik Kirchhofer, Gerald Timelthaler, Beata Szeitz, Melinda Rezeli, Clemens Aigner, Arvand Haschemi, Lukas W Unger, Balazs Dome, Karin Schelch.

   BACKGROUND: Small cell lung cancer (SCLC) is an aggressive malignancy with distinct molecular subtypes defined by transcription factors and inflammatory characteristics. This follow-up study aimed to validate the unique metabolic phenotype in achaete-scute homologue 1 (ASCL1)-driven SCLC cell lines and human tumor tissue.
METHODS: Metabolic alterations were analyzed using proteomic data. Structural and functional differences of mitochondria were investigated using qPCR, flow cytometry, confocal imaging, and transmission electron microscopy and seahorse assays. Several metabolic inhibitors were tested using MTT-based and clonogenic assays. Single-cell enzyme activity assays were conducted on cell lines and tumor tissue samples of SCLC patients.
RESULTS: We found increased mitochondrial numbers correlating with higher oxidative phosphorylation activity in ASCL1-dominant cells compared to other SCLC subtypes. Metabolic inhibitors targeting mitochondrial respiratory complex-I or carnitine palmitoyltransferase 1 revealed higher responsiveness in SCLC-A. Conversely, we demonstrated that non-ASCL1-driven SCLCs with lower oxidative signatures show dependence on glutaminolysis as evidenced by the enhanced susceptibility to glutaminase inhibition. Accordingly, we detected increased glutamate-dehydrogenase activity in non-ASCL1-dominant cell lines as well as in human SCLC tissue samples.
CONCLUSIONS: Distinct SCLC subtypes exhibit unique metabolic vulnerabilities, suggesting potential for subtype-specific therapies targeting the respiratory chain, fatty acid transport, or glutaminolysis.

Keywords:  Metabolism; Molecular subtypes; Oxidative phosphorylation; Small cell lung cancer

DOI:  https://doi.org/10.1186/s40170-025-00382-6
Expert Rev Hematol. 2025 Apr 02. 1-9

Oral decitabine in acute myeloid leukemia: assessing efficacy, safety, and future implications for older patients.

Pasquale Niscola.

   INTRODUCTION: Older patients with acute myeloid leukemia (AML) are often unsuitable for standard treatments and traditionally have a dismal prognosis. For 20 years, hypomethylating agents (HMAs), as single agents and recently as a backbone with venetoclax, have been used in this setting. The oral combination of decitabine and cedazuridine (C-DEC), which is therapeutically and pharmacologically equivalent to the intravenous (IV) formulation (IV-DEC), has expanded the therapeutic arsenal for AML, allowing for better convenience of administration. This review provides an overview of C-DEC, current clinical applications, and ongoing clinical studies, highlighting its potential role in managing AML in older patients.
AREAS COVERED: For the aim of this review, the authors searched the current English literature on C-DEC in AML patients through PubMed, using several pertinent keywords. To summarize the most recent developments as up-to-date as possible, we considered, with a few exceptions, only papers published over the last three years until March 2025.
EXPERT OPINION: Compared to IV-DEC, C-DEC provides similar therapeutic exposure and efficacy with an optional safety profile, enhanced treatment adherence, reduced treatment burden, and required healthcare facilities compared to those associated with IV-DEC, providing a precious tool to manage older and unfit AML patients.

Keywords:  AML; Acute myeloid leukemia; QOL; clinical treatment; managed care; novel agents; older patients; oral decitabine; quality of life

DOI:  https://doi.org/10.1080/17474086.2025.2487605
NMR Biomed. 2025 May;38(5): e70020

Hyperpolarized 13C-MRS can Quantify Lactate Production and Oxidative PDH Flux in Murine Skeletal Muscle During Exercise.

M Kate Curtis, Jordan J McGing, Brianna J Stubbs, Vicky Ball, Lowri E Cochlin, David P O'Neill, Christoffer Laustsen, Mark A Cole, Peter A Robbins, Damian J Tyler, Jack J Miller.

  Existing techniques for the non-invasive in vivo study of dynamic changes in skeletal muscle metabolism are subject to several limitations, for example, poor signal-to-noise ratios which result in long scan times and low temporal resolution. Hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy (HP-MRS) allows the real-time visualization of in vivo metabolic processes and has been used extensively to study cardiac metabolism, but has not resolved oxidative phosphorylation in contracting skeletal muscle. Combining HP-MRS with an in vivo muscle hindlimb electrical stimulation protocol that modelled voluntary exercise to exhaustion allows the simultaneous real-time assessment of both metabolism and function. The aim of this work was to validate the sensitivity of the method by assessing pyruvate dehydrogenase (PDH) flux in resting vs. working muscle: measuring the production of bicarbonate (H13CO3 -), a byproduct of the PDH-catalysed conversion of [1-13C]pyruvate to acetyl-CoA. Mice (n = 6) underwent two hyperpolarized [1-13C]pyruvate injections with 13C MR spectra obtained from the gastrocnemius muscle to measure conversion of pyruvate to lactate and bicarbonate, one before the stimulation protocol with the muscle in a resting state and one during the stimulation protocol. The muscle force generated during stimulation was also measured, and 13C MRS undertaken at a point of ~50% fatigue. We observed an increase in the bicarbonate/pyruvate ratio by a factor of ~1.5×, in the lactate/pyruvate ratio of ~2.7×, together with an increase in total carbon (~1.5×) that we attribute to perfusion. This demonstrates profound differences in metabolism between the resting and exercising states. These data therefore serve as preliminary evidence that hyperpolarized 13C MRS is an effective in vivo probe of PDH flux in exercising skeletal muscle and could be used in future studies to examine changes in muscle metabolism in states of disease and altered nutrition.

Keywords:  13C MRS; hyperpolarized 13C; magnetic resonance; mouse models; muscle metabolism

DOI:  https://doi.org/10.1002/nbm.70020
Methods Mol Biol. 2025 ;2901 159-165

Method for Detecting Mitochondrial ATP by Hybridization Chain Reaction.

Lei Luo, Xiaohai Yang, Kemin Wang.

  Adenosine triphosphate (ATP) plays a central role in energy transduction and signaling in living cells. For mitochondrial ATP detection, the appropriate probes should include the abilities to enter target cells noninvasively, target mitochondria, and then respond to the ATP reliably. Here, we provide a detailed protocol for imaging mitochondrial ATP in living cells exploiting the hybridization chain reaction (HCR).

Keywords:  Adenosine triphosphate (ATP); Hybridization chain reaction; Imaging; Mitochondria

DOI:  https://doi.org/10.1007/978-1-0716-4394-5_12
Oncogenesis. 2025 Mar 29. 14(1): 7

FLT3 inhibition upregulates OCT4/NANOG to promote maintenance and TKI resistance of FLT3-ITD+ acute myeloid leukemia.

Qi Zhou, Zijian Li, Pingping Zhao, Yongyu Guan, Huiyuan Chu, Yaming Xi.

Up to 30% of acute myeloid leukemia (AML) patients face unfavorable outcomes due to the FMS-like receptor tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutation. Although FLT3 inhibitors show encouraging outcomes in treatment, they fail to eliminate leukemia stem cells, the origin of persistent and resistant lesions. Exploration of the mechanism in FLT3-ITD+ AML maintenance and chemoresistance is crucial for the development of novel therapeutic approaches. The manifestation of pluripotency transcription factors (TFs) and their link to clinical outcomes have been documented in various tumors. This study investigates the correlation between core pluripotency TF and treatment in AML. We discovered that FLT3 inhibition induced upregulation of OCT4 and NANOG in FLT3-ITD+ AML cells. Subsequently, we demonstrated that downregulation of OCT4 or NANOG inhibited cell growth, promoted apoptosis, and induced G0/G1 cell cycle phase arrest in FLT3-ITD+ AML cells. Knockdown of OCT and NANOG inhibited tumor growth in a mouse tumor model. OCT4 promotes the malignant biological behavior of FLT3-ITD+ AML by enhancing the abnormal FLT3 signaling pathway through transcriptional activation of NANOG. Importantly, downregulation of OCT4 or NANOG increased responsiveness to FLT3-tyrosine kinase inhibitor (TKI) (Gilteritinib), implying that OCT4 and NANOG may contribute to TKI resistance in FLT3-ITD+ AML. Our study verifies the involvement of OCT4/NANOG in regulating TKI sensitivity and targeting them may improve the cytotoxicity of FLT3-TKIs in FLT3-ITD+ AML.

DOI: https://doi.org/10.1038/s41389-025-00553-6
Curr Obes Rep. 2025 Apr 03. 14(1): 30

Advancing Obesity Management: the Very Low-Energy Ketogenic therapy (VLEKT) as an Evolution of the "Traditional" Ketogenic Diet.

Francesco Balestra, Maria De Luca, Giorgia Panzetta, Rita Palieri, Endrit Shahini, Gianluigi Giannelli, Giovanni De Pergola, Maria Principia Scavo.

   PURPOSE OF REVIEW: This narrative review comprehensively analyzes VLEKT as an advanced nutritional strategy for obesity management. The focus is on the beneficial effects on key disease organs, such as adipose tissue and liver, as well as the modulation of intestinal permeability and its fundamental role in influencing the gut microbiota and inflammatory pathways.
RECENT FINDINGS: The impact of VLEKT on obesity-related comorbidities, including metabolic syndrome, cardiovascular disease, endocrine disorders, metabolic dysfunction-associated steatotic liver disease (MASLD), neurological disorders, and kidney alterations, is also investigated. Moreover, to assess its wider application in obesity treatment, the combination of ketogenic regimes with additional strategies such as physical activity, bariatric surgery, and digital health technologies is examined. Despite promising clinical results, adherence to VLEKT and potential nutritional deficiencies require careful follow-up and individualized programming monitored by specialists. Future research should focus on elucidating the molecular mechanisms underlying the effects on physiological systems, and long-term safety. Nevertheless, VLEKT is an innovative approach to obesity treatment, offering a target-oriented and highly effective strategy for people fighting against overweight and its associated medical complications. Obesity is a multifactorial and chronic disease associated with numerous comorbidities; given its increasing prevalence, effective and personalized intervention strategies are crucial to inhibit the "obesity pandemic" according to a "food re-educational" protocol. Among dietary interventions, the ketogenic diet (KD) has attracted attention for its effectiveness in weight management and metabolic benefits. A variant, the very low-calorie ketogenic diet (VLCKD), more recently defined as very low-energy ketogenic diet (VLEKD), combines the metabolic benefits of ketosis with substantial calorie restriction, improving overall health.

Keywords:  Ketogenic diet (KD); MASLD; Obesity; Obesity metabolism; Very low calorie ketogenic diet (VLCKD); Very low-energy ketogenic therapy (VLEKT)

DOI:  https://doi.org/10.1007/s13679-025-00622-2
Redox Biol. 2025 Mar 22. pii: S2213-2317(25)00119-3. [Epub ahead of print]82 103606

Oncogene-induced senescence mitochondrial metabolism and bioenergetics drive the secretory phenotype: further characterization and comparison with other senescence-inducing stimuli.

Inés Marmisolle, Eliana Chacón, Santiago Mansilla, Santiago Ruiz, Mariana Bresque, Jennyfer Martínez, Ricardo Iván Martínez-Zamudio, Utz Herbig, Jie Liu, Toren Finkel, Carlos Escande, Laura Castro, Celia Quijano.

  Cellular senescence is characterized by proliferation arrest and a senescence-associated secretory phenotype (SASP), that plays a role in aging and the progression of various age-related diseases. Although various metabolic alterations have been reported, no consensus exists regarding mitochondrial bioenergetics. Here we compared mitochondrial metabolism of human fibroblasts after inducing senescence with different stimuli: the oxidant hydrogen peroxide (H2O2), the genotoxic doxorubicin, serial passage, or expression of the H-RASG12V oncogene (RAS). In senescence induced by H2O2, doxorubicin or serial passage a decrease in respiratory control ratio (RCR) and coupling efficiency was noted, in relation to control cells. On the contrary, oncogene-induced senescent cells had an overall increase in respiration rates, RCR, spare respiratory capacity and coupling efficiency. In oncogene-induced senescence (OIS) the increase in respiration rates was accompanied by an increase in fatty acid catabolism, AMPK activation, and a persistent DNA damage response (DDR), that were not present in senescent cells induced by either H2O2 or doxorubicin. Inhibition of AMPK reduced mitochondrial oxygen consumption and secretion of proinflammatory cytokines in OIS. Assessment of enzymes involved in acetyl-CoA metabolism in OIS showed a 3- to 7.5-fold increase in pyruvate dehydrogenase complex (PDH), a 40% inhibition of mitochondrial aconitase, increased phosphorylation and activation of ATP-citrate lyase (ACLY), and inhibition of acetyl-CoA carboxylase (ACC). There was also a significant increase in expression and nuclear levels of the deacetylase sirtuin 6 (SIRT6). These changes can influence the sub-cellular distribution of acetyl-CoA and modulate protein acetylation reactions in the cytoplasm and nuclei. In fact, ACLY inhibition reduced histone 3 acetylation (H3K9Ac) in OIS and secretion of SASP components. In summary, our data show marked heterogeneity in mitochondrial energy metabolism of senescent cells, depending on the inducing stimulus, reveal new metabolic features of oncogene-induced senescent cells and identify AMPK and ACLY as potential targets for SASP modulation.

Keywords:  Bioenergetics; Fatty acid oxidation; Mitochondria; RAS oncogene; Senescence; TCA cycle

DOI:  https://doi.org/10.1016/j.redox.2025.103606
J Transl Genet Genom. 2025 ;9(1): 1-10

What can ATP content tell us about Barth syndrome muscle phenotypes?

Jeffrey J Brault, Simon J Conway.

  Adenosine triphosphate (ATP) is the energy currency within all living cells and is involved in many vital biochemical reactions, including cell viability, metabolic status, cell death, intracellular signaling, DNA and RNA synthesis, purinergic signaling, synaptic signaling, active transport, and muscle contraction. Consequently, altered ATP production is frequently viewed as a contributor to both disease pathogenesis and subsequent progression of organ failure. Barth syndrome (BTHS) is an X-linked mitochondrial disease characterized by fatigue, skeletal muscle weakness, cardiomyopathy, neutropenia, and growth delay due to inherited TAFAZZIN enzyme mutations. BTHS is widely hypothesized in the literature to be a model of defective mitochondrial ATP production leading to energy deficits. Prior patient data have linked both impaired ATP production and reduced phosphocreatine to ATP ratios (PCr/ATP) in BTHS children and adult hearts and muscles, suggesting a primary role for perturbed energetics. Moreover, although only limited direct measurements of ATP content and ADP/ATP ratio (an indicator of the energy available from ATP hydrolysis) have so far been carried out, analysis of divergent BTHS animal models, cultured cell types, and diverse organs has failed to uncover a unifying understanding of the molecular mechanisms linking TAFAZZIN deficiency to perturbed muscle energetics. This review mainly focuses on the energetics of striated muscle in BTHS mitochondriopathy.

Keywords:  Barth syndrome; TAFAZZIN; adenosine triphosphate; cardiolipin; energetics; mitochondria; striated muscle

DOI:  https://doi.org/10.20517/jtgg.2024.83
Sci Rep. 2025 Mar 29. 15(1): 10897

LDHB silencing enhances the effects of radiotherapy by impairing nucleotide metabolism and promoting persistent DNA damage.

Haibin Deng, Fatlind Malsiu, Huixiang Ge, Tereza Losmanova, Michaela Medová, Nicola Zamboni, Wenxiang Wang, Ren-Wang Peng, Jinming Tang, Patrick Dorn, Thomas Michael Marti.

  Lung cancer is the leading cause of cancer-related deaths globally, with radiotherapy as a key treatment modality for inoperable cases. Lactate, once considered a by-product of anaerobic cellular metabolism, is now considered critical for cancer progression. Lactate dehydrogenase B (LDHB) converts lactate to pyruvate and supports mitochondrial metabolism. In this study, a re-analysis of our previous transcriptomic data revealed that LDHB silencing in the NSCLC cell lines A549 and H358 dysregulated 1789 genes, including gene sets associated with cell cycle and DNA repair pathways. LDHB silencing increased H2AX phosphorylation, a surrogate marker of DNA damage, and induced cell cycle arrest at the G1/S or G2/M checkpoint depending on the p53 status. Long-term LDHB silencing sensitized A549 cells to radiotherapy, resulting in increased DNA damage and genomic instability as evidenced by increased H2AX phosphorylation levels and micronuclei accumulation, respectively. The combination of LDHB silencing and radiotherapy increased protein levels of the senescence marker p21, accompanied by increased phosphorylation of Chk2, suggesting persistent DNA damage. Metabolomics analysis revealed that LDHB silencing decreased nucleotide metabolism, particularly purine and pyrimidine biosynthesis, in tumor xenografts. Nucleotide supplementation partially attenuated DNA damage caused by combined LDHB silencing and radiotherapy. These findings suggest that LDHB supports metabolic homeostasis and DNA damage repair in NSCLC, while its silencing enhances the effects of radiotherapy by impairing nucleotide metabolism and promoting persistent DNA damage.

Keywords:  DNA damage; Lactate dehydrogenase; Lung cancer; Nucleotide metabolism; Radiotherapy

DOI:  https://doi.org/10.1038/s41598-025-95633-3
FEBS J. 2025 Apr 02.

Protein succinylome analysis identifies citrate synthase as a central regulator of osteoclast metabolic activity.

Dayoung Yu, Yue Gao, Marcin Luzarowski, Elisabeth Seebach, Thomas Heitkamp, Michael Börsch, Thomas Ruppert, Katharina F Kubatzky.

  Tumour necrosis factor ligand superfamily member 11 (TNFSF11; RANKL) and macrophage colony-stimulating factor 1 receptor (M-CSF) differentiate macrophages into osteoclasts. This process is characterised by changes in metabolic activity that support energy-consuming processes. Treatment with RANKL triggers a phenotype of accelerated metabolism with enhanced glycolysis and an initial disruption of the tricarboxylic acid cycle (TCA) through increased expression of the enzyme aconitate decarboxylase (ACOD1), which results in an upregulation of intracellular succinate levels. Succinate then causes post-translational succinylation of lysine residues. ACOD1 as an inducer of protein succinylation and the desuccinylase NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5) are regulated differentially, and the initially high expression of ACOD1 decreases towards the end of differentiation, whereas SIRT5 levels increase. To mimic the effect of protein succinylation, diethyl succinate or a SIRT5 inhibitor was added during differentiation, which reduced the formation of large osteoclasts, showing its relevance for osteoclastogenesis. To identify succinylated proteins, we used an immunoaffinity-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach. Most lysine succinylated proteins were mitochondrial metabolic enzymes. Citrate synthase (CS), the enzyme catalysing the first reaction of the TCA cycle, showed a notable difference in succinylation levels before and after RANKL stimulation, with succinylation detected exclusively in stimulated cells. Immunoprecipitation assays confirmed CS succinylation. Using whole cell extracts, we observed that RANKL treatment decreased CS activity in a concentration-dependent manner. This suggests that CS could be critical in the context of energy production during osteoclastogenesis and that protein succinylation modulates the differentiation program of osteoclasts.

Keywords:  PTM scan; RANKL; citrate synthase; metabolism; mitochondria; osteoclast; post‐translational modification; succinylation

DOI:  https://doi.org/10.1111/febs.70090
Nutr Rev. 2025 Apr 03. pii: nuaf038. [Epub ahead of print]

Dietary Glycemic Index, Glycemic Load, Sugar, and Fiber Intake in Association With Breast Cancer Risk: An Updated Meta-analysis.

Hugo Pomares-Millan, Solange M Saxby, Sham Al-Mashadi Dahl, Margaret R Karagas, Michael N Passarelli.

   CONTEXT: Several prospective cohort studies have investigated the association between glycemic index (GI), glycemic load (GL), dietary sugar, and total dietary fiber intake, with female breast cancer (BC) risk and reported inconsistent results. In the last decade, several large epidemiological studies have investigated these associations, suggesting the need to revisit the current body of evidence.
OBJECTIVE: The aim of this study was to update a systematic review and meta-analysis conducted by Schlesinger et al in 2017 using recent scientific evidence published since 2015.
DATA SOURCES: Publications indexed in PubMed, Embase, and The Cochrane Library were retrieved from the inception of the database up to January 2024.
DATA EXTRACTION: Two reviewers independently extracted data and assessed each study's quality.
DATA ANALYSIS: A random-effects model was used to estimate summary risk ratios (RRs) and 95% CIs for a meta-analysis that included 33 publications, with 26 prospective cohort studies cumulatively enrolling 2 212 645 women, among whom 79 777 were diagnosed with incident BC.
RESULTS: Dietary GI and GL (highest vs lowest exposure intake) were both associated with 5% higher BC risk-RR (95% CI): 1.05 (1.01-1.09; P = .007) and 1.05 (0.97-1.13; P = .24), respectively. No clear associations were observed for sugar and total dietary fiber intake (highest vs lowest exposure intake)-RR (95% CI): 1.12 (0.95-1.11; P = .16) and 0.93 (0.86-1.00; P = .05), respectively. For the latter, the association was more pronounced among premenopausal women (RR: 0.78; 95% CI: 0.68-0.90; P = .0008).
CONCLUSION: This meta-analysis supports a significant positive association between high dietary GI intake and higher risk of BC and a significant inverse association between high dietary fiber intake and lower risk of BC. Interventions promoting a high-fiber and low-sugar diet may be useful components of BC-prevention strategies.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42023463143.

Keywords:  breast cancer; carbohydrates; dietary fiber; dietary sugar; glycemic index; glycemic load; meta-analysis

DOI:  https://doi.org/10.1093/nutrit/nuaf038
bioRxiv. 2025 Mar 21. pii: 2025.03.20.644389. [Epub ahead of print]

In vivo validation of the palmitoylation cycle as a therapeutic target in NRAS -mutant cancer.

Matthew Decker, Benjamin J Huang, Timothy Ware, Christopher Boone, Michelle Tang, Julia Ybarra, Aishwarya C Ballapuram, Katrine A Taran, Pan-Yu Chen, Marcos Amendáriz, Camille J Leung, Max Harris, Karensa Tjoa, Henry Hongo, Sydney Abelson, Jose Rivera, Nhi Ngo, Dylan M Herbst, Radu M Suciu, Carlos Guijas, Kimia Sedighi, Taylor Andalis, Elysia Roche, Boer Xie, Yunlong Liu, Catherine C Smith, Elliot Stieglitz, Micah J Niphakis, Benjamin F Cravatt, Kevin Shannon.

Normal and oncogenic Ras proteins are functionally dependent on one or more lipid modifications 1,2 . Whereas K-Ras4b farnesylation is sufficient for stable association with the plasma membrane, farnesylated H-Ras, K-Ras4a, and N-Ras traffic to the Golgi where they must undergo palmitoylation before regulated translocation to cell membranes. N-Ras palmitoylation by the DHHC family of palmitoyl acyl transferases (PATs) and depalmitoylation by ABHD17 serine hydrolases is a dynamic process that is essential for the growth of acute myeloid leukemias (AMLs) harboring oncogenic NRAS mutations 3-6 . Here, we have tested whether co-targeting ABHD17 enzymes and Ras signal output would cooperatively inhibit the proliferation and survival of NRAS -mutant AMLs while sparing normal tissues that retain K-Ras4b function. We show that ABD778, a potent and selective ABHD17 inhibitor with in vivo activity, selectively reduces the growth of NRAS -mutant AML cells in vitro and is synergistic with the allosteric MEK inhibitor PD0325901 (PD901) 7,8 . Similarly, ABD778 and PD901 significantly extended the survival of recipient mice transplanted with three independent primary mouse AMLs harboring an oncogenic Nras G12D driver mutation. Resistant leukemias that emerged during continuous drug treatment acquired by-pass mutations that confer adaptive drug resistance and increase mitogen activated protein kinase (MAPK) signal output. ABD778 augmented the anti-leukemia activity of the pan-PI3 kinase inhibitor pictilisib 9 , the K/N-Ras G12C inhibitor sotorasib 10 , and the FLT3 inhibitor gilteritinib 11 . Co-treatment with ABD778 and gilteritinib restored drug sensitivity in a patient-derived xenograft model of adaptive resistance to FLT3 inhibition. These data validate the palmitoylation cycle as a promising therapeutic target in AML and support exploring it in other NRAS -mutant cancers.

DOI: https://doi.org/10.1101/2025.03.20.644389
Cell Death Discov. 2025 Apr 04. 11(1): 139

Integrative insights into the role of CAV1 in ketogenic diet and ferroptosis in pancreatic cancer.

Xue Liang, Ruofei Tian, Ting Li, Hao Wang, Yifei Qin, Meirui Qian, Jing Fan, Dan Wang, Hong-Yong Cui, Jianli Jiang.

Pancreatic cancer exhibits high mortality rates with limited therapeutic options. Emerging evidence suggests that the ketogenic diet may act as adjuvant therapy by triggering ferroptosis in cancer cells, though the underlying molecular mechanisms remain unclear. This study aims to investigate the molecular mechanisms linking ketogenic metabolism and ferroptosis, with an emphasis on key regulatory proteins. We demonstrated that pancreatic adenocarcinoma (PAAD) tissues significantly enhanced ketogenic and ferroptosis phenotypes compared to normal tissues, both correlating with poorer patient prognosis. These phenotypes showed strong interdependence mediated by CAV1. In the pancreatic tumor microenvironment, CAV1 was predominantly expressed in tumor cells. Through in vitro cell experiments, we clarified that Na-OHB downregulated CAV1 expression in pancreatic cancer cells, inhibiting the transcription of the CAV1/AMPK/NRF2 downstream ferroptosis-protective genes SLC7A11 and SLC40A1. Additionally, we demonstrated the interaction between CAV1 and SLC7A11 molecules; when CAV1 was downregulated, it affected the stability of SLC7A11, leading to the ubiquitination and degradation of the translated SLC7A11 protein. Through these dual mechanisms, Na-OHB caused Fe2+ overload, lipid peroxidation accumulation, and oxidative stress in pancreatic cancer cells, ultimately triggering ferroptosis. In ketogenic diet-fed tumor-bearing mouse models, we also observed a significant increase in lipid peroxidation and other related biomarkers, while CAV1 and SLC7A11 levels were markedly decreased compared to the normal diet group. Our findings identify CAV1 as a pivotal molecular link between ketogenic metabolism and ferroptosis in pancreatic cancer. The multi-level regulatory axis involving CAV1-mediated transcriptional regulation and post-translational modifications provides mechanistic insights into ketogenic diet-induced ferroptosis, suggesting potential therapeutic targets for pancreatic cancer adjuvant treatment.

DOI: https://doi.org/10.1038/s41420-025-02421-z
Adv Sci (Weinh). 2025 Mar 31. e2501553

HDAC6 and USP9X Control Glutamine Metabolism by Stabilizing GS to Promote Glioblastoma Tumorigenesis.

Go Woon Kim, Minhae Cha, Hien Thi My Ong, Jung Yoo, Yu Hyun Jeon, Sang Wu Lee, Soo Yeon Oh, Min-Jung Kang, Youngsoo Kim, So Hee Kwon.

  Glioblastoma (GBM) is the most common and the deadliest brain cancer. Glutamine anabolism mediated by glutamine synthetase (GS) is beneficial for GBM cell growth, especially under glutamine deprivation. However, the molecular mechanism underlying GS homeostasis in GBM remains undisclosed. Here, it is reported that histone deacetylase 6 (HDAC6) promotes GS deacetylation, stabilizing it via ubiquitin-mediated pathway. It is found that deubiquitination of GS is modulated by ubiquitin-specific peptidase 9, X-linked (USP9X). USP9X stabilizes GS by removing its K48-linked polyubiquitination on lysine 91 and 103. Accordingly, targeting HDAC6 and USP9X in vitro and in vivo represses GBM tumorigenesis by decreasing GS stability. Metabolic analysis shows that silencing HDAC6 and USP9X disrupts de novo nucleotide synthesis, thereby attenuating GBM cell growth. Furthermore, GS modulation by targeting HDAC6 and USP9X restrains the self-renewal capacity. These results suggest that HDAC6 and USP9X are crucial epigenetic enzymes that promote GBM tumorigenesis by modulating glutamine metabolism.

Keywords:  GS; HDAC6; USP9X; glioblastoma; glutamine metabolism

DOI:  https://doi.org/10.1002/advs.202501553
BMC Cancer. 2025 Apr 01. 25(1): 592

Sweet beverages and the risk of colorectal cancer: the Norwegian Women and Cancer Study.

Marie Hauan, Charlotta Rylander, Guri Skeie.

   BACKGROUND: Colorectal cancer (CRC) is the third most common type of cancer worldwide, with Norwegian women having the highest incidence rate of colon cancer in 2022. The consumption of sweet beverages is a suggested modifiable risk factor for CRC; however, current evidence is limited and inconclusive.
OBJECTIVE: To assess the associations between the intake of sugar-sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and juice and the risk of overall and subsite-specific CRC among Norwegian women.
METHODS: In this prospective cohort study, we included 73,921 participants aged 41-61 years at baseline. Information on sweet beverage consumption was collected using self-reported food frequency questionnaires at two time points between 1998 and 2014. We used Cox proportional hazards models to estimate hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for the associations between sweet beverage consumption and the risk of overall CRC, proximal colon cancer, distal colon cancer, and rectal cancer.
RESULTS: During a mean follow-up time of 16.5 years from baseline, 1,187 women were diagnosed with CRC. Compared to no consumption, juice consumption was inversely associated with overall CRC risk (HR≥ 7 glasses/wk = 0.81, 95% CI: 0.67-0.98; p-trend = 0.025), colon cancer (HR≥ 7 glasses/wk = 0.73, 95% CI: 0.58-0.94; p-trend = 0.015) and proximal colon cancer (HR≥ 7 glasses/wk = 0.71, 95% CI: 0.52-0.99; p-trend = 0.065) after adjusting for age, education, and diabetes status at baseline. No associations were observed between juice consumption and distal colon cancer or rectal cancer risk, or between the intake of SSBs or ASBs and CRC.
CONCLUSION: We observed no substantial association between the intake of SSBs or ASBs and the risk of CRC or cancer in colorectal subsites in our cohort of Norwegian women. Conversely, our results indicate that juice consumption is associated with a reduced risk of CRC, particularly in the colon. These results warrant further investigation in larger cohorts with power to detect possible differences in cancer risk across colorectal subsites, especially as patterns of sweet beverage consumption are changing.

Keywords:  Artificially sweetened beverages; Colorectal cancer risk; Colorectal neoplasms; Diet; Female; Fruit juices; Prospective studies; Repeated measures; Sugar-sweetened beverages; The NOWAC study

DOI:  https://doi.org/10.1186/s12885-025-13835-4
J Health Popul Nutr. 2025 Apr 01. 44(1): 97

The association between ultra-processed foods intake and the odds of prostate cancer: a case-control study.

Melika Mahmoudi-Zadeh, Yahya Jalilpiran, Zahra Maghsoudi, Mehran Nouri, Shiva Faghih.

   BACKGROUND: Ultra-processed foods (UPFs) are characterized by poor nutritional composition and the generating neo-formed carcinogens during high levels of processing. The current study aimed to investigate the association between UPFs consumption and the odds of prostate cancer (PC).
METHODS: This case-control study recruited 62 PC cases and 63 hospital-based controls from two major referral hospitals of Shiraz, Iran, in 2015. Eligible men, newly diagnosed with PC through histological confirmation, were included as cases. Along with demographic and anthropometric information data, participant's dietary intake was assessed using a semi-quantitative food frequency questionnaire. The NOVA classification was employed to categorize food items based on their level of industrial processing. The association between UPFs consumption (as a percentage of daily calorie intake) and the odds of developing PC was estimated using logistic regression models. BMI, education, physical activity, age, and fiber intake were considered confounders in the adjusted model.
RESULTS: The study included 60 cases and 60 controls, with mean UPFs intake of 8.3% and 6.4%, respectively. The crude analysis showed no significant association between UPFs intake and PC odds ratio (OR) (OR = 1.96, confidence interval (CI) 95%: 0.94-4.05, P = 0.069). However, after adjusting for potential confounders, the association became significant, with high versus low UPFs intake associated with 2.81 times higher odds of PC (OR = 2.81, CI 95%: 1.18-6.65, P = 0.019).
CONCLUSION: Our findings highlight UPFs consumption as a factor associated with higher odds of PC in the Iranian male population. The study emphasizes the importance of monitoring industrial food processing practices and implementing measures to reduce UPFs consumption.

Keywords:  Case–control studies; Diet; Prostate cancer; Ultra-processed foods

DOI:  https://doi.org/10.1186/s41043-025-00822-5
Leukemia. 2025 Apr 02.

Immune checkpoints regulate acute myeloid leukemia stem cells.

Chantal Reinhardt, Adrian F Ochsenbein.

Acute myeloid leukemia stem cells (LSCs) express major histocompatibility complex (MHC) class I and II and many different immune checkpoint ligands and receptors, in which respect they resemble professional antigen-presenting cells. In addition, LSCs reside in the bone marrow (BM), a primary and secondary lymphoid organ, surrounded by immune cells. The function of these immune checkpoints (ICs) in the regulation of an anti-tumor immune response is well studied and IC inhibitors (ICIs) became a standard of care in many solid tumors. However, ICIs have very limited efficacy in AML. Nevertheless, the expression especially of immune activating ligands and receptors on LSCs is somewhat unexpected, since these cells have to evade protective immunity. Many ICs have been shown to mediate direct signaling in AML blasts and LSCs and thereby regulate self-renewal, differentiation and expansion of leukemic cells. Thus, the expression of ICs on the cell surface or their soluble forms often correlate with worse survival. In this review we summarize recent data on selected ICs of the immunoglobulin superfamily (IgSF) and the tumor necrosis factor receptor superfamily (TNFRSF) that have a documented role in the regulation of LSCs, independent of their immune regulatory role, and might become novel therapeutic targets.

DOI: https://doi.org/10.1038/s41375-025-02566-x
J Clin Endocrinol Metab. 2025 Apr 02. pii: dgaf207. [Epub ahead of print]

A three-week Ketogenic Diet increases Global Cerebral Blood Flow and Brain-Derived Neurotrophic Factor.

Thien Vinh Luong, Kim Vang Hansen, Allan Kjeldsen Hansen, Stephen C Cunnane, Niels Møller, Esben Søndergaard, Lars Christian Gormsen, Mads Svart.

   PURPOSE: The beneficial effects of a ketogenic diet (KD) on neurodegenerative conditions such as mild cognitive impairment (MCI) and Alzheimer's disease (AD) are increasingly acknowledged, with potential implications for the general population as well. Thus, our study aimed to explore the effect of a KD on cerebral blood flow (CBF) and Brain-Derived Neurotrophic Factor (BDNF) in healthy individuals. We hypothesized that a KD would increase CBF and BDNF, thereby presenting itself as an approach to prevent cognitive decline.
METHODS: In total, 11 cognitively healthy individuals with overweight participated in a randomized, crossover trial consisting of two three-week interventions: 1) a KD and 2) a standard diet. Each diet period concluded with a positron emission tomography (PET) study day, accompanied by a separate magnetic resonance imaging (MRI) scan. Blood samples were collected prior to the PET scan to measure β-hydroxybutyrate (β-OHB) and BDNF levels. CBF was assessed using a [15O]H2O PET scan co-registered with an MRI scan.
RESULTS: A KD led to increased basal plasma β-OHB levels compared to the SDD (647 (418-724) vs. 50 (50-60) μmol/l, p<0.05), increased CBF by 22% (p=0.02), and elevated BDNF levels by 47% (p=0.04). Moreover, a correlation was observed between β-OHB levels and CBF measurements across the two diets (R2=0.54, p<0.001).
CONCLUSION: Implementing a KD improved CBF and raised BDNF levels in cognitively healthy individuals, indicating that a KD should be assessed for as a potential treatment for conditions associated with reduced CBF.

Keywords:  brain-derived neurotrophic factor; cerebral blood flow; ketogenic diet; ketosis; positron emission tomography

DOI:  https://doi.org/10.1210/clinem/dgaf207
PLoS One. 2025 ;20(4): e0318256

Association of overweight/obesity and digestive system cancers: A meta-analysis and trial sequential analysis of prospective cohort studies.

Ji Ren, Chunyan Tang, Jinghe Wang, Yanan Wang, Dongying Yang, Jianming Sheng, Shili Zhu, Yunli Liu, Xiaoqi Li, Wei Liu.

BACKGROUND: Previous researches have reported correlations between overweight/obesity and common digestive system cancers (DSCs), including gastric, liver, esophageal, colorectal, and pancreatic cancers. However, the inconsistency in defining overweight/obesity and the risk of recall bias from case-control and retrospective cohort studies may influence existing results. Therefore, we aimed to validate the relationship between overweight/obesity and common DSCs by combining prospective cohort studies based on the World Health Organization (WHO) criteria for defining overweight/obesity.
METHODS: A comprehensive literature search was conducted across PubMed, Embase, Web of Science, and Cochrane databases, covering all publications up to February 7, 2024. The inclusion criteria focused on prospective cohort studies that examined the link between overweight/obesity and risks of DSCs. R software 4.1.3 and STATA 12 were utilised to calculate the relative risk (RR), with 95% confidence interval (CI) and prediction interval (PI). TSA v0.9.5.10 Beta software was used for trial sequential analysis (TSA).
RESULTS: The meta-analysis encompassed 39 articles. The overall analysis showed that compared with normal weight, overweight/obesity increased the risks of liver cancer (overweight: RR [95% CI] = 1.237 [1.112-1.377]; 95% PI: 0.888-1.725; obesity: RR [95% CI] = 1.642 [1.466-1.839]; 95% PI: 1.143-2.358) and colorectal cancer (overweight: RR [95% CI] = 1.124 [1.056-1.197]; 95% PI: 0.931-1.357; obesity: RR [95% CI] = 1.366 [1.242-1.503]; 95% PI: 0.959-1.945) in the total population. Subgroup analysis revealed that overweight (RR [95% CI] = 1.237 [1.165-1.314]; 95% PI: 1.154-1.327) and obesity (RR [95% CI] = 1.306 [1.152-1.480]; 95% PI: 1.108-1.539) were associated with an increased risk of pancreatic cancer only in women, and overweight also increased the gastric cancer risk of women (RR [95% CI] = 1.041 [1.013-1.070], 95% PI: 0.806-1.230). No significant association of overweight/obesity and esophageal cancer was observed in both male and female.
CONCLUSION: Our study suggested that overweight/obesity elevated the risks of liver and colorectal cancer in both men and women. No significant association was found between overweight/obesity and the risk of developing esophageal cancer. Clinicians are advised to consider weight control as an effective measure for preventing pancreatic, liver, and colorectal cancers.

DOI: https://doi.org/10.1371/journal.pone.0318256
J Clin Endocrinol Metab. 2025 Apr 02. pii: dgaf196. [Epub ahead of print]

Effects of One-Month Very-Low-Calorie Ketogenic Diet on 24 h Energy Metabolism and Body Composition in Women with Obesity.

Alessio Basolo, Paolo Piaggi, Valentina Angeli, Paola Fierabracci, Chiara Bologna, Edda Vignali, Daniela Troiani, Roberta Jaccheri, Caterina Pelosini, Melania Paoli, Guido Salvetti, Luca Chiovato, Jonathan Krakoff, Alberto Landi, Ferruccio Santini.

   CONTEXT: Very-low-calorie ketogenic diet (VLCKD) is used for weight loss and management of obesity-related comorbidities.
OBJECTIVE: We aimed at evaluating the effects of VLCKD on body composition and energy metabolism.
METHODS: This prospective outpatient study included 17 women with obesity (mean age 41.6 yrs; BMI 37.5 kg/m2) who followed a 1-month VLCKD (700-800 kcal/day, CHO 11%, fat 46%, protein 43%) at the University Hospital of Pisa. Measurements of 24-hour energy expenditure (24hEE) and substrate oxidation were conducted in a metabolic chamber at day 1 (V1), day 8 (V2), and day 29 (V3). Body composition was assessed by DXA. Twenty-two women with obesity fed a balanced isocaloric diet served as controls.
RESULTS: Compared to controls, carbohydrate oxidation (CarbOx) was lower, whereas fat oxidation (FatOx) and protein oxidation (ProtOx) were higher in the VLCKD group at V1. CarbOx decreased by 65%, while FatOx increased by 11% at V3. The rate of protein oxidation was already higher than in controls at V1 and remained stable throughout the study. After 1 month, body weight decreased by 7%, reflecting an 8.8% reduction in fat mass (FM) and a 5.6% reduction in lean soft tissue (LST). A 10% decrease in 24hEE and 24 h sleeping metabolic rate was observed at V3 compared to V1.
CONCLUSION: VLCKD promotes weight loss in women with obesity. Our findings highlight the shift in energy metabolism towards increased fat oxidation accompanied by a modest increase in protein oxidation, a decrease in LST and a reduction in EE.

Keywords:  Ketogenic diet; energy expenditure; obesity; respiratory exchange ratio

DOI:  https://doi.org/10.1210/clinem/dgaf196
Sci Rep. 2025 Mar 29. 15(1): 10925

Characterization of a new mutation of mitochondrial ND6 gene in hepatocellular carcinoma and its effects on respiratory complex I.

Veronica Bazzani, Deepali L Kundnani, Mara Equisoain Redin, Francesca Agostini, Kirti Chhatlani, Angelo Corso Faini, Jakub Poziemski, Umberto Baccarani, Pawel Siedlecki, Silvia Deaglio, Francesca Storici, Carlo Vascotto.

  Hepatocellular carcinoma (HCC) is the most common form of liver cancer, which often arises from previous liver pathologies such as HBV, HCV, and alcohol abuse. It is typically associated with an enlarged cirrhotic organ. In this study, we analyzed tumor and distal tissues from a patient who underwent liver resection for HCC with no previous pathologies and whose liver showed normal function without signs of cirrhosis. Genetic analysis of mitochondrial DNA (mtDNA) revealed a novel variant of the gene encoding the NADH dehydrogenase subunit 6 (ND6) protein in the tumor tissue. The deletion of a thymidine generated an early stop codon, resulting in a truncated form of the protein (ΔND6) with 50% of the C-terminal primary sequence missing. ND6 is a subunit of the NADH dehydrogenase complex, also known as Complex I, the largest complex in the electron transport chain. Previous studies have linked mtDNA Complex I mutations to mitochondrial disorders and cancer. Through biochemical analyses, we characterized this new mutation and showed that the expression of ΔND6 negatively affects the stability and functionality of Complex I. Data were confirmed by molecular dynamics simulations suggesting conformational rearrangements, overall revealing a leading role of ND6 in the assembly of Complex I.

Keywords:  Hepatocellular carcinoma; Mitochondria; Mitochondrial DNA; Molecular dynamics simulations.; ND6 gene mutation; Respiratory complex I assembly

DOI:  https://doi.org/10.1038/s41598-025-91746-x