bims-medica 2024-10-27 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024‒10‒27
28 papers selected by
Brett Chrest, Wake Forest University

Measurement of Mitochondrial Respiration in Human and Mouse Skeletal Muscle Fibers by High-Resolution Respirometry.
European Society for the Study of Obesity (EASO) Position Statement on medical nutrition therapy for the management of individuals with overweight or obesity and cancer.
Mitoception, or transfer of normal cell mitochondria to cancer cells, reverses remodeling of store-operated Ca2+ entry in tumor cells.
Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking.
Mitochondrial Abundance and Function Differ Across Muscle Within Species.
Narrative Review of Lifestyle Interventions in Breast Cancer Survivors: Current Evidence and Future Directions.
Cancers attributable to diet in Italy.
Glycolysis: A multifaceted metabolic pathway and signalling hub.
The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.
The Acute and Chronic influence of Exercise on Mitochondrial Dynamics in Skeletal Muscle.
Metabolic obesity phenotypes and thyroid cancer risk: A systematic exploration of the evidence.
Altered fatty acid metabolism rewires cholangiocarcinoma stemness features.
METASPACE-ML: Context-specific metabolite annotation for imaging mass spectrometry using machine learning.
Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis.
The impact of 3 different dietary interventions on overweight or obese adults: A network meta-analysis.
GDH1-catalytic glutaminolysis feedback activate EGFR/PI3K/AKT pathway and reprogram glioblastoma metabolism.
A phase 1 study of the amino acid modulator pegcrisantaspase and venetoclax for relapsed/refractory acute myeloid leukemia.
Multi-Modal Investigation of Metabolism in Murine Breast Cancer Cell Lines Using Fluorescence Lifetime Microscopy and Hyperpolarized 13C-Pyruvate Magnetic Resonance Spectroscopy.
Calorie restriction modulates mitochondrial dynamics and autophagy in leukocytes of patients with obesity.
Metabolic Effects of Medium-Chain Triacylglycerol Consumption are Preserved in Obesity.
Targeted Metabolic Profiling in Determining the Metabolic Heterogeneity in Human Biopsies of Different Grades of Glioma.
Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice.
Azacitidine in combination with shortened venetoclax treatment cycles in patients with acute myeloid leukemia.
Associations between Circulating Biomarkers of One-Carbon Metabolism and Mitochondrial D-Loop Region Methylation Levels.
Dietary Flavonoids and Lung Cancer: A GRADE-Assessed Systematic Review and Meta-Analysis of Observational Studies.
Dissected antiporter modules establish minimal proton-conduction elements of the respiratory complex I.
Monocentric experience of venetoclax-based regimen in paediatric refractory and relapsed AML/MDS.
MALDI MSI Protocol for Spatial Bottom-Up Proteomics at Single-Cell Resolution.

J Vis Exp. 2024 Oct 04.

Measurement of Mitochondrial Respiration in Human and Mouse Skeletal Muscle Fibers by High-Resolution Respirometry.

Terri A Pietka, Rita T Brookheart.

Mitochondrial function, a cornerstone of cellular energy production, is critical for maintaining metabolic homeostasis. Its dysfunction in skeletal muscle is linked to prevalent metabolic disorders (e.g., diabetes and obesity), muscular dystrophies, and sarcopenia. While there are many techniques to evaluate mitochondrial content and morphology, the hallmark method to assess mitochondrial function is the measurement of mitochondrial oxidative phosphorylation (OXPHOS) by respirometry. Quantification of mitochondrial OXPHOS provides insight into the efficiency of mitochondrial oxidative energy production and cellular bioenergetics. A high-resolution respirometer provides highly sensitive, robust measurements of mitochondrial OXPHOS in permeabilized muscle fibers by measuring real-time changes in mitochondrial oxygen consumption rate. The use of permeabilized muscle fibers, as opposed to isolated mitochondria, preserves mitochondrial networks, maintains mitochondrial membrane integrity, and ultimately allows for more physiologically relevant measurements. This system also allows for the measurement of fuel preference and metabolic flexibility - dynamic aspects of muscle energy metabolism. Here, we provide a comprehensive guide for mitochondrial OXPHOS measurements in human and mouse skeletal muscle fibers using a high-resolution respirometer. Skeletal muscle groups are composed of different fiber types that vary in their mitochondrial fuel preference and bioenergetics. Using a high-resolution respirometer, we describe methods for evaluating both aerobic glycolytic and fatty acid substrates to assess fuel preference and metabolic flexibility in a fiber-type-dependent manner. The protocol is versatile and applicable to both human and rodent muscle fibers. The goal is to enhance the reproducibility and accuracy of mitochondrial function assessments, which will improve our understanding of an organelle important to muscle health.

DOI: https://doi.org/10.3791/66834
Obes Facts. 2024 Oct 21. 1-37

European Society for the Study of Obesity (EASO) Position Statement on medical nutrition therapy for the management of individuals with overweight or obesity and cancer.

EASO Nutrition Working Group

BACKGROUND: Obesity, a prevalent and multifactorial disease, is linked to a range of metabolic abnormalities, including insulin resistance, dyslipidemia, and chronic inflammation. These imbalances not only contribute to cardiometabolic diseases but also play a significant role in cancer pathogenesis. The rising prevalence of obesity underscores the need to investigate dietary strategies for effective weight management for individuals with overweight or obesity and cancer. This European Society for the Study of Obesity (EASO) position statement aimed to summarize current evidence on the role of obesity in cancer and to provide insights on the major nutritional interventions, including Mediterranean Diet (MedDiet), ketogenic diet (KD), and intermittent fasting (IF), that should be adopted to manage individuals with overweight or obesity and cancer.RESULTS: The MedDiet, characterized by high consumption of plant-based foods and moderate intake of olive oil, fish, and nuts, has been associated with a reduced cancer risk. The KD and the IF are emerging dietary interventions with potential benefits for weight loss and metabolic health. KD, by inducing ketosis, and IF, through periodic fasting cycles, may offer anticancer effects by modifying tumor metabolism and improving insulin sensitivity.
KEY MESSAGES: Despite the promising results, current evidence on these dietary approaches in cancer management in individuals with overweight or obesity is limited and inconsistent, with challenges including variability in adherence and the need for personalized dietary plans.

DOI: https://doi.org/10.1159/000542155
Biochim Biophys Acta Mol Cell Res. 2024 Oct 20. pii: S0167-4889(24)00205-2. [Epub ahead of print]1872(1): 119862

Mitoception, or transfer of normal cell mitochondria to cancer cells, reverses remodeling of store-operated Ca2+ entry in tumor cells.

Verónica Feijóo, Sendoa Tajada, Alejandra Méndez-Mena, Lucía Núñez, Carlos Villalobos.

  Most cancer cells show the Warburg effect, the rewiring of aerobic metabolism to glycolysis due to defective mitochondrial ATP synthesis. As a consequence, tumor cells display enhanced mitochondrial potential (∆Ψ), the driving force for mitochondrial Ca2+ uptake. Mitochondria control the Ca2+-dependent inactivation of store-operated channels (SOCs), leading to enhanced and sustained store-operated Ca2+ entry (SOCE) involved in cancer hallmarks. We asked here whether the transfer of mitochondria (mitoception) from normal cells to tumor cells may reverse SOCE remodeling in cancer cells. For this end, we labeled mitochondria in normal NCM460 human colonic cells, isolated them and transferred them to tumor HT29 cells. We tested the viability and efficiency of mitoception using flow cytometry and confocal microscopy, as well as calcium imaging to investigate the effects of mitoception on SOCE. Our results show that mitoception of tumor HT29 cells with normal mitochondria restores a low ∆Ψ and SOCE. Conversely, self-mitoception of tumor HT29 cells with tumor cell mitochondria increases further ∆Ψ and SOCE, thus excluding the possibility that effects of mitoception are due to increased mitochondrial mass. Strikingly, mitoception of normal NCM460 cells with tumor cell mitochondria has no effects on either ∆Ψ or SOCE. These results are consistent with the previous proposal that transformed mitochondria may modulate SOC channels involved in SOCE. Further research is warranted to test whether mitoception of cancer cells with normal mitochondria may reverse Ca2+ remodeling associated to cancer.

Keywords:  Colon cancer; Mitoception; Mitochondria; Store-operated Ca(2+) entry

DOI:  https://doi.org/10.1016/j.bbamcr.2024.119862
Cell Chem Biol. 2024 Oct 14. pii: S2451-9456(24)00404-5. [Epub ahead of print]

Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking.

Kelly H Sokol, Cameron J Lee, Thomas J Rogers, Althea Waldhart, Abigail E Ellis, Sahithi Madireddy, Samuel R Daniels, Rachel Rae J House, Xinyu Ye, Mary Olesnavich, Amy Johnson, Benjamin R Furness, Ryan D Sheldon, Evan C Lien.

  Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic and adrenic acid. These PUFAs then accumulate in phospholipids, including ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools contributes to their sensitivity to ferroptosis.

Keywords:  cancer; ferroptosis; lipid metabolism; phospholipids; polyunsaturated fatty acids; triglycerides

DOI:  https://doi.org/10.1016/j.chembiol.2024.09.008
Metabolites. 2024 Oct 16. pii: 553. [Epub ahead of print]14(10):

Mitochondrial Abundance and Function Differ Across Muscle Within Species.

Con-Ning Yen, Jocelyn S Bodmer, Jordan C Wicks, Morgan D Zumbaugh, Michael E Persia, Tim H Shi, David E Gerrard.

  Background: Mitochondria are considered the powerhouse of cells, and skeletal muscle cells are no exception. However, information regarding muscle mitochondria from different species is limited. Methods: Different muscles from cattle, pigs and chickens were analyzed for mitochondrial DNA (mtDNA), protein and oxygen consumption. Results: Bovine oxidative muscle mitochondria contain greater mtDNA (p < 0.05), protein (succinate dehydrogenase, SDHA, p < 0.01; citrate synthase, CS, p < 0.01; complex I, CI, p < 0.05), and oxygen consumption (p < 0.01) than their glycolytic counterpart. Likewise, porcine oxidative muscle contains greater mtDNA (p < 0.01), mitochondrial proteins (SDHA, p < 0.05; CS, p < 0.001; CI, p < 0.01) and oxidative phosphorylation capacity (OXPHOS, p < 0.05) in comparison to glycolytic muscle. However, avian oxidative skeletal muscle showed no differences in absolute mtDNA, SDHA, CI, complex II, lactate dehydrogenase, or glyceraldehyde 3 phosphate dehydrogenase compared to their glycolytic counterpart. Even so, avian mitochondria isolated from oxidative muscles had greater OXPHOS capacity (p < 0.05) than glycolytic muscle. Conclusions: These data show avian mitochondria function is independent of absolute mtDNA content and protein abundance, and argue that multiple levels of inquiry are warranted to determine the wholistic role of mitochondria in skeletal muscle.

Keywords:  metabolism; mitochondria; skeletal muscle

DOI:  https://doi.org/10.3390/metabo14100553
JNCI Cancer Spectr. 2024 Oct 24. pii: pkae108. [Epub ahead of print]

Narrative Review of Lifestyle Interventions in Breast Cancer Survivors: Current Evidence and Future Directions.

Kelsey Gabel, Kaitlin Chakos, Manoela Lima Oliveira, Julienne Sanchez Perez, Kate Cares, Natalia Salvatierra Lima, Pamela Ganschow, Betina Yanez, Vijayakrishna Gadi, Lisa Tussing-Humphreys.

  BACKGROUND: One in eight females will be diagnosed with breast cancer in their lifetime. While medical advances have increased the likelihood of survival, up to 90% of females will gain weight during and after treatment increasing the risk of breast cancer recurrence and obesity related co-morbidities in survivorship. Behavioral lifestyle interventions focused on diet with or without physical activity can provide breast cancer survivors non-pharmacological options to decrease weight gain and cardiometabolic risk.METHOD: A PubMed search was conducted to identify all behavioral lifestyle interventions focused on diet or diet combined with physical activity longer than 4 weeks of duration in breast cancer survivors that included body weight as an outcome. This review aims to summarize the effects on body weight, body composition and cardiometabolic risk markers are summarized.
RESULTS: Based on the review, there is high heterogeneity in type and duration of the intervention to affect weight and cardiometabolic risk in survivorship. Calorie restriction with and without physical activity appears to promote weight loss among breast cancer survivors. However, the effects on cardiometabolic factors are less clear.
CONCLUSION: Future studies should be powered for both body weight and cardiometabolic effects. Researchers should also consider interventions that are: 1) less complex, 2) recruit a more racially and ethnically diverse sample, 3) integrate resistance training, 4) implement the intervention in closer proximity to diagnosis, 5) target weight management in this population before it occurs and 6) analyze body composition in addition to body weight measurements.

Keywords:  Diet; body weight; breast neoplasms; energy intake; exercise

DOI:  https://doi.org/10.1093/jncics/pkae108
Int J Cancer. 2024 Oct 24.

Cancers attributable to diet in Italy.

Federica Turati, Gianfranco Alicandro, Giulia Collatuzzo, Claudio Pelucchi, Matteo Malvezzi, Fabio Parazzini, Eva Negri, Paolo Boffetta, Carlo La Vecchia, Matteo Di Maso.

  Cancer burden can be reduced by controlling modifiable risk factors, including diet. We provided an evidence-based assessment of cancer cases and deaths attributable to diet in Italy in 2020. We considered dietary factor-cancer type pairs for which the World Cancer Research Fund/American Institute for Cancer Research - Continuous Update Project reported either 'convincing' or 'probable' evidence of causal association. Relative risks were retrieved from recent meta-analyses and dietary intakes (around 2005) from a national food consumption survey. Sex-specific population attributable fractions (PAFs) were computed by comparing the distribution of dietary intakes in the Italian population against counterfactual scenarios based on dietary recommendations. Using data from national cancer and mortality registries in 2020, we estimated the number of attributable cancer cases and deaths, assuming ~15-year lag period. Unhealthy diet accounted for 6.3% (95% CI: 2.5%-9.9%) of all cancer cases in men and 4.5% (95% CI: 1.7%-7.4%) in women. PAFs of colorectal cancer were 10.5% and 7.0% for any intake of processed meat, 3.3% and 2.0% for high red meat, 4.8% and 4.3% for low dairy products, and 7.9% and 9.0% for low fiber intakes in men and women, respectively. PAFs for low intake of non-starchy vegetables and fruit ranged from 0.8% to 16.5% in men and 0.6%-17.8% in women for cancers of the aerodigestive tract. The estimated cancer burden associated with unfavorable dietary habits in Italy is considerable, but appears lower than for other high-income countries, reflecting the typically Mediterranean diet.

Keywords:  attributable cancer cases; attributable cancer deaths; dietary factors; population attributable fraction

DOI:  https://doi.org/10.1002/ijc.35227
J Biol Chem. 2024 Oct 21. pii: S0021-9258(24)02408-6. [Epub ahead of print] 107906

Glycolysis: A multifaceted metabolic pathway and signalling hub.

Sarah J Kierans, Cormac T Taylor.

Glycolysis is a highly conserved metabolic pathway responsible for the anaerobic production of adenosine triphosphate (ATP) from the breakdown of glucose molecules. While serving as a primary metabolic pathway in prokaryotes, glycolysis is also utilised by respiring eukaryotic cells, providing pyruvate to fuel oxidative metabolism. Furthermore, glycolysis is the primary source of ATP production in multiple cellular states (e.g. hypoxia) and is particularly important in maintaining bioenergetic homeostasis in the most abundant cell type in the human body, the erythrocyte. Beyond its role in ATP production, glycolysis also functions as a signalling hub, producing several metabolic intermediates which serve roles in both signalling and metabolic processes. These signals emanating from the glycolytic pathway can profoundly impact cell function, phenotype and fate, and have previously been overlooked. In this review, we will discuss the role of the glycolytic pathway as a source of signalling molecules in eukaryotic cells, emphasising the newfound recognition of glycolysis' multifaceted nature and its importance in maintaining cellular homeostasis, beyond its traditional role in ATP synthesis.

DOI: https://doi.org/10.1016/j.jbc.2024.107906
Proc Natl Acad Sci U S A. 2024 Oct 29. 121(44): e2401218121

The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.

Yumei Yang, Baomin Wang, Haoru Dong, Huige Lin, Melody Yuen-Man Ho, Ke Hu, Na Zhang, Jing Ma, Rong Xie, Kenneth King-Yip Cheng, Xiaomu Li.

  Defective glucose-stimulated insulin secretion (GSIS) and β-cell senescence are hallmarks in diabetes. The mitochondrial enzyme pyruvate carboxylase (PC) has been shown to promote GSIS and β-cell proliferation in the clonal β-cell lines, yet its physiological relevance remains unknown. Here, we provide animal and human data showing a role of PC in protecting β-cells against senescence and maintaining GSIS under different physiological and pathological conditions. β-cell-specific deletion of PC impaired GSIS and induced β-cell senescence in the mouse models under either a standard chow diet or prolonged high-fat diet feeding. Transcriptomic analysis indicated that p53-related senescence and cell cycle arrest are activated in PC-deficient islets. Overexpression of PC inhibited hyperglycemia- and aging-induced p53-related senescence in human and mouse islets as well as INS-1E β-cells, whereas knockdown of PC provoked senescence. Mechanistically, PC interacted with MDM2 to prevent its degradation via the MDM2 binding motif, which in turn restricts the p53-dependent senescent program in β-cells. On the contrary, the regulatory effects of PC on GSIS and the tricarboxylic acid (TCA) anaplerotic flux are p53-independent. We illuminate a function of PC in controlling β-cell senescence through the MDM2-p53 axis.

Keywords:  MDM2; cellular senescence; diabetes; p53; pyruvate carboxylase

DOI:  https://doi.org/10.1073/pnas.2401218121
Am J Physiol Endocrinol Metab. 2024 Oct 23.

The Acute and Chronic influence of Exercise on Mitochondrial Dynamics in Skeletal Muscle.

Elya Janis Ritenis, Camila S Padilha, Matthew B Cooke, Christos George Stathis, Andrew Philp, Donny M Camera.

  Exercise and nutritional modulation are potent stimuli for eliciting increases in mitochondrial mass and function. Collectively, these beneficial adaptations are increasingly recognized to coincide with improvements to skeletal muscle health. Mitochondrial dynamics of fission and fusion are increasingly implicated as having a central role in mediating aspects of key organelle adaptions that are seen with exercise. Exercise-induced mitochondrial adaptations that dynamics have been implicated in are: 1) Increases to mitochondrial turnover, resulting from elevated rates of mitochondrial synthesis (biogenesis) and degradative (mitophagy) processes. 2) Morphological changes to the 3D tubular network, known as the mitochondrial reticulum, that mitochondria form in skeletal muscle. Notably, mitochondrial fission has also been implicated in coordinating increases in mitophagy, following acute exercise. Further, increased fusion following exercise training promotes increased connectivity of the mitochondrial reticulum and is associated with improved metabolism and mitochondrial function. However, the molecular basis and fashion in which exercise infers beneficial mitochondrial adaptations through mitochondrial dynamics remains poorly understood. This review attempts to highlight recent developments investigating the effects of exercise on mitochondrial dynamics, while attempting to offer a perspective of the methodological refinements and potential variables, such as substrate/glycogen availability, which should be considered going forward.

Keywords:  Exercise; Mitochondrial Dynamics; Skeletal Muscle

DOI:  https://doi.org/10.1152/ajpendo.00311.2024
Obes Sci Pract. 2024 Oct;10(5): e70019

Metabolic obesity phenotypes and thyroid cancer risk: A systematic exploration of the evidence.

Mehdi Hedayati, Majid Valizadeh, Behnaz Abiri.

  Background: Obesity is recognized as a risk factor for various cancers, including thyroid cancer. However, the association between different metabolic obesity phenotypes and thyroid cancer risk remains unclear. This systematic review aimed to comprehensively evaluate the existing literature to elucidate the association between metabolic obesity phenotypes and thyroid cancer risk.Methods: This systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Scopus, EMBASE, Web of Science, and Google Scholar were searched for relevant studies until April 2024. Studies examining the link between metabolic obesity phenotypes and thyroid cancer risk were included.
Results: Five cohort studies involving 831,510 participants met the inclusion criteria. Metabolically unhealthy obesity was consistently associated with an increased risk of thyroid cancer in both men and women. Central adiposity emerged as a significant predictor of thyroid cancer risk. Mechanistically, chronic inflammation, dysregulated adipokine secretion, hormonal imbalances, and altered signaling pathways may contribute to thyroid carcinogenesis. There is an ongoing debate regarding the risk associated with metabolically healthy obesity, with some suggesting potential protective effects due to favorable metabolic profiles.
Conclusion: This systematic review highlights the complex relationship between metabolic obesity phenotypes and thyroid cancer risk. The findings highlighted the importance of considering metabolic status alongside obesity in thyroid cancer risk assessment and intervention strategies.

Keywords:  cancer risk; metabolic obesity phenotypes; obesity; thyroid cancer

DOI:  https://doi.org/10.1002/osp4.70019
JHEP Rep. 2024 Oct;6(10): 101182

Altered fatty acid metabolism rewires cholangiocarcinoma stemness features.

Giulia Lori, Mirella Pastore, Nadia Navari, Benedetta Piombanti, Richell Booijink, Elisabetta Rovida, Ignazia Tusa, Monika Lewinska, Jesper B Andersen, Tiziano Lottini, Annarosa Arcangeli, Maria Letizia Taddei, Erica Pranzini, Caterina Mancini, Cecilia Anceschi, Stefania Madiai, Elena Sacco, Stefano Rota, Adriana Trapani, Gennaro Agrimi, Matteo Ramazzotti, Paola Ostano, Caterina Peraldo Neia, Matteo Parri, Fabrizia Carli, Silvia Sabatini, Amalia Gastaldelli, Fabio Marra, Chiara Raggi.

  Background & Aims: Among the reprogrammed metabolic pathways described in cancer stem cells, aberrant lipid metabolism has recently drawn increasing attention. Our study explored the contribution of fatty acids (FA) in the regulation of stem-like features in intrahepatic cholangiocarcinoma (iCCA).Methods: We previously identified a functional stem-like subset in human iCCA by using a three-dimensional sphere (SPH) model in comparison to parental cells grown as monolayers (MON). In this study, quantification of intracellular free FA and lipidomic analysis (triacylglycerol [TAG] composition, de novo synthesis products) was performed by Liquid chromatography-mass spectrometry (LC-MS); quadrupole time-of-flight liquid chromatography/mass spectrometry (Q-TOF LC/MS), respectively, in both SPH and MON cultures.
Results: Stem-like SPH showed a superior content of free FA (citric, palmitic, stearic, and oleic acids) and unsaturated TAG. Molecularly, SPH showed upregulation of key metabolic enzymes involved in de novo FA biosynthesis (AceCS1, ACLY, ACAC, FASN, ACSL1) and the mTOR signalling pathway. In patients with iCCA (n = 68), tissue expression of FASN, a key gene involved in FA synthesis, correlated with 5-year overall survival. Interference with FASN activity in SPH cells through both specific gene silencing (siRNA) or pharmacological inhibition (orlistat) decreased sphere-forming ability and expression of stem-like markers. In a murine xenograft model obtained by injection of iCCA-SPH cells, FASN inhibition by orlistat or injection of FASN-silenced cells significantly reduced tumour growth and expression of stem-like genes.
Conclusion: Altered FA metabolism contributes to the maintenance of a stem-like phenotype in iCCA. FASN inhibition may represent a new approach to interfere with the progression of this deadly disease.
Impact and implications: Recent evidence indicates that metabolic disorders correlate with an increased susceptibility to intrahepatic cholangiocarcinoma (iCCA). Our investigation emphasises the pivotal involvement of lipid metabolism in the tumour stem cell biology of iCCA, facilitated by the upregulation of crucial enzymes and the mTOR signalling pathway. From a clinical perspective, this underscores the dual role of FASN as both a prognostic indicator and a therapeutic target, suggesting that FASN inhibitors could enhance patient outcomes by diminishing stemness and tumour aggressiveness. These findings pave the way for novel therapeutic strategies for iCCA and shed light on its relationship with metabolic disorders such as diabetes, obesity, metabolic syndrome, and metabolic dysfunction-associated steatotic liver disease.

Keywords:  Cancer stem cells; Hepatobiliary tumours; Lipid droplets; Lipid metabolism; Oleic acid; Palmitoleic acid; triglycerides

DOI:  https://doi.org/10.1016/j.jhepr.2024.101182
Nat Commun. 2024 Oct 22. 15(1): 9110

METASPACE-ML: Context-specific metabolite annotation for imaging mass spectrometry using machine learning.

Bishoy Wadie, Lachlan Stuart, Christopher M Rath, Bernhard Drotleff, Sergii Mamedov, Theodore Alexandrov.

Imaging mass spectrometry is a powerful technology enabling spatial metabolomics, yet metabolites can be assigned only to a fraction of the data generated. METASPACE-ML is a machine learning-based approach addressing this challenge which incorporates new scores and computationally-efficient False Discovery Rate estimation. For training and evaluation, we use a comprehensive set of 1710 datasets from 159 researchers from 47 labs encompassing both animal and plant-based datasets representing multiple spatial metabolomics contexts derived from the METASPACE knowledge base. Here we show that, METASPACE-ML outperforms its rule-based predecessor, exhibiting higher precision, increased throughput, and enhanced capability in identifying low-intensity and biologically-relevant metabolites.

DOI: https://doi.org/10.1038/s41467-024-52213-9
EMBO Mol Med. 2024 Oct 21.

Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis.

Tobias Ackermann, Engy Shokry, Ruhi Deshmukh, Jayanthi Anand, Laura C A Galbraith, Louise Mitchell, Giovanny Rodriguez-Blanco, Victor H Villar, Britt Amber Sterken, Colin Nixon, Sara Zanivan, Karen Blyth, David Sumpton, Saverio Tardito.

  The limited availability of therapeutic options for patients with triple-negative breast cancer (TNBC) contributes to the high rate of metastatic recurrence and poor prognosis. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation and counteracted by the antioxidant activity of the selenoprotein GPX4. Here, we show that TNBC cells secrete an anti-ferroptotic factor in the extracellular environment when cultured at high cell densities but are primed to ferroptosis when forming colonies at low density. We found that secretion of the anti-ferroptotic factors, identified as monounsaturated fatty acid (MUFA) containing lipids, and the vulnerability to ferroptosis of single cells depends on the low expression of stearyl-CoA desaturase (SCD) that is proportional to cell density. Finally, we show that the inhibition of Sec-tRNAsec biosynthesis, an essential step for selenoprotein production, causes ferroptosis and impairs the lung seeding of circulating TNBC cells that are no longer protected by the MUFA-rich environment of the primary tumour.

Keywords:  Breast Cancer; Ferroptosis; Lipid Metabolism; Metastasis; Selenium Metabolism

DOI:  https://doi.org/10.1038/s44321-024-00142-x
Medicine (Baltimore). 2024 Oct 18. 103(42): e39749

The impact of 3 different dietary interventions on overweight or obese adults: A network meta-analysis.

Tianrong Liao, Jiayu Su, Tingwei Quan, Yu Luo, Yiqian Zeng, Dandan Chen, Hongzhen Tang.

OBJECTIVE: This network meta-analysis aims to investigate and compare the effectiveness of 3 dietary interventions - Mediterranean, ketogenic, and low-fat diet - on overweight and obese adults, with a comparison to traditional low-calorie diet.METHODS: A systematic review was conducted in both Chinese and English databases, including the China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database (VIP), SinoMed, PubMed, Web of Science, Cochrane Library and Embase to identify relevant randomized controlled trials (RCTs) up to January 31, 2024. Two researchers independently screened and extracted data from the identified literature. The quality of these studies was assessed using the Cochrane bias risk assessment tool. A random-effects network meta-analysis was performed using Review Manager 5.4.1 and Stata 16.0 software.
RESULTS: A total of 17 randomized controlled trials involving 5802 subjects were included in this study. The network meta-analysis revealed a descending order of effectiveness for reducing body weight (BW), body mass index (BMI), and waist circumference (WC): ketogenic diet > low-fat diet > low-calorie diet > Mediterranean diet.
CONCLUSIONS: The ketogenic diet was identified as the most effective intervention for reducing BW, BMI, and WC in the studied dietary comparisons. It consistently showed superior outcomes, ranking highest in effectiveness among the 4 evaluated dietary approaches. Nevertheless, additional high-quality randomized controlled trials are necessary to validate these findings.

DOI: https://doi.org/10.1097/MD.0000000000039749
Neuro Oncol. 2024 Oct 24. pii: noae222. [Epub ahead of print]

GDH1-catalytic glutaminolysis feedback activate EGFR/PI3K/AKT pathway and reprogram glioblastoma metabolism.

Rui Yang, Guanghui Zhang, Zhen Meng, Li Wang, Yanping Li, Haibin Li, Siyuan Yan, Xiaonan Wei, Shanshan Wang, Hongjuan Cui.

  BACKGROUND: Glutamine is an important nutriment for cancer cell growth that provides biological sources for nucleic acid and fatty acid synthesis, but the role of glutaminolysis in signal transduction and glioblastoma (GBM) progression remains little known.METHODS: Knockdown and overexpression cells were obtained to explore the functional roles of GDH1 in cell proliferation, tumor formation and aerobic glycolysis. RNA-seq, Chromatin immunoprecipitation, luciferase assay and western blot were performed to verify the regulation of EGFR-AKT pathway by the glutamate dehydrogenase 1 (GDH1, also known as GLUD1) and KDM6A. Metabolite-level measurements and Seahorse Assay were performed to assess the functional role of GHD1 in reprogramming glycolysis.
RESULTS: Here, we report that GDH1 catalytic glutaminolysis is essential for GBM cell line proliferation and brain tumorigenesis even in high-glucose conditions. Glutamine is metabolized through glutaminolysis to produce α-ketoglutarate (α-KG). We demonstrate that glutamine in combination with leucine activates mammalian TORC1 by enhancing glutaminolysis and α-KG production. α-KG increases the transcription of PDPK1 by reducing the suppressive histone modification H3K27me3, and then promotes the activation of PI3K/AKT/mTOR pathway. This transcriptional activation induced by α-KG requires histone demethylase KDM6A, which is a 2-oxoglutarate oxygenase that plays important roles in converting α-KG to succinate. Furthermore, we show that GDH1-catalytic glutaminolysis also increases the expression of HK2 and promotes glycolysis in high-glucose condition dependent on KDM6A-mediated demethylation of H3K27.
CONCLUSION: These findings suggest a novel function of glutaminolysis in regulation of signal transduction and metabolism reprograming, provide further evidence for unique role of glutaminolysis in GBM progression.

Keywords:  EGFR-AKT pathway; GBM; GDH1; KDM6A; metabolism reprogramming

DOI:  https://doi.org/10.1093/neuonc/noae222
Blood. 2024 Oct 22. pii: blood.2024024837. [Epub ahead of print]

A phase 1 study of the amino acid modulator pegcrisantaspase and venetoclax for relapsed/refractory acute myeloid leukemia.

Yuchen Liu, Dominique R Bollino, Osman M Bah, Erin T Strovel, Tien Van Le, Jinoos Zarrabi, Sunita Philip, Rena G Lapidus, Maria R Baer, Sandrine Niyongere, Vu H Duong, Christine C Dougherty, Jan Hendrik Beumer, Katherine D Caprinolo, Farin Kamangar, Ashkan Emadi.

Glutamine dependency has been shown to be a metabolic vulnerability in acute myeloid leukemia (AML). Prior studies using several in vivo AML models showed that depletion of plasma glutamine induced by the long-acting crisantaspase (pegcrisantaspase or PegC) was synergistic with the BCL-2 inhibitor venetoclax (Ven), resulting in significantly reduced leukemia burden and enhanced survival. Here, we report a phase 1 study (NCT04666649) of Ven and PegC combination (VenPegC) for treating adult patients with relapsed or refractory AML, including patients who had previously received Ven. The primary endpoints were incidence of regimen limiting toxicities (RLT) and maximum tolerated dose (MTD). Twenty-five patients received at least one PegC dose with Ven and 18 efficacy-evaluable patients completed at least one VenPegC cycle; 12 (67%) had previously received Ven. Hyperbilirubinemia was the RLT and occurred in 60% of patients treated with VenPegC; 20% had Grade ≥3 bilirubin elevations. MTD was determined to be Ven 400 mg daily with biweekly PegC 750 IU/m2. The most common treatment-related adverse events of any Grade in 25 patients who received VenPegC included antithrombin III decrease (52%), elevated transaminases (36-48%), fatigue (28%), and hypofibrinogenemia (24%). No thromboembolic or hemorrhagic adverse events or clinical pancreatitis were observed. The overall complete remission rate in efficacy-evaluable patients was 33%. Response correlated with alterations in proteins involved in mRNA translation. In patients with RUNX1 mutations, the composite complete rate was 100%.

DOI: https://doi.org/10.1182/blood.2024024837
Metabolites. 2024 Oct 15. pii: 550. [Epub ahead of print]14(10):

Multi-Modal Investigation of Metabolism in Murine Breast Cancer Cell Lines Using Fluorescence Lifetime Microscopy and Hyperpolarized 13C-Pyruvate Magnetic Resonance Spectroscopy.

Sarah Erickson-Bhatt, Benjamin L Cox, Erin Macdonald, Jenu V Chacko, Paul Begovatz, Patricia J Keely, Suzanne M Ponik, Kevin W Eliceiri, Sean B Fain.

  Background/Objectives: Despite the role of metabolism in breast cancer metastasis, we still cannot predict which breast tumors will progress to distal metastatic lesions or remain dormant. This work uses metabolic imaging to study breast cancer cell lines (4T1, 4T07, and 67NR) with differing metastatic potential in a 3D collagen gel bioreactor system. Methods: Within the bioreactor, hyperpolarized magnetic resonance spectroscopy (HP-MRS) is used to image lactate/pyruvate ratios, while fluorescence lifetime imaging microscopy (FLIM) of endogenous metabolites measures metabolism at the cellular scale. Results: HP-MRS results showed no lactate peak for 67NR and a comparatively large lactate/pyruvate ratio for both 4T1 and 4T07 cell lines, suggestive of greater pyruvate utilization with greater metastatic potential. Similar patterns were observed using FLIM with significant increases in FAD intensity, redox ratio, and NAD(P)H lifetime. The lactate/pyruvate ratio was strongly correlated to NAD(P)H lifetime, consistent with the role of NADH as an electron donor for the glycolytic pathway, suggestive of an overall upregulation of metabolism (both glycolytic and oxidative), for the 4T07 and 4T1 cell lines compared to the non-metastatic 67NR cell line. Conclusions: These findings support a complementary role for HP-MRS and FLIM enabled by a novel collagen gel bioreactor system to investigate metastatic potential and cancer metabolism.

Keywords:  FLIM; MRS; breast cancer; carbon-13; hyperpolarized; metabolism; metastatic potential

DOI:  https://doi.org/10.3390/metabo14100550
Free Radic Biol Med. 2024 Oct 22. pii: S0891-5849(24)00997-3. [Epub ahead of print]

Calorie restriction modulates mitochondrial dynamics and autophagy in leukocytes of patients with obesity.

Zaida Abad-Jiménez, Sandra López-Domènech, María Pelechá, Laura Perea-Galera, Susana Rovira-Llopis, Celia Bañuls, Ana Blas-García, Nadezda Apostolova, Carlos Morillas, Víctor Manuel Víctor, Milagros Rocha.

  BACKGROUND: Although it is established that caloric restriction offers metabolic and clinical benefits, the molecular mechanisms underlying these effects remain unclear. Thus, this study aimed to investigate whether caloric restriction can modulate mitochondrial function and remodelling and stimulate autophagic flux in the PBMCs of patients with obesity.METHODS: This was an interventional study of 38 obese subjects (BMI > 35 kg/m2) who underwent 6 months of dietary therapy, including a 6-week very-low-calorie diet (VLCD) followed by an 18-week low-calorie diet (LCD). We determined clinical variables, mitochondrial function parameters (by fluorescence imaging of mitochondrial ROS and membrane potential), and protein expression of markers of mitochondrial dynamics (MNF1, MFN2, OPA, DRP1 and FIS1) and autophagy (LC3, Beclin, BCL2 and NBR1) by western blot.
RESULTS: Caloric restriction induced an improvement in metabolic outcomes that was accompanied by an increase in AMPK expression, a decrease of mitochondrial ROS and mitochondrial membrane potential, which was associated with increased markers of mitochondrial dynamics (MFN2, DRP1 and FIS1) and activation of autophagy as evidenced by augmented LC3 II/I, Beclin1 and NBR1, and a decrease in BCL2.
CONCLUSION: These findings shed light on the specific molecular mechanisms by which caloric restriction facilitates metabolic improvements, highlighting the relevance of pathways involving energy homeostasis and cell recovery, including mitochondrial function and dynamics and autophagy.

Keywords:  Obesity; PBMCs; VLCD; autophagy; mitochondrial quality control; oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.295
Am J Physiol Endocrinol Metab. 2024 Oct 23.

Metabolic Effects of Medium-Chain Triacylglycerol Consumption are Preserved in Obesity.

Josephine M Kanta, Anne-Marie Lundsgaard, Jesper F Havelund, Sarah L Amour, Ole Bæk, Duc Ninh Nguyen, Erik A Richter, Jakob G Knudsen, Maximilian Kleinert, Nils Faergeman, Andreas M Fritzen, Bente Kiens.

  Several health beneficial effects are associated with intake of medium-chain triacylglycerol (MCT), however, the underlying mechanisms are unknown. Furthermore, it remains uncertain whether the acute metabolic effects of MCT differ between lean individuals and individuals with obesity - and whether these effects are sustained following chronic intake. This study aimed to elucidate the postprandial physiological and metabolic effects of MCT before and after eight days intake compared to intake of energy-matched triacylglycerol consisting of long-chain fatty acids (LCT) using a randomized cross-over design in lean individuals (n=8) and individuals with obesity (n=8). The study revealed that consumption of MCT increased ketogenesis and metabolic rate, while lowering blood glucose levels over five hours. The hypoglycemic action of MCT intake was accompanied by a concomitant transient increase in plasma insulin and glucagon levels. Interestingly, the effects on ketogenesis, metabolic rate, and glycemia were preserved in individuals with obesity and sustained after eight days of daily supplementation. Lipidomic plasma analysis in lean individuals (n=4) showed that a part of the ingested MCT bypasses the liver and entered the systemic circulation as medium-chain fatty acids (MCFA). The findings suggest that MCFA, along with ketone bodies from the liver, may act as signaling molecules and/or substrates in the peripheral tissues, thereby contributing to the effects of MCT intake. In summary, these findings underscore the health benefits of MCT in metabolically compromised individuals after daily supplementation. Moreover, we uncover novel aspects of MCFA biology, providing insights into how these fatty acids orchestrate physiological effects in humans.

Keywords:  Medium-chain fatty acids; Metabolism; ketone bodies; lipid metabolism

DOI:  https://doi.org/10.1152/ajpendo.00234.2024
Mol Neurobiol. 2024 Oct 24.

Targeted Metabolic Profiling in Determining the Metabolic Heterogeneity in Human Biopsies of Different Grades of Glioma.

Arambakkam Janardhanam Vanisree, Gangadharan Thamizhoviya, Arumugam Thiruvalluvan.

  Gliomas are intricate tumors with numerous metabolic and genetic abnormalities contributing to their aggressive phenotypes and poor prognoses. The study aims at identifying the key molecular metabolic as well as gene expressional variations that could be used to differentiate between different grades of glioma to obtain deeper insights the about metabolic status of glioma that may serve as good candidates of diagnosis in future. In the present study, the metabolomic profiling along with clinical and expressional analyses of glioma biopsies (n = 52; patients comprising both of benign and malignant lesions) was analyzed. The biopsies were subjected to gene/protein expressional analysis using RT-PCR and western blotting and also were subjected to metabolite analyses. The results of the gene/protein expressional analysis exhibited elevated levels of carnitine palmitoyltransferase, monoglyceride lipase, human phosphofructokinase, and isocitrate dehydrogenase in higher grades of glioma when compared to those of control. Our study suggested that the metabolites and gene/protein expressional levels were found to be discriminative among the grades of glioma. The study is deemed as a provider of deeper insights that are essential for differential therapeutic approaches that specifically target the dysregulated metabolome to the benefit of patients.

Keywords:  Carnitine palmitoyltransferase; Glioma; Metabolites; Monoglyceride lipase; Phosphofructokinase

DOI:  https://doi.org/10.1007/s12035-024-04538-1
Nat Commun. 2024 Oct 21. 15(1): 9063

Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice.

Cristiane Dos Santos, Amanda Cambraia, Shristi Shrestha, Melanie Cutler, Matthew Cottam, Guy Perkins, Varda Lev-Ram, Birbickram Roy, Christopher Acree, Keun-Young Kim, Thomas Deerinck, Danielle Dean, Jean Philippe Cartailler, Patrick E MacDonald, Martin Hetzer, Mark Ellisman, Rafael Arrojo E Drigo.

Caloric restriction (CR) can extend the organism life- and health-span by improving glucose homeostasis. How CR affects the structure-function of pancreatic beta cells remains unknown. We used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis reveal that CR activates transcription factors important for beta cell identity and homeostasis, while imaging metabolomics demonstrates that beta cells upon CR are more energetically competent. In fact, high-resolution microscopy show that CR reduces beta cell mitophagy to increase mitochondria mass and the potential for ATP generation. However, CR beta cells have impaired adaptive proliferation in response to high fat diet feeding. Finally, we show that long-term CR delays the onset of beta cell aging hallmarks and promotes cell longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cell structure-function during aging and diabetes.

DOI: https://doi.org/10.1038/s41467-024-53127-2
Ann Hematol. 2024 Oct 25.

Azacitidine in combination with shortened venetoclax treatment cycles in patients with acute myeloid leukemia.

Maximilian Fleischmann, Madlen Jentzsch, Annamaria Brioli, Florian Eisele, Jochen J Frietsch, Farina Eigendorff, Romy Tober, Karin G Schrenk, Jakob Friedrich Hammersen, Olaposi Yomade, Inken Hilgendorf, Andreas Hochhaus, Sebastian Scholl, Ulf Schnetzke.

  The combination of venetoclax with hypomethylating agents is currently the standard of care for elderly patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. Despite its favorable efficacy, clinical use is often associated with post-remission cytopenia, frequently necessitating treatment delays and dose modifications. This study aims to evaluate the efficacy and safety of shortened venetoclax treatment durations. A multicenter analysis was conducted involving 20 adult AML patients receiving venetoclax (7 or 14 days with 9 and 11 patients, respectively) combined with 5-azacitidine (5-7 days) between 2021 and 2024. The cohort included patients from four German academic centers all treated in first line. Outcome measures included bone marrow response, transfusion dependence, overall survival (OS) and progression-free survival (PFS). Median age was 73.5 years, with 70% of patients having secondary AML. Adverse molecular risk was observed in 75% of patients. The overall response rate (ORR) was 100%, with a composite complete remission rate of 78%. No significant differences in response rates were observed between the 7-day and 14-day venetoclax regimens. Median OS for the cohort was 15 months. Infection-related complications were observed in 55% of patients, with severe sepsis in 20% of cases. In this cohort, shortened venetoclax regimens demonstrated efficacy comparable to standard treatment protocols, with a potential reduction in hematologic toxicity. These findings support the individualization of treatment regimens to optimize clinical outcomes while potentially minimizing adverse effects.

Keywords:  5-azacitidine; 7 + 7; Acute myeloid leukemia; Shortened treatment; Toxicity; Venetoclax

DOI:  https://doi.org/10.1007/s00277-024-06048-5
Epigenomes. 2024 Oct 09. pii: 38. [Epub ahead of print]8(4):

Associations between Circulating Biomarkers of One-Carbon Metabolism and Mitochondrial D-Loop Region Methylation Levels.

Andrea Stoccoro, Martina Lari, Lucia Migliore, Fabio Coppedè.

  BACKGROUND/OBJECTIVES: One-carbon metabolism is a critical pathway for epigenetic mechanisms. Circulating biomarkers of one-carbon metabolism have been associated with changes in nuclear DNA methylation levels in individuals affected by age-related diseases. More and more studies are showing that even mitochondrial DNA (mtDNA) could be methylated. In particular, methylation of the mitochondrial displacement (D-loop) region modulates the gene expression and replication of mtDNA and, when altered, can contribute to the development of human illnesses. However, no study until now has demonstrated an association between circulating biomarkers of one-carbon metabolism and D-loop methylation levels.METHODS: In the study presented herein, we searched for associations between circulating one-carbon metabolism biomarkers, including folate, homocysteine, and vitamin B12, and the methylation levels of the D-loop region in DNA obtained from the peripheral blood of 94 elderly voluntary subjects.
RESULTS: We observed a positive correlation between D-loop methylation and vitamin B12 (r = 0.21; p = 0.03), while no significant correlation was observed with folate (r = 0.02; p = 0.80) or homocysteine levels (r = 0.02; p = 0.82). Moreover, D-loop methylation was increased in individuals with high vitamin B12 levels compared to those with normal vitamin B12 levels (p = 0.04).
CONCLUSIONS: This is the first study suggesting an association between vitamin B12 circulating levels and mtDNA methylation in human subjects. Given the potential implications of altered one-carbon metabolism and mitochondrial epigenetics in human diseases, a deeper understanding of their interaction could inspire novel interventions with beneficial effects for human health.

Keywords:  DNA methylation; mitochondrial D-loop; mitochondrial epigenetics; one-carbon metabolism; vitamin B12

DOI:  https://doi.org/10.3390/epigenomes8040038
Nutr Cancer. 2024 Oct 24. 1-15

Dietary Flavonoids and Lung Cancer: A GRADE-Assessed Systematic Review and Meta-Analysis of Observational Studies.

Kimia Rostampour, Kimia Alipour, Fatemeh Mirjalili, Bita Forootani, Hooman Yekrang Safakar, Sara Beigrezaei, Scott C Forbes, Amin Salehi-Abargouei.

Individual observational studies examining the association between polyphenols and the risk of lung cancer have reported mixed findings. Therefore, we performed a systematic review and meta-analysis to determine the pooled effects between polyphenol intake and lung cancer risk. A systematic search was performed on PubMed, Scopus, and Web of Science databases in April 2023. Random-effect models were used to estimate odd ratios (OR) and 95% confidence intervals (95% CI). In total, 20 studies were included in the systematic review. The pooled analyses indicated that a higher intake of flavonoids (OR = 0.81; 95% CI: 0.67,0.98; p = 0.03) and isoflavone (OR = 0.82; 95% CI: 0.74,0.92; p < 0.001) were associated with lower odds of lung cancer. In addition, the ingestion of anthocyanidin (OR = 0.80; 95% CI: 0.65,0.98; p = 0.04), kaempferol (OR = 0.78; 95% CI: 0.64,0.96; p = 0.02), quercetin (OR = 0.66; 95% CI: 0.48,0.91; p = 0.01) and flavanones (OR = 0.71; 95% CI: 0.59,0.85; p < 0.001) reduced the likelihood of developing lung cancer. Overall, our findings suggest that flavonoids, isoflavones, anthocyanidin, kaempferol, quercetin, and flavanones may protect against lung cancer.

DOI: https://doi.org/10.1080/01635581.2024.2417457
Nat Commun. 2024 Oct 22. 15(1): 9098

Dissected antiporter modules establish minimal proton-conduction elements of the respiratory complex I.

Adel Beghiah, Patricia Saura, Sofia Badolato, Hyunho Kim, Johanna Zipf, Dirk Auman, Ana P Gamiz-Hernandez, Johan Berg, Grant Kemp, Ville R I Kaila.

The respiratory Complex I is a highly intricate redox-driven proton pump that powers oxidative phosphorylation across all domains of life. Yet, despite major efforts in recent decades, its long-range energy transduction principles remain highly debated. We create here minimal proton-conducting membrane modules by engineering and dissecting the key elements of the bacterial Complex I. By combining biophysical, biochemical, and computational experiments, we show that the isolated antiporter-like modules of Complex I comprise all functional elements required for conducting protons across proteoliposome membranes. We find that the rate of proton conduction is controlled by conformational changes of buried ion-pairs that modulate the reaction barriers by electric field effects. The proton conduction is also modulated by bulky residues along the proton channels that are key for establishing a tightly coupled proton pumping machinery in Complex I. Our findings provide direct experimental evidence that the individual antiporter modules are responsible for the proton transport activity of Complex I. On a general level, our findings highlight electrostatic and conformational coupling mechanisms in the modular energy-transduction machinery of Complex I with distinct similarities to other enzymes.

DOI: https://doi.org/10.1038/s41467-024-53194-5
Br J Haematol. 2024 Oct 24.

Monocentric experience of venetoclax-based regimen in paediatric refractory and relapsed AML/MDS.

Sophie Cousson, Charlotte Calvo, Lauriane Goldwirt, Mathieu Simonin, Julie Roupret-Serzec, Marie Émilie Dourthe, Marion Strullu, André Baruchel, Jean-Hugues Dalle, Benoît Brethon.

  BCL-2 inhibitor venetoclax demonstrates promising efficacy in paediatric relapsed/refractory acute myeloid leukaemia (r/r AML). This retrospective analysis evaluated 12 patients treated with venetoclax-based regimens under compassionate use for r/r myeloid malignancies. The overall response rate (ORR) was 41.6%, with complete response (CR) achieved in 33% of patients. Three patients successfully underwent allogeneic haematopoietic scell transplantation (HSCT) after venetoclax bridging therapy. Venetoclax demonstrated a favourable safety profile with manageable side effects. These findings suggest venetoclax's potential as a valuable therapeutic option for paediatric r/r AML, particularly for heavily pretreated patients. Further investigation in larger multicentre trials is warranted to refine treatment strategy.

Keywords:  Bcl‐2 inhibitor; paediatric acute leukaemia; refractory or relapsed AML; venetoclax ABT‐199

DOI:  https://doi.org/10.1111/bjh.19849
J Proteome Res. 2024 Oct 24.

MALDI MSI Protocol for Spatial Bottom-Up Proteomics at Single-Cell Resolution.

Andrej Grgic, Eva Cuypers, Ludwig J Dubois, Shane R Ellis, Ron M A Heeren.

  Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) started with spatial mapping of peptides and proteins. Since then, numerous bottom-up protocols have been developed. However, achievable spatial resolution and sample preparation with many wet steps hindered the development of single cell-level workflows for bottom-up spatial proteomics. This study presents a protocol optimized for MALDI-MSI measurements of single cells within the context of their 2D culture. Sublimation of CHCA, followed by a dip in ice-cold ammonium phosphate monobasic (AmP), produced peptide-rich mass spectra while maintaining matrix crystal sizes around 400 nm. This enables MALDI-MSI imaging of proteins in single cells grown on an ITO slide with a throughput of approximately 7800 cells per day. 89 peptide-like features corresponding to a single MDA-MB-231 breast cancer cell were detected. Furthermore, by combining the MALDI-MSI data with LC-MS/MS data obtained on cell pellets, we have successfully identified 24 peptides corresponding to 17 proteins, including actin, vimentin, and transgelin-2.

Keywords:  MALDI; MSI; high spatial resolution; mass spectrometry imaging; proteomics; single-cell

DOI:  https://doi.org/10.1021/acs.jproteome.4c00528