bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2024–11–03
forty-four papers selected by
Brett Chrest, Wake Forest University
  1. Noncanonical TCA cycle fosters canonical TCA cycle and mitochondrial integrity in acute myeloid leukemia.
  2. A thermodynamic bottleneck in the TCA cycle contributes to acetate overflow in Staphylococcus aureus.
  3. Pyruvate dehydrogenase kinase 1 controls triacylglycerol hydrolysis in cardiomyocytes.
  4. Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.
  5. Ketogenic Diet: A Review of Composition Diversity, Mechanism of Action and Clinical Application.
  6. Gluconeogenesis and glycogenolysis required in metastatic breast cancer cells.
  7. Efficacy and safety of second‑generation FLT3 inhibitors in acute myeloid leukemia: A systematic review and meta‑analysis of randomized controlled trials.
  8. RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax.
  9. Role of Exogenous Pyruvate in Maintaining Adenosine Triphosphate Production under High-Glucose Conditions through PARP-Dependent Glycolysis and PARP-Independent Tricarboxylic Acid Cycle.
  10. Effects of a Carbohydrate Meal on Lipolysis.
  11. Modeling compound lipid homeostasis using stable isotope tracing.
  12. Colorectal cancer cells establish metabolic reprogramming with cancer-associated fibroblasts (CAFs) through lactate shuttle to enhance invasion, migration, and angiogenesis.
  13. Amino acid is a major carbon source for hepatic lipogenesis.
  14. Oral Administration of a Novel, Synthetic Ketogenic Compound Elevates Blood β-Hydroxybutyrate Levels in Mice in Both Fasted and Fed Conditions.
  15. A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones.
  16. Targeting NOX2 and glycolytic metabolism as a therapeutic strategy in acute myeloid leukaemia.
  17. In the Brain, It Is Not All about Sugar.
  18. Chronic obesity does not alter cancer survival in Tp53 R270H/+ mice.
  19. Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.
  20. Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2.
  21. Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase.
  22. Exploring the Impact of Fasting and Fasting-Mimicking Diets on Type 2 Diabetes Management in Adults: A Systematic Review.
  23. Mass Spectrometry Probe Combined with Machine Learning to Capture the Relationship between Metabolites and Mitochondrial Complex Activity at the Whole-Cell Level.
  24. Is a Meta-Analysis of Clinical Trial Outcomes for Ketogenic Diets Justifiable? A Critical Assessment Based on Systematic Research.
  25. Mapping the evolution and impact of ketogenic diet research on diabetes management: a comprehensive bibliometric analysis from 2005 to 2024.
  26. Empirical dietary inflammatory pattern could increase the odds of breast cancer: a case-control study.
  27. Diet changes and colorectal cancer risk in the UK Biobank.
  28. Site of breast cancer metastasis is independent of single nutrient levels.
  29. Dietary advanced glycation end-products (dAGEs) are not associated with the risk of cancer incidence. A systematic review and meta-analysis of prospective cohort studies.
  30. Is Fasting Superior to Continuous Caloric Restriction for Weight Loss and Metabolic Outcomes in Obese Adults? A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
  31. ACSS2 regulates ferroptosis in an E2F1-dependent manner in breast cancer brain metastatic cells.
  32. A review of the isocitrate dehydrogenase inhibitors in management of adult patients with AML and MDS.
  33. Obesity-dependent selection of driver mutations in cancer.
  34. Glutamate Transport Proteins and Metabolic Enzymes are Poor Prognostic Factors in Invasive Lobular Carcinoma.
  35. High mitochondrial DNA levels accelerate lung adenocarcinoma progression.
  36. One-carbon-mediated purine synthesis underlies temozolomide resistance in glioblastoma.
  37. Treatment approaches and survival outcomes in elderly colorectal cancer patients: a single-center comparative study.
  38. Branched-chain amino acid catabolism promotes ovarian cancer cell proliferation via phosphorylation of mTOR.
  39. Optical control of sphingolipid biosynthesis using photoswitchable sphingosines.
  40. Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes.
  41. Membrane potential stimulates ADP import and ATP export by the mitochondrial ADP/ATP carrier due to its positively charged binding site.
  42. Cerebral and myocardial kinetics of [11C]acetoacetate and [11C]β-hydroxybutyrate: A comparative crossover study in healthy rats.
  43. Comparative small molecule screening of primary human acute leukemias, engineered human leukemia and leukemia cell lines.
  44. Non-genetic differences underlie variability in proliferation among esophageal epithelial clones.
  1. Cancer Sci. 2024 Oct 31.
    Noncanonical TCA cycle fosters canonical TCA cycle and mitochondrial integrity in acute myeloid leukemia.
    Atsushi Watanabe, Chartsiam Tipgomut, Haruhito Totani, Kentaro Yoshimura, Tomohiko Iwano, Hamed Bashiri, Lee Hui Chua, Chong Yang, Toshio Suda.
      Cancer cells rely on mitochondrial oxidative phosphorylation (OXPHOS) and the noncanonical tricarboxylic acid (TCA) cycle. In this paper, we shed light on the vital role played by the noncanonical TCA cycle in a host-side concession to mitochondria, especially in highly energy-demanding malignant tumor cells. Inhibition of ATP-citrate lyase (ACLY), a key enzyme in the noncanonical TCA cycle, induced apoptosis by increasing reactive oxygen species levels and DNA damage while reducing mitochondrial membrane potential. The mitochondrial membrane citrate transporter inhibitor, CTPI2, synergistically enhanced these effects. ACLY inhibition reduced cytosolic citrate levels and CTPI2 lowered ACLY activity, suggesting that the noncanonical TCA cycle is sustained by a positive feedback mechanism. These inhibitions impaired ATP production, particularly through OXPHOS. Metabolomic analysis of mitochondrial and cytosolic fractions revealed reduced levels of glutathione pathway-related and TCA cycle-related metabolite, except fumarate, in mitochondria following noncanonical TCA cycle inhibition. Despite the efficient energy supply to the cell by mitochondria, this symbiosis poses challenges related to reactive oxygen species and mitochondrial maintenance. In conclusion, the noncanonical TCA cycle is indispensable for the canonical TCA cycle and mitochondrial integrity, contributing to mitochondrial domestication.
    Keywords:  ATP‐citrate lyase; antimetabolites; apoptosis; cancer metabolism; cell lines; hematopoietic organ; mitochondria; noncanonical TCA cycle; others; reactive oxygen species
    DOI:  https://doi.org/10.1111/cas.16347
  2. bioRxiv. 2024 Oct 18. pii: 2024.10.16.618751. [Epub ahead of print]
    A thermodynamic bottleneck in the TCA cycle contributes to acetate overflow in Staphylococcus aureus.
    Nabia Shahreen, Jongsam Ahn, Adil Alsiyabi, Niaz Bahar Chowdhury, Dhananjay Shinde, Sujata S Chaudhari, Kenneth W Bayles, Vinai C Thomas, Rajib Saha.
      During aerobic growth, S. aureus relies on acetate overflow metabolism, a process where glucose is incompletely oxidized to acetate, for its bioenergetic needs. Acetate is not immediately captured as a carbon source and is excreted as waste by cells. The underlying factors governing acetate overflow in S. aureus have not been identified. Here, we show that acetate overflow is favored due to a thermodynamic bottleneck in the TCA cycle, specifically involving the oxidation of succinate to fumarate by succinate dehydrogenase. This bottleneck reduces flux through the TCA cycle, making it more efficient for S. aureus to generate ATP via acetate overflow metabolism. Additionally, the protein allocation cost of maintaining ATP flux through the restricted TCA cycle is greater than that of acetate overflow metabolism. Finally, we show that the TCA cycle bottleneck provides S. aureus the flexibility to redirect carbon towards maintaining redox balance through lactate overflow when oxygen becomes limiting, albeit at the expense of ATP production through acetate overflow. Overall, our findings suggest that overflow metabolism offers S. aureus distinct bioenergetic advantages over a thermodynamically constrained TCA cycle, potentially supporting its commensal-pathogen lifestyle.
    DOI:  https://doi.org/10.1101/2024.10.16.618751
  3. bioRxiv. 2024 Oct 14. pii: 2024.10.14.618123. [Epub ahead of print]
    Pyruvate dehydrogenase kinase 1 controls triacylglycerol hydrolysis in cardiomyocytes.
    Michael G Atser, Chelsea D Wenyonu, Elyn M Rowe, Connie L K Leung, Haoning Howard Cen, Eric D Queathem, Leo T Liu, Renata Moravcova, Jason Rogalski, David Perrin, Peter Crawford, Leonard J Foster, Armando Alcazar, James D Johnson.
      Pyruvate dehydrogenase kinase (PDK) 1 is one of four isozymes that inhibit the oxidative decarboxylation of pyruvate to acetyl-CoA via pyruvate dehydrogenase. PDK activity is elevated in fasting or starvation conditions to conserve carbohydrate reserves. PDK has also been shown to increase mitochondrial fatty acid utilization. In cardiomyocytes, metabolic flexibility is crucial for the fulfillment of high energy requirements. The PDK1 isoform is abundant in cardiomyocytes, but its specific contribution to cardiomyocyte metabolism is unclear. Here we show that PDK1 regulates cardiomyocyte fuel preference by mediating triacylglycerol turnover in differentiated H9c2 myoblasts using lentiviral shRNA to knockdown Pdk1. Somewhat surprisingly, PDK1 loss did not affect overall PDH activity, basal glycolysis, or glucose oxidation revealed by oxygen consumption rate experiments and 13C6 glucose labelling. On the other hand, we observed decreased triacylglycerol turnover in H9c2 cells with PDK1 knockdown, which was accompanied by decreased mitochondrial fatty acid utilization following nutrient deprivation. 13C16 palmitate tracing of uniformly labelled acyl chains revealed minimal acyl chain shuffling within triacylglycerol, indicating that the triacylglycerol hydrolysis, and not re-esterification, was dysfunctional in PDK1 suppressed cells. Importantly, PDK1 loss did not significantly impact the cellular lipidome or triacylglycerol accumulation following palmitic acid treatment, suggesting that effects of PDK1 on lipid metabolism were specific to the nutrient-deprived state. We validated that PDK1 loss decreased triacylglycerol turnover in Pdk1 knockout mice. Together, these findings implicate a novel role for PDK1 in lipid metabolism in cardiomyocytes, independent of its canonical roles in glucose metabolism.
    Keywords:  carbohydrate metabolism; cardiac metabolism; lipid metabolism; pyruvate dehydrogenase kinase; triacylglycerol
    DOI:  https://doi.org/10.1101/2024.10.14.618123
  4. bioRxiv. 2024 Oct 14. pii: 2024.10.10.617261. [Epub ahead of print]
    Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.
    Joseph Longo, Lisa M DeCamp, Brandon M Oswald, Robert Teis, Alfredo Reyes-Oliveras, Michael S Dahabieh, Abigail E Ellis, Michael P Vincent, Hannah Damico, Kristin L Gallik, Shelby E Compton, Colt D Capan, Kelsey S Williams, Corinne R Esquibel, Zachary B Madaj, Hyoungjoo Lee, Dominic G Roy, Connie M Krawczyk, Brian B Haab, Ryan D Sheldon, Russell G Jones.
      Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8+ T cell expansion and cytotoxic function in vivo. Using 13C-based stable isotope tracing, we demonstrate that CD8+ effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UGP2 or UGCG impairs CD8+ T cell expansion and cytolytic activity without affecting glucose-dependent energy production. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and aggregation following TCR stimulation. Moreover, UGCG-deficient CD8+ T cells display reduced granzyme expression and tumor control in vivo. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-independent of energy production-required for CD8+ T cell responses in vivo.
    Keywords:  CD8+ T cells; UGCG; cytotoxic function; glucose; glycosphingolipids; immunometabolism; lipid rafts; lipidomics; metabolomics; nucleotide sugar metabolism
    DOI:  https://doi.org/10.1101/2024.10.10.617261
  5. J Nutr Metab. 2024 ;2024 6666171
    Ketogenic Diet: A Review of Composition Diversity, Mechanism of Action and Clinical Application.
    Dominika Malinowska, Małgorzata Żendzian-Piotrowska.
      The ketogenic diet (KD) is a special high-fat, very low-carbohydrate diet with the amount of protein adjusted to one's requirements. By lowering the supply of carbohydrates, this diet induces a considerable change in metabolism (of protein and fat) and increases the production of ketone bodies. The purpose of this article is to review the diversity of composition, mechanism of action, clinical application and risk associated with the KD. In the last decade, more and more results of the diet's effects on obesity, diabetes and neurological disorders, among other examples have appeared. The beneficial effects of the KD on neurological diseases are related to the reconstruction of myelin sheaths of neurons, reduction of neuron inflammation, decreased production of reactive oxygen species, support of dopamine production, repair of damaged mitochondria and formation of new ones. Minimizing the intake of carbohydrates results in the reduced absorption of simple sugars, thereby decreasing blood glucose levels and fluctuations of glycaemia in diabetes. Studies on obesity indicate an advantage of the KD over other diets in terms of weight loss. This may be due to the upregulation of the biological activity of appetite-controlling hormones, or to decreased lipogenesis, intensified lipolysis and increased metabolic costs of gluconeogenesis. However, it is important to be aware of the side effects of the KD. These include disorders of the digestive system as well as headaches, irritability, fatigue, the occurrence of vitamin and mineral deficiencies and worsened lipid profile. Further studies aimed to determine long-term effects of the KD are required.
    Keywords:  clinical application; diabetes; ketogenic diet; mechanism; neurological disease; nutrition support; obesity
    DOI:  https://doi.org/10.1155/2024/6666171
  6. Front Oncol. 2024 ;14 1476459
    Gluconeogenesis and glycogenolysis required in metastatic breast cancer cells.
    Emily Hicks, Marjorie Anne Layosa, Chaylen Andolino, Caitlin Truffer, Yazhen Song, Timothy D Heden, Shawn S Donkin, Dorothy Teegarden.
       Introduction: Metabolic adaptability, including glucose metabolism, enables cells to survive multiple stressful environments. Glycogen may serve as a critical storage depot to provide a source of glucose during times of metabolic demand during the metastatic cascade; therefore, understanding glycogen metabolism is critical. Our goal was to determine mechanisms driving glycogen accumulation and its role in metastatic (MCF10CA1a) compared to nonmetastatic (MCF10A-ras) human breast cancer cells.
    Methodology: 13C6-glucose flux analysis in combination with inhibitors of the gluconeogenic pathway via phosphoenolpyruvate carboxykinase (PCK), the anaplerotic enzyme pyruvate carboxylase (PC), and the rate-limiting enzyme of the pentose phosphate pathway (PPP) glucose 6-phosphate dehydrogenase (G6PD). To determine the requirement of glycogenolysis for migration or survival in extracellular matrix (ECM) detached conditions, siRNA inhibition of glycogenolysis (liver glycogen phosphorylase, PYGL) or glycophagy (lysosomal enzyme α-acid glucosidase, GAA) enzymes was utilized.
    Results: Metastatic MCF10CA1a cells had 20-fold greater glycogen levels compared to non-metastatic MCF10A-ras cells. Most glucose incorporated into glycogen of the MCF10CA1a cells was in the five 13C-containing glucose (M+5) instead of the expected M+6 glycogen-derived glucose moiety, which occurs through direct glucose conversion to glycogen. Furthermore, 13C6-glucose in glycogen was quickly reduced (~50%) following removal of 13C-glucose. Incorporation of 13C6-glucose into the M+5 glucose in the glycogen stores was reduced by inhibition of PCK, with additional contributions from flux through the PPP. Further, inhibition of PC reduced total glycogen content. However, PCK inhibition increased total unlabeled glucose accumulation into glycogen, suggesting an alternative pathway to glycogen accumulation. Inhibition of the rate-limiting steps in glycogenolysis (PYGL) or glycophagy (GAA) demonstrated that both enzymes are necessary to support MCF10CA1a, but not MCF10A-ras, cell migration. GAA inhibition, but not PYGL, reduced viability of MCF10CA1a cells, but not MCF10A-ras, in ECM detached conditions.
    Conclusion: Our results indicate that increased glycogen accumulation is primarily mediated through the gluconeogenesis pathway and that glycogen utilization is required for both migration and ECM detached survival of metastatic MCF10CA1a cells. These results suggest that glycogen metabolism may play an important role in the progression of breast cancer metastasis.
    Keywords:  breast cancer; gluconeogenesis; glucose; glycogen; glycogenolysis; glycophagy
    DOI:  https://doi.org/10.3389/fonc.2024.1476459
  7. Mol Clin Oncol. 2024 Dec;21(6): 93
    Efficacy and safety of second‑generation FLT3 inhibitors in acute myeloid leukemia: A systematic review and meta‑analysis of randomized controlled trials.
    Wei-Ting Lin, Chien-Ming Chao, Cheng-Yao Lin, Ya-Ting Hsu, Sheng-Yen Hsiao, Teng-Song Weng.
      Acute myeloid leukemia (AML) is one of the most frequent forms of acute leukemia and the second most common leukemia subtype in adults. In 2020, the incidence of AML in the United States was estimated to be ~4 cases per 100,000 adults. The FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutation are major prognostic indicators of AML. They are more frequently observed in younger AML patients (aged <60 years), likely due to their association with de novo. Additionally, these mutations have a stronger negative impact on survival in younger patients. Therefore, quizartinib and gilteritinib are second-generation FLT3 inhibitors that are frequently applied for treating patients with AML. However, to the best of our knowledge, few studies have compared the efficacy of second-generation FLT3 inhibitors for AML treatment. Therefore, the present study conducted a comprehensive search for studies on the efficacy and safety of FLT3 inhibitors across PubMed, Embase, the Cochrane Library and ClinicalTrials.gov. The search criteria were limited to randomized controlled trials (RCTs). Subsequently, a meta-analysis was performed on a total of five randomized controlled trials, involving 1,543 participants in total, using a random-effects model. In each RCT, compared to the salvage chemotherapy used in the control group, the groups that received second-generation FLT3 inhibitors experienced significant improvements in overall survival (hazard ratio, 0.717; 95% CI, 0.604-0.850; P<0.001). In addition, overall survival was found to be consistent across the different types of second-generation FLT3 inhibitors used and different types of AML. The risks associated with a prolonged heart-rate corrected QT interval (QTc) interval were next evaluated. Compared with the salvage chemotherapy used in the control group, the second-generation FLT3 inhibitor group exhibited a significantly higher risk of having a prolonged QTc interval (odds ratio, 6.311; 95% CI, 3.061-13.013; P<0.001). In conclusion, these findings suggest that second-generation FLT3 inhibitors can improve the overall survival of patients with AML. However, QTc prolongation is a potential adverse effect that should be monitored.
    Keywords:  gilteritinib; overall survival; prolonged heart-rate corrected QT interval; quizartinib; second-generation FMS-like tyrosine kinase 3 inhibitors
    DOI:  https://doi.org/10.3892/mco.2024.2791
  8. Nature. 2024 Oct 30.
    RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax.
    Junya Sango, Saul Carcamo, Maria Sirenko, Abhishek Maiti, Hager Mansour, Gulay Ulukaya, Lewis E Tomalin, Nataly Cruz-Rodriguez, Tiansu Wang, Malgorzata Olszewska, Emmanuel Olivier, Manon Jaud, Bettina Nadorp, Benjamin Kroger, Feng Hu, Lewis Silverman, Stephen S Chung, Elvin Wagenblast, Ronan Chaligne, Ann-Kathrin Eisfeld, Deniz Demircioglu, Dan A Landau, Piro Lito, Elli Papaemmanuil, Courtney D DiNardo, Dan Hasson, Marina Konopleva, Eirini P Papapetrou.
      Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukaemia, upon progression or relapsed/refractory disease1-6. Here, by using human leukaemogenesis models, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte-monocyte progenitors) harbouring previously acquired driver mutations, showing that advanced leukaemic clones can originate from a different cell type in the haematopoietic hierarchy than ancestral clones. Furthermore, we demonstrate that RAS-mutant leukaemia stem cells (LSCs) give rise to monocytic disease, as observed frequently in patients with poor responses to treatment with the BCL2 inhibitor venetoclax. We show that this is because RAS-mutant LSCs, in contrast to RAS-wild-type LSCs, have altered BCL2 family gene expression and are resistant to venetoclax, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver shapes the non-genetic cellular hierarchy of acute myeloid leukaemia by imposing a specific LSC target cell restriction and critically affects therapeutic outcomes in patients.
    DOI:  https://doi.org/10.1038/s41586-024-08137-x
  9. Int J Mol Sci. 2024 Oct 15. pii: 11089. [Epub ahead of print]25(20):
    Role of Exogenous Pyruvate in Maintaining Adenosine Triphosphate Production under High-Glucose Conditions through PARP-Dependent Glycolysis and PARP-Independent Tricarboxylic Acid Cycle.
    Hideji Yako, Naoko Niimi, Shizuka Takaku, Ayako Kato, Koichi Kato, Kazunori Sango.
      Pyruvate serves as a key metabolite in energy production and as an anti-oxidant. In our previous study, exogenous pyruvate starvation under high-glucose conditions induced IMS32 Schwann cell death because of the reduced glycolysis-tricarboxylic acid (TCA) cycle flux and adenosine triphosphate (ATP) production. Thus, this study focused on poly-(ADP-ribose) polymerase (PARP) to investigate the detailed molecular mechanism of cell death. Rucaparib, a PARP inhibitor, protected Schwann cells against cell death and decreased glycolysis but not against an impaired TCA cycle under high-glucose conditions in the absence of pyruvate. Under such conditions, reduced pyruvate dehydrogenase (PDH) activity and glycolytic and mitochondrial ATP production were observed but not oxidative phosphorylation or the electric transfer chain. In addition, rucaparib supplementation restored glycolytic ATP production but not PDH activity and mitochondrial ATP production. No differences in the increased activity of caspase 3/7 and the localization of apoptosis-inducing factor were found among the experimental conditions. These results indicate that Schwann cells undergo necrosis rather than apoptosis or parthanatos under the aforementioned conditions. Exogenous pyruvate plays a pivotal role in maintaining the flux in PARP-dependent glycolysis and the PARP-independent TCA cycle in Schwann cells under high-glucose conditions.
    Keywords:  PARP; Schwann cells; adenosine triphosphate depletion; cell death; exogenous pyruvate; glycolysis; high-glucose; tricarboxylic acid cycle
    DOI:  https://doi.org/10.3390/ijms252011089
  10. Nutrients. 2024 Oct 18. pii: 3531. [Epub ahead of print]16(20):
    Effects of a Carbohydrate Meal on Lipolysis.
    Kerstin Kempf, Stephan Martin.
       BACKGROUND: Due to the increasing prevalence of obesity and type 2 diabetes, effective dietary recommendations are needed. Previously, we developed the low-insulin method: by avoiding insulinogenic, i.e., insulin-release-triggering foods, insulin secretion becomes reduced, lipolysis is stimulated, and energy production is shifted to ketosis with excess ketone bodies exhaled in the form of acetone. Now, we investigate how quickly stable ketosis (defined as fasting breath acetone concentration ≥ 7.0 ppm) is achieved, whether and for how long a carbohydrate meal inhibits ketosis, and whether the responses differ in healthy adults with different insulin levels.
    METHODS: An oral glucose tolerance test was conducted, and body composition and fasting insulin were determined at the beginning and end of the 14-day study. Participants (n = 10) followed a ketogenic diet and performed continuous glucose monitoring. Ketosis levels were determined by measuring breath acetone concentrations. On day 8, two white bread rolls with jam (72 g carbohydrates) were consumed for breakfast.
    RESULTS: After seven days, all participants achieved stable ketosis (defined as fasting breath acetone concentration ≥ 7.0 ppm), which dropped from 8.2 to 5.7 ppm (p = 0.0014) after the carbohydrate meal. It took five days to achieve stable ketosis again. The stratification of participants into tertiles according to their fasting insulin levels demonstrated that individuals with low fasting insulin levels achieved stable ketosis again after two days and those with medium insulin levels after five days, while those with high baseline values did not reach stable ketosis by the end of the study.
    CONCLUSIONS: By carbohydrate restriction, stable ketosis can be achieved within one week. However, a single carbohydrate meal inhibits ketosis for several days. This effect is pronounced in individuals with elevated fasting insulin levels.
    Keywords:  acetone; carbohydrates; insulin; ketogenic diet; ketone; ketosis; lipolysis; obesity; overweight; type 2 diabetes; weight loss
    DOI:  https://doi.org/10.3390/nu16203531
  11. bioRxiv. 2024 Oct 17. pii: 2024.10.16.618599. [Epub ahead of print]
    Modeling compound lipid homeostasis using stable isotope tracing.
    Karl Wessendorf-Rodriguez, Maureen L Ruchhoeft, Ethan L Ashley, Hector M Galvez, Christopher W Murray, Grace McGregor, Shrikaar Kambhampati, Reuben J Shaw, Christian M Metallo.
      Lipids represent the most diverse pool of metabolites found in cells, facilitating compartmentation, signaling, and other functions. Dysregulation of lipid metabolism is linked to disease states such as cancer and neurodegeneration. However, limited tools are available for quantifying metabolic fluxes across the lipidome. To directly measure reaction fluxes encompassing compound lipid homeostasis, we applied stable isotope tracing, high-resolution mass spectrometry, and network-based isotopologue modeling to non-small cell lung cancer (NSCLC) models. Compound lipid metabolic flux analysis (CL-MFA) enables the concurrent quantitation of fatty acid synthesis, elongation, headgroup assembly, and salvage reactions within virtually any biological system. Here, we resolve liver kinase B1 (LKB1)-mediated regulation of sphingolipid recycling in NSCLC cells and precision-cut lung slice cultures. We also demonstrate that widely used tissue culture conditions drive cells to upregulate fatty acid synthase flux to supraphysiological levels. Finally, we identify previously uncharacterized isozyme specificity of ceramide synthase inhibitors, highlighting the molecular detail revealed by CL-MFA.
    DOI:  https://doi.org/10.1101/2024.10.16.618599
  12. Int Immunopharmacol. 2024 Oct 28. pii: S1567-5769(24)01992-1. [Epub ahead of print]143(Pt 2): 113470
    Colorectal cancer cells establish metabolic reprogramming with cancer-associated fibroblasts (CAFs) through lactate shuttle to enhance invasion, migration, and angiogenesis.
    Xingchen Wang, Yaru Qu, Jianbo Ji, He Liu, Huiyuan Luo, Junnan Li, Xiuzhen Han.
      Fibroblasts undergo metabolic reprogramming after contact with cancer cells in tumor microenvironment, producing lactate to provide a metabolic substrate for neighboring tumor cells. The exchange of lactate between cancer cells and fibroblasts via monocarboxylate transporters (MCTs) is known as the lactate shuttle. Colorectal cancer cells may establish a metabolic coupling akin to the lactate shuttle in collaboration with cancer-associated fibroblasts (CAFs) to augment their invasive and migratory capabilities. However, the specific phenomena and underlying mechanisms are not clear. In this study, we investigated the phenomena and explored the correlation and possible mechanism between CAFs and the invasion and migration of colorectal cancer cells by using two different co-culture models. The results showed that colorectal cancer cells established a lactate metabolic coupling with fibroblasts through the oxidative stress effect, triggering the metabolic reprogramming process of themselves and those of fibroblasts. In addition, lactate enhanced the invasion and migration of colorectal cancer by stabilizing the protein expression levels of nuclear factor kappa-B (NF-κB) and hypoxia-inducible factor-1α (HIF-1α). Blocking oxidative stress and lactate metabolic coupling with reactive oxygen species removers and MCT1-specific inhibitors, respectively, could effectively suppress metastasis in colorectal cancer. These findings suggest that targeting the lactate metabolic coupling between tumor cells and CAFs will offer a new strategy to combat colorectal cancer.
    Keywords:  CAFs; Lactate shuttle; MCT1; Metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2024.113470
  13. Cell Metab. 2024 Oct 22. pii: S1550-4131(24)00397-8. [Epub ahead of print]
    Amino acid is a major carbon source for hepatic lipogenesis.
    Yilie Liao, Qishan Chen, Lei Liu, Haipeng Huang, Jingyun Sun, Xiaojie Bai, Chenchen Jin, Honghao Li, Fangfang Sun, Xia Xiao, Yahong Zhang, Jia Li, Weiping Han, Suneng Fu.
      Increased de novo lipogenesis is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD) in obesity, but the macronutrient carbon source for over half of hepatic fatty acid synthesis remains undetermined. Here, we discover that dietary protein, rather than carbohydrates or fat, is the primary nutritional risk factor for MASLD in humans. Consistently, ex vivo tracing studies identify amino acids as a major carbon supplier for the tricarboxylic acid (TCA) cycle and lipogenesis in isolated mouse hepatocytes. In vivo, dietary amino acids are twice as efficient as glucose in fueling hepatic fatty acid synthesis. The onset of obesity further drives amino acids into fatty acid synthesis through reductive carboxylation, while genetic and chemical interventions that divert amino acid carbon away from lipogenesis alleviate hepatic steatosis. Finally, low-protein diets (LPDs) not only prevent body weight gain in obese mice but also reduce hepatic lipid accumulation and liver damage. Together, this study uncovers the significant role of amino acids in hepatic lipogenesis and suggests a previously unappreciated nutritional intervention target for MASLD.
    Keywords:  DNL; MASH; MASLD; NAFLD; amino acids; dietary protein; glucose; glutamine; lipogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.001
  14. Nutrients. 2024 Oct 18. pii: 3526. [Epub ahead of print]16(20):
    Oral Administration of a Novel, Synthetic Ketogenic Compound Elevates Blood β-Hydroxybutyrate Levels in Mice in Both Fasted and Fed Conditions.
    Maricel A Soliven, Christopher Q Rogers, Michael S Williams, Natalya N Thomas, Edward Turos, Dominic P D'Agostino.
       BACKGROUND/OBJECTIVES: Elevating ketone levels with therapeutic nutritional ketosis can help to metabolically manage disease processes associated with epilepsy, diabetes, obesity, cancer, and neurodegenerative disease. Nutritional ketosis can be achieved with various dieting strategies such as the classical ketogenic diet, the modified Atkins diet, caloric restriction, periodic fasting, or the consumption of exogenous ketogenic supplements such as medium-chain triglycerides (MCTs). However, these various strategies can be unpleasant and difficult to follow, so that achieving and sustaining nutritional ketosis can be a major challenge. Thus, investigators continue to explore the science and applications of exogenous ketone supplementation as a means to further augment the therapeutic efficacy of this metabolic therapy.
    METHODS: Here, we describe a structurally new synthetic triglyceride, glycerol tri-acetoacetate (Gly-3AcAc), that we prepared from glycerol and an acetoacetate precursor that produces hyperketonemia in the therapeutic range (2-3 mM) when administered to mice under both fasting and non-fasting conditions. Animal studies were undertaken to evaluate the potential effects of eliciting a ketogenic response systemically. Acute effects (24 h or less) were determined in male VM/Dk mice in both fasted and unfasted dietary states.
    RESULTS: Concentration levels of β-hydroxybutyrate in blood were elevated (βHB; 2-3 mM) under both conditions. Levels of glucose were reduced only in the fasted state. No detrimental side effects were observed.
    CONCLUSIONS: Pending further study, this novel compound could potentially add to the repertoire of methods for inducing therapeutic nutritional ketosis.
    Keywords:  diabetes; exogenous ketones; hyperketonemia; hypoglycemia; ketogenic diet; ketone metabolic therapy; ketosis; medium-chain triglycerides; nutritional supplements
    DOI:  https://doi.org/10.3390/nu16203526
  15. Cell Metab. 2024 Oct 25. pii: S1550-4131(24)00409-1. [Epub ahead of print]
    A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones.
    Adam J Rauckhorst, Ryan D Sheldon, Daniel J Pape, Adnan Ahmed, Kelly C Falls-Hubert, Ronald A Merrill, Reid F Brown, Kshitij Deshmukh, Thomas A Vallim, Stanislaw Deja, Shawn C Burgess, Eric B Taylor.
      Hepatic de novo lipogenesis (DNL) is a fundamental physiologic process that is often pathogenically elevated in metabolic disease. Treatment is limited by incomplete understanding of the metabolic pathways supplying cytosolic acetyl-CoA, the obligate precursor to DNL, including their interactions and proportional contributions. Here, we combined extensive 13C tracing with liver-specific knockout of key mitochondrial and cytosolic proteins mediating cytosolic acetyl-CoA production. We show that the mitochondrial pyruvate carrier (MPC) and ATP-citrate lyase (ACLY) gate the major hepatic lipogenic acetyl-CoA production pathway, operating in parallel with acetyl-CoA synthetase 2 (ACSS2). Given persistent DNL after mitochondrial citrate carrier (CiC) and ACSS2 double knockout, we tested the contribution of exogenous and leucine-derived acetoacetate to acetoacetyl-CoA synthetase (AACS)-dependent DNL. CiC knockout increased acetoacetate-supplied hepatic acetyl-CoA production and DNL, indicating that ketones function as mitochondrial-citrate reciprocal DNL precursors. By delineating a mitochondrial-cytosolic DNL substrate supply network, these findings may inform strategies to therapeutically modulate DNL.
    Keywords:  AACS; ACLY; ACSS2; ATP-citrate lyase; CiC; DNL; MPC; acetoacetyl-CoA synthetase; acetyl-CoA synthetase 2; de novo lipogenesis; liver; metabolomics; mitochondrial citrate carrier; mitochondrial pyruvate carrier; stable isotope tracers
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.013
  16. Biomark Res. 2024 Oct 29. 12(1): 128
    Targeting NOX2 and glycolytic metabolism as a therapeutic strategy in acute myeloid leukaemia.
    Carla Ijurko, Marta Romo-González, Rodrigo Prieto-Bermejo, María Díez-Campelo, María-Belén Vidriales, Sandra Muntión, Fermín Sánchez-Guijo, Jesús Sánchez-Yagüe, Ángel Hernández-Hernández.
      Acute myeloid leukaemia (AML) is a highly heterogeneous malignancy, with a poor 5-year overall survival rate of approximately 30%. Consequently, the search for novel therapeutic strategies is ongoing, and the identification of new vulnerabilities could accelerate progress. Oxidative stress and metabolic rewiring are established hallmarks of cancer, and recent evidence suggests that NADPH oxidases may regulate metabolism, potentially linking these two processes. Increasing research highlights the importance of NOX2 in AML, particularly its role in metabolic regulation. In this study, we investigated the effects of simultaneously inhibiting NOX2 and glycolysis in AML cells. Dual inhibition of NOX2 and glycolysis-by targeting hexokinase or lactate dehydrogenase (LDH)-significantly reduced cell proliferation, markedly impaired clonogenic potential, and induced extensive cell death in a broad panel of AML cell lines. Importantly, these findings were further validated in primary bone marrow samples derived from AML patients, where combined inhibition triggered similar potent anti-leukemic effects. Furthermore, the combined inhibition of NOX2 and LDH enhanced the efficacy of cytarabine (AraC), suggesting this approach could boost the effectiveness of conventional therapies. In an in vivo AML model, targeting NOX2 and LDH in myeloid progenitor cells delayed the onset of leukaemia and extended survival. In conclusion, our findings propose a novel therapeutic strategy for AML through the dual targeting of NOX2 and glycolysis.
    Keywords:   CYBB ; Acute myeloid leukaemia; Glycolysis; Hexokinase; Lactate dehydrogenase (LDH); NADPH oxidase; NOX2
    DOI:  https://doi.org/10.1186/s40364-024-00674-x
  17. NeuroSci. 2024 Jun;5(2): 209-221
    In the Brain, It Is Not All about Sugar.
    Bernardo C Antunes, Tomás Mateus, Vanessa A Morais.
      The maintenance of energetic homeostasis relies on a tight balance between glycolysis and mitochondrial oxidative phosphorylation. The case of the brain is a peculiar one, as although entailing a constant demand for energy, it is believed to rely mostly on glucose, particularly at the level of neurons. Nonetheless, this has been challenged by studies that show that alternatives such as lactate, ketone bodies, and glutamate can be used as fuels to sustain neuronal activity. The importance of fatty acid (FA) metabolism to this extent is still unclear, albeit sustaining a significant energetic output when compared to glucose. While several authors postulate a possible role of FA for the energetic homeostasis of the brain, several others point out the intrinsic features of this pathway that make its contribution difficult to explain in the context of neuronal bioenergetics. Moreover, fueling preference at the synapse level is yet to be uncovered. In this review, we discuss in detail the arguments for and against the brain usage of FA. Furthermore, we postulate that the importance of this fuel may be greater at the synapse, where local mitochondria possess a set of features that enable a more effective usage of this fuel source.
    Keywords:  brain; fatty acid metabolism; mitochondria; synapse
    DOI:  https://doi.org/10.3390/neurosci5020016
  18. bioRxiv. 2024 Oct 16. pii: 2024.10.14.618190. [Epub ahead of print]
    Chronic obesity does not alter cancer survival in Tp53 R270H/+ mice.
    Ilaria Panzeri, Zachary Madaj, Luca Fagnocchi, Stefanos Apostle, Megan Tompkins, Galen Hostetter, J Andrew Pospisilik.
      Obesity is a complex chronic disease characterized by excessive adiposity and associations with numerous co-morbidities, including cancer. Despite extensive research, we have limited understanding of the mechanisms coupling obesity to cancer risk, and, of the contexts in which obesity does or does not exacerbate disease. Here, we show that chronic high-fat diet (HFD)-induced obesity has no significant effect on the Tp53 R270H/+ mouse, a model of human Li-Fraumeni multi-cancer syndrome. Surprisingly, despite inducing rapid and highly penetrant obesity and long-term differences in metabolic and adiposity, greater than one year of HFD had no significant effect on survival or tumor burden. These findings were replicated in two separate cohorts and thus provide important negative data for the field. Given strong publication bias against negative data in the literature, this large cohort study represents a clear case where chronic diet-induced obesity does not accelerate or aggravate cancer outcomes. The data thus carry high impact for researchers, funders, and policymakers alike.
    Keywords:  Cancer; Li-Fraumeni; Tp53; Tp53R270H; high-fat diet; obesity
    DOI:  https://doi.org/10.1101/2024.10.14.618190
  19. Sci Adv. 2024 Nov;10(44): eadk8801
    Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.
    Spencer D Shelton, Sara House, Luiza Martins Nascentes Melo, Vijayashree Ramesh, Zhenkang Chen, Tao Wei, Xun Wang, Claire B Llamas, Siva Sai Krishna Venigalla, Cameron J Menezes, Gabriele Allies, Jonathan Krystkiewicz, Jonas Rösler, Sven W Meckelmann, Peihua Zhao, Florian Rambow, Dirk Schadendorf, Zhiyu Zhao, Jennifer G Gill, Ralph J DeBerardinis, Sean J Morrison, Alpaslan Tasdogan, Prashant Mishra.
      Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood.
    DOI:  https://doi.org/10.1126/sciadv.adk8801
  20. Cell Metab. 2024 Oct 19. pii: S1550-4131(24)00396-6. [Epub ahead of print]
    Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2.
    Deguan Lv, Deobrat Dixit, Andrea F Cruz, Leo J Y Kim, Likun Duan, Xin Xu, Qiulian Wu, Cuiqing Zhong, Chenfei Lu, Zachary C Gersey, Ryan C Gimple, Qi Xie, Kailin Yang, Xiaojing Liu, Xiaoguang Fang, Xujia Wu, Reilly L Kidwell, Xiuxing Wang, Shideng Bao, Housheng H He, Jason W Locasale, Sameer Agnihotri, Jeremy N Rich.
      Tumors reprogram their metabolism to generate complex neoplastic ecosystems. Here, we demonstrate that glioblastoma (GBM) stem cells (GSCs) display elevated activity of the malate-aspartate shuttle (MAS) and expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 attenuated GSC proliferation, self-renewal, and in vivo tumor growth, partially rescued by aspartate. Targeting MDH2 induced accumulation of alpha-ketoglutarate (αKG), a critical co-factor for dioxygenases, including the N6-methyladenosine (m6A) RNA demethylase AlkB homolog 5, RNA demethylase (ALKBH5). Forced expression of MDH2 increased m6A levels and inhibited ALKBH5 activity, both rescued by αKG supplementation. Reciprocally, targeting MDH2 reduced global m6A levels with platelet-derived growth factor receptor-β (PDGFRβ) as a regulated transcript. Pharmacological inhibition of MDH2 in GSCs augmented efficacy of dasatinib, an orally bioavailable multi-kinase inhibitor, including PDGFRβ. Collectively, stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes and reveal possible therapeutic paradigms.
    Keywords:  ALKBH5; MDH2; PDGFRβ; alpha-ketoglutarate; cancer stem cell; epitranscriptomics; glioblastoma; m6A; malate-aspartate shuttle; metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.014
  21. Cell Metab. 2024 Oct 26. pii: S1550-4131(24)00410-8. [Epub ahead of print]
    Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase.
    Joyce Y Liu, Ramya S Kuna, Laura V Pinheiro, Phuong T T Nguyen, Jaclyn E Welles, Jack M Drummond, Nivitha Murali, Prateek Sharma, Julianna G Supplee, Mia Shiue, Steven Zhao, Aimee T Farria, Avi Kumar, Mauren L Ruchhoeft, Christina Demetriadou, Daniel S Kantner, Adam Chatoff, Emily Megill, Paul M Titchenell, Nathaniel W Snyder, Christian M Metallo, Kathryn E Wellen.
      ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in metabolic dysfunction-associated steatotic liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol-lowering drug bempedoic acid (BPA), which also improves steatosis in mice. While BPA potently suppresses hepatic DNL and increases fat catabolism, it is unclear if ACLY is its primary molecular target in reducing liver triglyceride. We show that on a Western diet, loss of hepatic ACLY alone or together with the acetyl-CoA synthetase ACSS2 unexpectedly exacerbates steatosis, linked to reduced PPARα target gene expression and fatty acid oxidation. Importantly, BPA treatment ameliorates Western diet-mediated triacylglyceride accumulation in both WT and liver ACLY knockout mice, indicating that its primary effects on hepatic steatosis are ACLY independent. Together, these data indicate that hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation and that BPA exerts substantial effects on hepatic lipid metabolism independently of ACLY.
    Keywords:  ACLY; ACSS2; PPARα; bempedoic acid; lipid metabolism; metabolic dysfunction-associated steatotic liver disease
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.014
  22. Cureus. 2024 Sep;16(9): e70332
    Exploring the Impact of Fasting and Fasting-Mimicking Diets on Type 2 Diabetes Management in Adults: A Systematic Review.
    José Amilcar Rivera Regalado, Juan García, Isabella Ramirez, Plinio Hermosilla, Jose Rascon, Sergio José Fausto Girón.
      Type 2 diabetes poses significant global health challenges, affecting both the quality of life and healthcare systems. This systematic review evaluates the efficacy of fasting and fasting-mimicking diets (FMD) in managing type 2 diabetes, with a focus on their effects on glycemic control, lipid profiles, and overall metabolic health in adult patients. A comprehensive search of PubMed and Cochrane Library databases identified several studies utilizing various fasting protocols, including intermittent fasting and FMD. Data synthesis and bias assessment were conducted using established methodologies, including the Cochrane Risk of Bias 2 (RoB 2) tool. The review found that fasting interventions significantly improve glycemic control and reduce body weight, with some protocols notably lowering HbA1c levels (p<0.05), highlighting the strong potential of fasting in diabetes management. However, the results varied, suggesting that individual differences in metabolic responses and adherence levels influence outcomes. In conclusion, while fasting and FMD show promise for improving metabolic health and managing diabetes, more standardized research is needed to understand the underlying mechanisms, optimize protocols, and confirm long-term benefits. Future research should prioritize larger sample sizes and extended follow-up periods to inform comprehensive clinical practice guidelines.
    Keywords:  diabetes; fasting diet; fasting-mimicking diet; systematic review; type 2 diabetes
    DOI:  https://doi.org/10.7759/cureus.70332
  23. Anal Chem. 2024 Nov 01.
    Mass Spectrometry Probe Combined with Machine Learning to Capture the Relationship between Metabolites and Mitochondrial Complex Activity at the Whole-Cell Level.
    Jia-Yi Zheng, Xiao-Yuan Ji, An-Qi Zhao, Fang-Yuan Sun, Li-Fang Liu, Gui-Zhong Xin.
      Mitochondrial complex activity controls a multitude of physiological processes by regulating the cellular metabolism. Current methods for evaluating mitochondrial complex activity mainly focus on single metabolic reactions within mitochondria. These methods often require fresh samples in large quantities for mitochondria purification or intact mitochondrial membranes for real-time monitoring. Confronting these limitations, we shifted the analytical perspective toward interactive metabolic networks at the whole-cell level to reflect mitochondrial complex activity. To this end, we compiled a panel of mitochondrial respiratory chain-mapped metabolites (MRCMs), whose perturbations theoretically provide an overall reflection on mitochondrial complex activity. By introducing N-dimethyl-p-phenylenediamine and N-methyl-p-phenylenediamine as a pair of mass spectrometry probes, an ultraperformance liquid chromatography-tandem mass spectrometry method with high sensitivity (LLOQ as low as 0.2 fmol) was developed to obtain accurate quantitative data of MRCMs. Machine learning was then combined to capture the relationship between MRCMs and mitochondrial complex activity. Using Complex I as a proof-of-concept, we identified NADH, alanine, and phosphoenolpyruvate as metabolites associated with Complex I activity based on the whole-cell level. The effectiveness of using their concentrations to reflect Complex I activity was further validated in external data sets. Hence, by capturing the relationship between metabolites and mitochondrial complex activity at the whole-cell level, this study explores a novel analytical paradigm for the interrogation of mitochondrial complex activity, offering a favorable complement to existing methods particularly when sample quantities, type, and treatment timeliness pose challenges. More importantly, it shifts the focus from individual metabolic reactions within mitochondria to a more comprehensive view of an interactive metabolic network, which should serve as a promising direction for future research into the functional architecture between mitochondrial complexes and metabolites.
    DOI:  https://doi.org/10.1021/acs.analchem.4c04376
  24. Foods. 2024 Oct 10. pii: 3219. [Epub ahead of print]13(20):
    Is a Meta-Analysis of Clinical Trial Outcomes for Ketogenic Diets Justifiable? A Critical Assessment Based on Systematic Research.
    Nicole Hunter, László Czina, Edit Murányi, Balázs Németh, Tímea Varjas, Katalin Szendi.
      While the macronutrient content of a ketogenic diet specifically utilized for childhood epilepsy is clearly defined in the literature, variations among other ketogenic diets exhibit substantial heterogeneity. Furthermore, studies utilizing ketogenic diets contain several confounders with notable impacts on outcomes, thereby rendering both their findings and those of the meta-analyses less reliable. The objective of this meta-epidemiological assessment was to scrutinize existing clinical trials that investigated the effects of ketogenic diets on patients with obesity and diabetes, thereby determining the feasibility of conducting a meta-analysis. The Ovid Medline, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase databases were searched from 1946 to 24 September 2024. Of the studies reviewed, none met the predefined inclusion criteria. However, seven articles met these criteria very closely. In the future, studies investigating the effects of ketogenic diets containing significant confounding factors should adopt a single definition of a ketogenic diet. Additionally, accurate measurement of actual macronutrient and caloric intake, along with regularly monitored nutritional ketosis, will be essential to highlight the true effects of a ketogenic diet.
    Keywords:  clinical trial; ketogenic diet; meta-epidemiological assessment; nutritional ketosis; review; systematic search
    DOI:  https://doi.org/10.3390/foods13203219
  25. Front Nutr. 2024 ;11 1485642
    Mapping the evolution and impact of ketogenic diet research on diabetes management: a comprehensive bibliometric analysis from 2005 to 2024.
    Zonghuai Li, Anxia Li, Pingping Liu, Bo Zhang, Yuanyuan Yan.
       Objective: The ketogenic diet (KD) has been explored for diabetes management; however, a quantitative synthesis of its specific effects on diabetes has not yet been conducted. This study aims to examine the current status and research hotspots of KD in diabetes management from 2005 to 2024, providing a reference for future research.
    Methods: We retrieved articles published between 2005 and 2024 from the Web of Science database and analyzed them using R software, VOSviewer, and CiteSpace.
    Results: This study includes 432 relevant publications. From 2005 to 2024, the volume of literature in this field has shown a steady upward trend, with a notable increase from 2017 to 2021, and a slight decline observed from 2021 to 2023. The United States is the leading country in terms of the number of publications, followed by China, Australia, and Canada. The United States not only leads in publication volume but also maintains a broader international collaboration network. Nutrients and the American Journal of Clinical Nutrition are the most frequently published and cited journals. Current research hotspots primarily focus on the impact of KD on blood glucose control, insulin resistance, and lipid metabolism in diabetic patients. Mechanistic studies on KD in diabetes management concentrate on aspects such as the "regulation of genes by β-hydroxybutyrate," "anti-inflammatory effects," and "oxidative stress." The role of the gut microbiome is also emerging as an important research area. Currently, exploring the application of KD in managing different age groups and types of diabetes has become a significant research trend.
    Conclusion: As an emerging dietary intervention, KD is gradually attracting widespread attention from researchers around the world and is expected to become a major research focus in the future for diabetes management and control. This paper provides a systematic review and analysis of the current research status and hotspots of KD in diabetes management, offering important references and insights for future research in related fields.
    Keywords:  bibliometrics; diabetes; gut microbiome; insulin resistance; ketogenic diet
    DOI:  https://doi.org/10.3389/fnut.2024.1485642
  26. BMC Res Notes. 2024 Oct 28. 17(1): 325
    Empirical dietary inflammatory pattern could increase the odds of breast cancer: a case-control study.
    Masoud Amini Kahrizsangi, Pegah Hadi Sichani, Zainab Shateri, Ava Mashoufi, Mehran Nouri, Hossein Firoozbakht, Bahram Rashidkhani.
       BACKGROUND: It has been shown that chronic inflammation is a significant factor in cancer development and progression. The current study aimed to investigate whether a higher score on the empirical dietary inflammatory pattern (EDIP), which indicates a more pro-inflammatory diet, is related to higher odds of breast cancer in Iranian women.
    METHODS: In the present case-control study, subjects in the case (n = 133) and control (n = 265) groups were chosen from the hospitals in Tehran, Iran. The cases consisted of women with newly diagnosed breast cancer, while the controls were selected from other parts of the same hospital and had no history of cancer or hormone therapy. Individuals whose reported energy intake deviated by three standard deviations above or below the mean energy intake of the population were excluded from the study. A reliable and valid semi-quantitative food frequency questionnaire was used to determine the participants' dietary intake. Additionally, the association between breast cancer and EDIP was evaluated by logistic regression analysis in both crude and adjusted models.
    RESULTS: The median scores of EDIP in the case and control groups were 0.65 and 0.61, respectively. The findings also indicated that, in the adjusted model, the odds of developing breast cancer significantly increased in the last tertile of EDIP compared to the first tertile (odds ratio (OR) = 1.859; 95% confidence interval (CI): 1.059-3.265; P = 0.031). Additionally, after adjusting for potential confounders, higher odds of breast cancer were observed in the last tertile of EDIP compared to the first tertile in postmenopausal women (OR = 2.516; 95% CI: 1.081-5.856; P = 0.033).
    CONCLUSIONS: The current study indicated that individuals with a higher pro-inflammatory diet score were more likely to develop breast cancer.
    Keywords:  Breast cancer; Empirical dietary inflammatory pattern; Iran
    DOI:  https://doi.org/10.1186/s13104-024-06985-4
  27. Cancer Epidemiol Biomarkers Prev. 2024 Oct 31.
    Diet changes and colorectal cancer risk in the UK Biobank.
    Tung Hoang, Sooyoung Cho, Aesun Shin.
       BACKGROUND: Modifying dietary behaviors into healthier habits may attenuate the risk of colorectal cancer (CRC) risk. This study aimed to investigate the association between dietary changes and the risk of CRC.
    METHODS: Following dietary recommendations for red and processed meat, fruit and vegetables, and alcohol consumption, we classified 50,640 participants into poor and good adherence groups in the UK Biobank. Changes in dietary habits were defined as stable poor, poor to good, good to poor, and stable to good adherence. A Cox proportional hazard model was used to examine the association between dietary changes and CRC risk.
    RESULTS: Women were more likely to follow dietary recommendations than men. After a median of 3.3 years from the latest follow-up, 8,328 (16.4%) participants followed an improved dietary habit and 5,808 (11.5%) participants had a worsened diet. Compared to men who stably consumed fruit and vegetables <5 servings/day, those who increased their consumption to ≥5 servings/day were related to CRC risk reduction (hazard ratio: 0.24, [0.09-0.63]). However, the beneficial associations of increased fruit and vegetable consumption were not statistically significant in women (hazard ratio: 0.41, [0.11-1.56]).
    CONCLUSIONS: Our findings support the evidence that increasing fruit and vegetable intake could serve as a beneficial strategy to mitigate CRC risk in men.
    IMPACT: Participants from the UK Biobank significantly changes their adherence to dietary recommendations during the follow-up. Increasing fruit and vegetable consumption was inversely associated with CRC risk among men.
    DOI:  https://doi.org/10.1158/1055-9965.EPI-24-0847
  28. bioRxiv. 2024 Oct 25. pii: 2024.10.24.616714. [Epub ahead of print]
    Site of breast cancer metastasis is independent of single nutrient levels.
    Keene L Abbott, Sonu Subudhi, Raphael Ferreira, Yetiş Gültekin, Sophie C Steinbuch, Muhammad Bin Munim, Sophie E Honeder, Ashwin S Kumar, Diya L Ramesh, Michelle Wu, Jacob A Hansen, Sharanya Sivanand, Lisa M Riedmayr, Mark Duquette, Ahmed Ali, Nicole Henning, Anna Shevzov-Zebrun, Florian Gourgue, Anna M Barbeau, Millenia Waite, Tenzin Kunchok, Gino B Ferraro, Brian T Do, Virginia Spanoudaki, Francisco J Sánchez-Rivera, Xin Jin, George M Church, Rakesh K Jain, Matthew G Vander Heiden.
      Cancer metastasis is a major contributor to patient morbidity and mortality 1 , yet the factors that determine the organs where cancers can metastasize are incompletely understood. In this study, we quantify the absolute levels of over 100 nutrients available across multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different organs. We then asked how tumor growth in different tissues relates to nutrient availability and tumor biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. Additionally, we identify purine synthesis as a requirement for tumor growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumor de novo nucleotide synthesis activity. These data suggest that a complex interplay of multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases.
    DOI:  https://doi.org/10.1101/2024.10.24.616714
  29. Food Sci Nutr. 2024 Oct;12(10): 7788-7797
    Dietary advanced glycation end-products (dAGEs) are not associated with the risk of cancer incidence. A systematic review and meta-analysis of prospective cohort studies.
    Elham Sharifi-Zahabi, Sepideh Soltani, Fatemeh Hajizadeh-Sharafabad, Hadi Abdollahzad.
      A growing body of evidence indicates the association of dietary advanced glycation end-products (dAGEs) with the risk of cancer. This systematic review and meta-analysis aimed to assess the overall association between dAGEs and cancer incidence. An extensive search was carried out through online databases including PubMed, Scopus, and Web of Science up to June 2024. All reported HRs and their 95% CIs for risk of cancer were used to estimate log HRs and their standard errors (SEs). The overall risk estimate was obtained using a random effects model. Inter-study heterogeneity was determined using Cochrane's Q test and I-squared. Five prospective cohort studies with a total of 1,220,096 participants and 23,229 incident cancer cases (2193 pancreatic cancers, 11,443 breast cancers, 6162 colorectal cancers, and 3431 total cancers) were included in this meta-analysis. Compared with the lowest category of dAGEs, the pooled hazard ratio (HR) for overall cancers was 1.04 (95% CI: 0.94, 1.15; I 2 = 67.9%) for the highest category of dAGEs. Pooled estimates for different types of cancer showed no significant relationship between dAGEs and risk of breast cancer (HR: 1.119; 95% CI: 0.868, 1.444; I 2 = 77.6%; N = 2 studies), pancreatic cancer (HR: 1.242; 95% CI: 0.971, 1.588; I 2 = 0.0%; N = 2 studies), colon cancer (HR: 10.985; 95% CI: 0.887, 1.094; I 2 = 0.0%; N = 2 studies) and rectal cancer (HR: 0.940; 95% CI: 0.616, 1.433; I 2 = 57.7%; N = 2 studies). Dietary AGEs had no significant link with cancer risk. More well-designed prospective studies are required.
    Keywords:  AGEs; advanced glycation end‐products; cancer; systematic review
    DOI:  https://doi.org/10.1002/fsn3.4396
  30. Nutrients. 2024 Oct 18. pii: 3533. [Epub ahead of print]16(20):
    Is Fasting Superior to Continuous Caloric Restriction for Weight Loss and Metabolic Outcomes in Obese Adults? A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
    Víctor Siles-Guerrero, Jose M Romero-Márquez, Rosa Natalia García-Pérez, Cristina Novo-Rodríguez, Juan Manuel Guardia-Baena, María Hayón-Ponce, Carmen Tenorio-Jiménez, Martín López-de-la-Torre-Casares, Araceli Muñoz-Garach.
       BACKGROUND: fasting-based strategies (FBS) and continuous caloric restriction (CCR) are popular methods for weight loss and improving metabolic health. FBS alternates between eating and fasting periods, while CCR reduces daily calorie intake consistently. Both aim to create a calorie deficit, but it is still uncertain as to which is more effective for short- and long-term weight and metabolic outcomes.
    OBJECTIVES: this systematic review and meta-analysis aimed to compare the effectiveness of FBS and CCR on these parameters in obese adults.
    METHODS: after screening 342 articles, 10 randomized controlled trials (RCTs) with 623 participants were included.
    RESULTS: both interventions led to weight loss, with a reduction of 5.5 to 6.5 kg observed at the six-month mark. However, the results showed that FBS led to slightly greater short-term reductions in body weight (-0.94 kg, p = 0.004) and fat mass (-1.08 kg, p = 0.0001) compared to CCR, although these differences are not clinically significant. Both interventions had similar effects on lean mass, waist and hip circumference, blood pressure, lipid profiles, and glucose metabolism. However, FBS improved insulin sensitivity, with significant reductions in fasting insulin (-7.46 pmol/L, p = 0.02) and HOMA-IR (-0.14, p = 0.02).
    CONCLUSIONS: despite these short-term benefits, FBS did not show superior long-term outcomes compared to CCR. Both strategies are effective for weight management, but more research is needed to explore the long-term clinical relevance of FBS in obese populations.
    Keywords:  caloric deficit; daily caloric restriction; intermittent fasting; obesity; time restricted fasting; time restricted feeding; weight reduction
    DOI:  https://doi.org/10.3390/nu16203533
  31. bioRxiv. 2024 Oct 21. pii: 2024.10.18.619082. [Epub ahead of print]
    ACSS2 regulates ferroptosis in an E2F1-dependent manner in breast cancer brain metastatic cells.
    Emily M Esquea, Riley G Young, Lorela Ciraku, Jessica Merzy, Nusaiba N Ahmed, Alexandra N Talarico, Mangalam Karuppiah, Wiktoria Gocal, Nicole L Simone, Alexej Dick, Mauricio J Reginato.
      Brain metastasis diagnosis in breast cancer patients is considered an end-stage event. The median survival after diagnosis is measured in months, thus there is an urgent need to develop novel treatment strategies. Breast cancers that metastasize to the brain must adapt to the unique brain environment and are highly dependent on acetate metabolism for growth and survival. However, the signaling pathways that regulate survival in breast cancer brain metastatic (BCBM) tumors are not known. Primary brain tumor cells can convert acetate to acetyl-CoA via phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by the cyclin-dependent kinase-5 (CDK5) regulated by the nutrient sensor O-GlcNAc transferase (OGT). Here, we show that breast cancer cells selected to metastasize to the brain contain increased levels of O-GlcNAc, OGT and ACSS2-Ser267 phosphorylation compared to parental breast cancer cells. Moreover, OGT and CDK5 are required for breast cancer cell growth in the brain parenchyma in vivo. Importantly, ACSS2 and ACSS2-S267D phospho-mimetic mutant are critical for in vivo breast cancer growth in the brain but not in the mammary fat pad. Mechanistically, we show that ACSS2 regulates BCBM cell survival by suppressing ferroptosis via regulation of E2F1-mediated expression of anti-ferroptotic proteins SLC7A11 and GPX4. Lastly, we show treatment with a novel brain-permeable small molecule ACSS2 inhibitor induced ferroptosis and reduced BCBM growth ex vivo and in vivo . These results suggest a crucial role for ACSS2 in protecting from ferroptosis in breast cancer brain metastatic cells and suggests that breast cancer brain metastatic cells may be susceptible to ferroptotic inducers.
    DOI:  https://doi.org/10.1101/2024.10.18.619082
  32. Expert Rev Hematol. 2024 Oct 30.
    A review of the isocitrate dehydrogenase inhibitors in management of adult patients with AML and MDS.
    Mallory Norman, Katelyn Yamartino, Rachel Gerstein, Rory Shallis, Lourdes Mendez, Nikolai Podoltsev, Maximilian Stahl, William Eighmy, Amer Zeidan.
       INTRODUCTION: The development of oral therapies impacts management of acute myeloid leukemia and myelodysplastic syndromes, especially for targetable mutations including IDH1/2.
    AREAS COVERED: We discuss IDH1/2 activity and inhibitor therapy in various settings, including as monotherapy, combination therapy with hypomethylating agents, and other approaches.
    EXPERT OPINION: Olutasidenib, enasidenib, and ivosidenib are approved for relapsed AML. Ivosidenib is approved for relapsed MDS and alone or with azacitidine in newly diagnosed AML. However, unanswered questions exist. In newly diagnosed AML ivosidenib + azacitidine shows a survival benefit compared to azacitidine but it is unknown whether ivosidenib + azacitidine demonstrates improved survival compared to ivosidenib. Ivosidenib + azacitidine demonstrated a survival benefit not seen with enasidenib + azacitidine. It is unclear whether newly diagnosed AML should be treated with azacitidine + ivosidenib or azacitidine + venetoclax. Azacitidine + venetoclax shows excellent response rates in IDH mutated disease. Retrospective data shows low response rates of IDH inhibitor therapy post venetoclax whereas HMA + venetoclax retains activity post IDH inhibition. The role of IDH inhibition post-transplant is unclear. Single arm studies show post-transplant maintenance is safe, however, randomized trials are needed. Similarly, IDH inhibitors can be combined with chemotherapy however randomized studies are needed.
    Keywords:  IDH mutation; Leukemia; MDS; hematology; oral therapy
    DOI:  https://doi.org/10.1080/17474086.2024.2422554
  33. Nat Genet. 2024 Oct 28.
    Obesity-dependent selection of driver mutations in cancer.
    Cerise Tang, Venise Jan Castillon, Michele Waters, Chris Fong, Tricia Park, Sonia Boscenco, Susie Kim, Kelly Pekala, Jian Carrot-Zhang, A Ari Hakimi, Nikolaus Schultz, Irina Ostrovnaya, Alexander Gusev, Justin Jee, Ed Reznik.
      Obesity is a risk factor for cancer, but whether obesity is linked to specific genomic subtypes of cancer is unknown. We examined the relationship between obesity and tumor genotype in two clinicogenomic corpora. Obesity was associated with specific driver mutations in lung adenocarcinoma, endometrial carcinoma and cancers of unknown primaries, independent of clinical covariates, demographic factors and genetic ancestry. Obesity is therefore a driver of etiological heterogeneity in some cancers.
    DOI:  https://doi.org/10.1038/s41588-024-01969-3
  34. bioRxiv. 2024 Sep 29. pii: 2024.09.29.615681. [Epub ahead of print]
    Glutamate Transport Proteins and Metabolic Enzymes are Poor Prognostic Factors in Invasive Lobular Carcinoma.
    Todd A Young, Shaymaa Bahnassy, Theresa C Abalum, Eden A Pope, Amanda Torres Rivera, Aileen I Fernandez, Ayodeji O Olukoya, Dua Mobin, Suman Ranjit, Nicole E Libbey, Sonali Persaud, Aaron M Rozeboom, Krysta Chaldekas, Brent T Harris, Zeynep Madak-Erdogan, Joseph L Sottnik, Matthew J Sikora, Rebecca B Riggins.
      Invasive Lobular Carcinoma (ILC) is a subtype of breast cancer characterized by distinct biological features, and limited glucose uptake coupled with increased reliance on amino acid and lipid metabolism. Our prior studies highlight the importance of glutamate as a key regulator of ILC tumor growth and therapeutic response. Here we examine the expression of four key proteins involved in glutamate transport and metabolism - SLC3A2, SLC7A11, GPX4, and GLUD1/2 - in a racially diverse cohort of 72 estrogen receptor-positive (ER+) ILC and 50 ER+ invasive ductal carcinoma, no special type (IDC/NST) patients with primary disease. All four proteins are associated with increased tumor size in ILC, but not IDC/NST, with SLC3A2 also specifically linked to shorter overall survival and the presence of comorbidities in ILC. Notably, GLUD1/2 expression is associated with ER expression in ILC, and is most strongly associated with increased tumor size and stage in Black women with ILC from our cohort and TCGA. We further explore the effects of GLUD1 inhibition in endocrine therapy-resistant ILC cells using the small-molecule inhibitor R162, which reduces ER protein levels, increases reactive oxygen species, and inhibits oxidative phosphorylation. These findings highlight a potentially important role for glutamate metabolism in ILC, particularly for Black women, and position several of these glutamate-handling proteins as potential targets for therapeutic intervention in ILC.
    Keywords:  GLUD1; GPX4; Invasive lobular carcinoma; disparities; glutamate metabolism
    DOI:  https://doi.org/10.1101/2024.09.29.615681
  35. Sci Adv. 2024 Nov;10(44): eadp3481
    High mitochondrial DNA levels accelerate lung adenocarcinoma progression.
    Mara Mennuni, Stephen E Wilkie, Pauline Michon, David Alsina, Roberta Filograna, Markus Lindberg, David E Sanin, Florian Rosenberger, Alina Schaaf, Erik Larsson, Erika L Pearce, Nils-Göran Larsson.
      Lung adenocarcinoma is a common aggressive cancer and a leading cause of mortality worldwide. Here, we report an important in vivo role for mitochondrial DNA (mtDNA) copy number during lung adenocarcinoma progression in the mouse. We found that lung tumors induced by KRASG12D expression have increased mtDNA levels and enhanced mitochondrial respiration. To experimentally assess a possible causative role in tumor progression, we induced lung cancer in transgenic mice with a general increase in mtDNA copy number and found that they developed a larger tumor burden, whereas mtDNA depletion in tumor cells reduced tumor growth. Immune cell populations in the lung and cytokine levels in plasma were not affected by increased mtDNA levels. Analyses of large cancer databases indicate that mtDNA copy number is also important in human lung cancer. Our study thus reports experimental evidence for a tumor-intrinsic causative role for mtDNA in lung cancer progression, which could be exploited for development of future cancer therapies.
    DOI:  https://doi.org/10.1126/sciadv.adp3481
  36. Cell Death Dis. 2024 Oct 25. 15(10): 774
    One-carbon-mediated purine synthesis underlies temozolomide resistance in glioblastoma.
    Kimia Ghannad-Zadeh, Alyona Ivanova, Megan Wu, Taylor M Wilson, Alyssa Lau, Robert Flick, David G Munoz, Sunit Das.
      Glioblastoma accounts for nearly half of all primary malignant brain tumors in adults, and despite an aggressive standard of care, including excisional surgery and adjuvant chemoradiation, recurrence remains universal, with an overall median survival of 14.6 months. Recent work has revealed the importance of passenger mutations as critical mediators of metabolic adaptation in cancer progression. In our previous work, we identified a role for the epigenetic modifier ID-1 in temozolomide resistance in glioblastoma. Here, we show that ID-1-mediated glioblastoma tumourigenesis is accompanied by upregulation of one-carbon (1-C) mediated de novo purine synthesis. ID-1 knockout results in a significant reduction in the expression of 1-C metabolism and purine synthesis enzymes. Analysis of glioblastoma surgical specimens at initial presentation and recurrence reveals that 1-C purine synthesis metabolic enzymes are enriched in recurrent glioblastoma and that their expression correlates with a shorter time to tumor recurrence. Further, we show that the 1-C metabolic phenotype underlies proliferative capacity and temozolomide resistance in glioblastoma cells. Supplementation with exogenous purines restores proliferation in ID-1-deficient cells, while inhibition of purine synthesis with AICAR sensitizes temozolomide-resistant glioblastoma cells to temozolomide chemotherapy. Our data suggest that the metabolic phenotype observed in treatment-resistant glioma cells is a potential therapeutic target in glioblastoma.
    DOI:  https://doi.org/10.1038/s41419-024-07170-y
  37. Clin Transl Oncol. 2024 Oct 28.
    Treatment approaches and survival outcomes in elderly colorectal cancer patients: a single-center comparative study.
    Beliz Bahar Karaoğlan, Erman Akkuş, Mehmet Kayaalp, Cihangir Akyol, Ayhan Bülent Erkek, Hakan Akbulut, Güngör Utkan.
       BACKGROUND: Geriatric patients account for nearly half of new colorectal cancer (CRC) cases. This study compares clinicopathological features, treatments, outcomes, and frailty in elderly (≥ 70) and younger (< 70) CRC patients at our center.
    MATERIALS AND METHODS: Patients diagnosed with non-metastatic or de novo metastatic CRC between January 2015 and April 2024 were included. Demographic, pathological, and survival data were retrospectively collected. Analyses were performed using SPSS version 25, with statistical significance set at P < 0.05.
    RESULTS: Of the 414 non-metastatic CRC patients, 26.6% were aged ≥ 70. Elderly patients received less perioperative chemotherapy (60% vs. 81.6%, P < 0.001) and had more dose reductions (41.6% vs. 19.2%, P < 0.001). Frailty reduced perioperative chemotherapy in elderly non-metastatic patients (54.5% vs. 92.1%, P < 0.001) but did not affect dose reduction (37.9% vs. 33.3%, P = 0.764) or treatment duration (median 24 weeks for both groups, P = 0.909). In metastatic patients, frailty shortened chemotherapy duration (9.5 vs. 15.5 weeks, P = 0.129). Elderly patients had lower 5- and 8-year overall survival (OS) rates (64.7%, 60.1% vs. 83.0%, 78.8%, P = 0.004). In the de novo metastatic cohort (135 patients), age did not affect OS (19.4 vs. 17.3 months, P = 0.590) or PFS (9.8 vs. 7.5 months, P = 0.209). Rectal cancer (HR: 2.751, P = 0.005) and early chemotherapy termination (HR: 4.138, P < 0.001) worsened OS in non-metastatic CRC, while absence of RAS (HR: 2.043, P = 0.047), BRAF mutations (HR: 8.263, P = 0.010), and metastasectomy (HR: 3.650, P = 0.036) improved OS in metastatic CRC.
    CONCLUSION: Age does not independently worsen CRC survival, though early chemotherapy discontinuation impacts outcomes. Reduced-dose chemotherapy or monotherapy can help minimize adverse effects in elderly patients.
    Keywords:  Chemotherapy dose reduction; Colorectal cancer; Elderly; Fraility; Geriatric oncology
    DOI:  https://doi.org/10.1007/s12094-024-03758-0
  38. bioRxiv. 2024 Oct 18. pii: 2024.10.15.618560. [Epub ahead of print]
    Branched-chain amino acid catabolism promotes ovarian cancer cell proliferation via phosphorylation of mTOR.
    Hannah J Lusk, Monica A Haughan, Tova M Bergsten, Joanna E Burdette, Laura M Sanchez.
      Ovarian cancer is the sixth leading cause of cancer-related mortality among individuals with ovaries, and high-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype. Characterized by a distinct and aggressive metastatic pattern, HGSOC can originate in the fallopian tube with the transformation of fallopian tube epithelial (FTE) cells, which metastasize to the ovary and subsequently to the omentum and peritoneal cavity. The omentum is a privileged metastatic site, and the metabolic exchange underlying omental metastasis could provide enzyme or receptor targets to block spread. In this study, we adapted a mass spectrometry imaging (MSI) protocol to investigate spatial location of 3D cocultures of tumorigenic FTE cells when grown in proximity to murine omental explants as a model of early metastatic colonization. Our analysis revealed several altered metabolites in tumorigenic FTE/omentum cocultures, namely changes in branched-chain amino acids (BCAA), including valine. We quantified the heightened consumption of valine, other BCAAs, and other amino acid-derived metabolites in omental cocultures using LC-MS assays. Our analysis revealed that metabolite concentrations when monitored with MSI from cell culture media in living culture systems have notable considerations for how MSI data may produce signatures that induce ionization suppression. Supplementation with valine enhanced proliferation and mTOR signaling in tumorigenic FTE cells, suggesting the potential of BCAA's as a nutrient utilized by tumor cells during omental colonization and a possible target for metastasis.
    Keywords:  branched-chain amino acids; fallopian tube; mass spectrometry imaging; metabolomics; omental metastasis; ovarian cancer
    DOI:  https://doi.org/10.1101/2024.10.15.618560
  39. bioRxiv. 2024 Oct 24. pii: 2024.10.24.619506. [Epub ahead of print]
    Optical control of sphingolipid biosynthesis using photoswitchable sphingosines.
    Matthijs Kol, Alexander J E Novak, Johannes Morstein, Christian Schröer, Tolulope Sokoya, Svenja Mensing, Sergei M Korneev, Dirk Trauner, Joost C M Holthuis.
      Sphingolipid metabolism comprises a complex interconnected web of enzymes, metabolites and modes of regulation that influence a wide range of cellular and physiological processes. Deciphering the biological relevance of this network is challenging as numerous intermediates of sphingolipid metabolism are short-lived molecules with often opposing biological activities. Here, we introduce clickable, azobenzene-containing sphingosines, termed caSph s, as light-sensitive substrates for sphingolipid biosynthesis. Photo-isomerization of the azobenzene moiety enables reversible switching between a straight trans - and curved cis -form of the lipid's hydrocarbon tail. Combining in vitro enzyme assays with metabolic labeling studies, we demonstrate that trans -to- cis isomerization of caSph s profoundly stimulates their metabolic conversion by ceramide synthases and downstream sphingomyelin synthases. These light-induced changes in sphingolipid production rates are acute, reversible, and can be implemented with great efficiency in living cells. Our findings establish caSph s as versatile tools with unprecedented opportunities to manipulate sphingolipid biosynthesis and function with the spatiotemporal precision of light.
    DOI:  https://doi.org/10.1101/2024.10.24.619506
  40. J Cachexia Sarcopenia Muscle. 2024 Oct 31.
    Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes.
    Makayla S Lancaster, Paul Hafen, Andrew S Law, Catalina Matias, Timothy Meyer, Kathryn Fischer, Marcus Miller, Chunhai Hao, Patrick Gillespie, David McKinzie, Jeffrey J Brault, Brett H Graham.
       BACKGROUND: Pathogenic variants in subunits of succinyl-CoA synthetase (SCS) are associated with mitochondrial encephalomyopathy in humans. SCS catalyses the conversion of succinyl-CoA to succinate coupled with substrate-level phosphorylation of either ADP or GDP in the TCA cycle. This report presents a muscle-specific conditional knock-out (KO) mouse model of Sucla2, the ADP-specific beta subunit of SCS, generating a novel in vivo model of mitochondrial myopathy.
    METHODS: The mouse model was generated using the Cre-Lox system, with the human skeletal actin (HSA) promoter driving Cre-recombination of a CRISPR-Cas9-generated Sucla2 floxed allele within skeletal muscle. Inactivation of Sucla2 was validated using RT-qPCR and western blot, and both enzyme activity and serum metabolites were quantified by mass spectrometry. To characterize the model in vivo, whole-body phenotyping was conducted, with mice undergoing a panel of strength and locomotor behavioural assays. Additionally, ex vivo contractility experiments were performed on the soleus (SOL) and extensor digitorum longus (EDL) muscles. SOL and EDL cryosections were also subject to imaging analyses to assess muscle fibre-specific phenotypes.
    RESULTS: Molecular validation confirmed 68% reduction of Sucla2 transcript within the mutant skeletal muscle (p < 0.001) and 95% functionally reduced SUCLA2 protein (p < 0.0001). By 3 weeks of age, Sucla2 KO mice were 44% the size of controls by body weight (p < 0.0001). Mutant mice also exhibited 34%-40% reduced grip strength (p < 0.01) and reduced spontaneous exercise, spending about 88% less cumulative time on a running wheel (p < 0.0001). Contractile function was also perturbed in a muscle-specific manner; although no genotype-specific deficiencies were seen in EDL function, SUCLA2-deficient SOL muscles generated 40% less specific tetanic force (p < 0.0001), alongside slower contraction and relaxation rates (p < 0.001). Similarly, a SOL-specific threefold increase in mitochondria (p < 0.0001) was observed, with qualitatively increased staining for both COX and SDH, and the proportion of Type 1 myosin heavy chain expressing fibres within the SOL was nearly doubled (95% increase, p < 0.0001) in the Sucla2 KO mice compared with that in controls.
    CONCLUSIONS: SUCLA2 loss within murine skeletal muscle yields a model of SCS-deficient mitochondrial myopathy with reduced body weight, muscle weakness and exercise intolerance. Physiological and morphological analyses of hindlimb muscles showed remarkable differences in ex vivo function and cellular consequences between the EDL and SOL muscles, with SOL muscles significantly more impacted by Sucla2 inactivation. This novel model will provide an invaluable tool for investigations of muscle-specific and fibre type-specific pathogenic mechanisms to better understand SCS-deficient myopathy.
    Keywords:  contractility; extensor digitorum longus; fibre‐type switching; mitochondrial myopathy; soleus; succinyl‐CoA synthetase
    DOI:  https://doi.org/10.1002/jcsm.13617
  41. Sci Adv. 2024 Nov;10(44): eadp7725
    Membrane potential stimulates ADP import and ATP export by the mitochondrial ADP/ATP carrier due to its positively charged binding site.
    Vasiliki Mavridou, Martin S King, Andre Bazzone, Roger Springett, Edmund R S Kunji.
      The mitochondrial adenosine 5'-diphosphate (ADP)/adenosine 5'-triphosphate (ATP) carrier imports ADP into the mitochondrion and exports ATP to the cell. Here, we demonstrate that 3.3 positive charges are translocated with the negatively charged substrate in each transport step. They can be assigned to three positively charged residues of the central substrate-binding site and two asparagine/arginine pairs. In this way, the membrane potential stimulates not only the ATP4- export step, as a net -0.7 charge is transported, but also the ADP3- import step, as a net +0.3 charge is transported with the electric field. These positive charge movements also inhibit the import of ATP and export of ADP in the presence of a membrane potential, allowing these nucleotides to be maintained at high concentrations in the cytosol and mitochondrial matrix to drive the hydrolysis and synthesis of ATP, respectively. Thus, this is the mechanism by which the membrane potential drives adenine nucleotide exchange with high directional fluxes to fuel the cellular processes.
    DOI:  https://doi.org/10.1126/sciadv.adp7725
  42. Nucl Med Biol. 2024 Oct 24. pii: S0969-8051(24)00093-3. [Epub ahead of print]138-139 108967
    Cerebral and myocardial kinetics of [11C]acetoacetate and [11C]β-hydroxybutyrate: A comparative crossover study in healthy rats.
    Mette Louise Gram Kjærulff, Thien Vinh Luong, Gabriel Richard, Valérie St-Pierre, Esben Søndergaard, Niels Møller, Lars Christian Gormsen, Sébastien Tremblay, Etienne Croteau, Stephen C Cunnane.
       BACKGROUND: Ketone metabolism has been studied using positron emission tomography (PET) with the radiotracers [11C]acetoacetate and [11C]β-hydroxybutyrate. However, whether these two radiotracers actually yield equivalent estimates of cerebral and myocardial ketone metabolism has not yet been investigated. This study aimed to investigate and compare the kinetics of both tracers in the brain and heart of healthy rats under varying levels of circulating ketones at baseline and after a single-dose exogenous ketone ester (KE) supplement.
    METHODS: Six healthy Sprague-Dawley rats each underwent two scans with each tracer: one following oral KE administration and one with a placebo. Cerebral kinetic parameters (Ki, VT, and cerebral metabolic rate (CMR)) were obtained using the Patlak method, whereas myocardial kinetic parameters (K1, k2, and VT) were derived using a 1-tissue compartment model. Parameters were compared through mixed-effects, correlation, and Bland-Altman analyses.
    RESULTS: Global CMR increased 3-4-fold in the KE group versus placebo, with strong positive correlations between CMR and plasma ketone levels for both tracers. Correlations between [11C]acetoacetate and [11C]β-hydroxybutyrate were moderate and non-significant for relative cerebral uptake expressed as Ki (ρ = 0.40) and for VT (ρ = 0.38) but strongly positive for absolute uptake, CMR (r = 0.84), with a non-significant mean bias of -0.03. In contrast, myocardial kinetics showed only non-significant weak to moderate correlations between the radiotracers (K1 (r = 0.04), k2 (r = -0.27), and VT (ρ = 0.43)), with no systematic biases.
    CONCLUSION: [11C]acetoacetate and [11C]β-hydroxybutyrate can be used interchangeably for measuring global CMR in healthy rats but differ in certain cerebral and myocardial kinetics. Whether these findings are generalizable to pathological conditions warrants further studies to explore the kinetics of these tracers in disease models.
    Keywords:  Acetoacetate; Ketone bodies; Ketone metabolism; Positron emission tomography; Tracer kinetics; beta-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.nucmedbio.2024.108967
  43. Leukemia. 2024 Oct 29.
    Comparative small molecule screening of primary human acute leukemias, engineered human leukemia and leukemia cell lines.
    Safia Safa-Tahar-Henni, Karla Páez Martinez, Verena Gress, Nayeli Esparza, Élodie Roques, Florence Bonnet-Magnaval, Mélanie Bilodeau, Valérie Gagné, Eva Bresson, Sophie Cardin, Nehme El-Hachem, Isabella Iasenza, Gabriel Alzial, Isabel Boivin, Naoto Nakamichi, Anne-Cécile Soufflet, Cristina Mirela Pascariu, Jean Duchaine, Simon Mathien, Éric Bonneil, Kolja Eppert, Anne Marinier, Guy Sauvageau, Geneviève Deblois, Pierre Thibault, Josée Hébert, Connie J Eaves, Sonia Cellot, Frédéric Barabé, Brian T Wilhelm.
      Targeted therapeutics for high-risk cancers remain an unmet medical need. Here we report the results of a large-scale screen of over 11,000 molecules for their ability to inhibit the survival and growth in vitro of human leukemic cells from multiple sources including patient samples, de novo generated human leukemia models, and established human leukemic cell lines. The responses of cells from de novo models were most similar to those of patient samples, both of which showed striking differences from the cell-line responses. Analysis of differences in subtype-specific therapeutic vulnerabilities made possible by the scale of this screen enabled the identification of new specific modulators of apoptosis, while also highlighting the complex polypharmacology of anti-leukemic small molecules such as shikonin. These findings introduce a new platform for uncovering new therapeutic options for high-risk human leukemia, in addition to reinforcing the importance of the test sample choice for effective drug discovery.
    DOI:  https://doi.org/10.1038/s41375-024-02400-w
  44. PLoS Comput Biol. 2024 Oct 28. 20(10): e1012360
    Non-genetic differences underlie variability in proliferation among esophageal epithelial clones.
    Raúl A Reyes Hueros, Rodrigo A Gier, Sydney M Shaffer.
      Individual cells grown in culture exhibit remarkable differences in their growth, with some cells capable of forming large clusters, while others are limited or fail to grow at all. While these differences have been observed across cell lines and human samples, the growth dynamics and associated cell states remain poorly understood. In this study, we performed clonal tracing through imaging and cellular barcoding of an in vitro model of esophageal epithelial cells (EPC2-hTERT). We found that about 10% of clones grow exponentially, while the remaining have cells that become non-proliferative leading to a halt in the growth rate. Using mathematical models, we demonstrate two distinct growth behaviors: exponential and logistic. Further, we discovered that the propensity to grow exponentially is largely heritable through four doublings and that the less proliferative clones can become highly proliferative through increasing plating density. Combining barcoding with single-cell RNA-sequencing (scRNA-seq), we identified the cellular states associated with the highly proliferative clones, which include genes in the WNT and PI3K pathways. Finally, we identified an enrichment of cells resembling the highly proliferative cell state in the proliferating healthy human esophageal epithelium.
    DOI:  https://doi.org/10.1371/journal.pcbi.1012360
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