bims-medica 2024-01-28 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–01–28
thirty-one papers selected by
Brett Chrest, East Carolina University

Forward Genetic Screens Identify Mechanisms of Resistance to Small-Molecule Lactate Dehydrogenase Inhibitors.
Sucrose-Enriched and Carbohydrate-Free High-Fat Diets Distinctly Affect Substrate Metabolism in Oxidative and Glycolytic Muscles of Rats.
Oxygen and Iron Availability Shapes Metabolic Adaptations of Cancer Cells.
Targeting the Metabolic Paradigms in Cancer and Diabetes.
The imipridone ONC213 targets α-ketoglutarate dehydrogenase to induce mitochondrial stress and suppress oxidative phosphorylation in acute myeloid leukemia.
Mitochondrial complex I inhibition triggers NAD+-independent glucose oxidation via successive NADPH formation, "futile" fatty acid cycling, and FADH2 oxidation.
Distinguishing metabolic signals of liver tumors from surrounding liver cells using hyperpolarized 13 C MRI and gadoxetate.
A mouse model to study glutathione limitation in vivo.
Methodological Challenges and Confounders in Research on the Effects of Ketogenic Diets: A Literature Review of Meta-Analyses.
Transmembrane pH gradient imaging in rodent glioma models.
Metabolic heterogeneity in cancer.
Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms.
Reprogramming neuroblastoma by diet-enhanced polyamine depletion.
A ketogenic diet lowers myocardial fatty acid oxidation but does not affect oxygen consumption: a study in overweight humans.
A genetically-encoded fluorescent biosensor for visualization of acetyl-CoA in live cells.
Recent Advances in Electrochemical Detection of Cell Energy Metabolism.
In-vivo correlations of fluorescent or radioisotope glucose-analogs in imaging cancer metabolism.
IDH1-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation.
Venetoclax Combined with Intensive Chemotherapy: A New Hope for Refractory and/or Relapsed Acute Myeloid Leukemia?
Spatially resolved quantification of oxygen consumption rate in ex vivo lymph node slices.
Glutathione peroxidase 4 suppresses manganese-dependent oxidative stress to reduce colorectal tumorigenesis.
A continuous flow bioreactor system for high-throughput hyperpolarized metabolic flux analysis.
Targeting apoptosis and unfolded protein response: the impact of β-hydroxybutyrate in clear cell renal cell carcinoma under glucose-deprived conditions.
Lipids as mediators of cancer progression and metastasis.
Emerging pathophysiological roles of ketone bodies.
Oncogenic fatty acid metabolism rewires energy supply chain in gastric carcinogenesis.
A Comprehensive Metabolism-Related Gene Signature Predicts the Survival of Patients with Acute Myeloid Leukemia.
Erythrocyte metabolism.
Specific changes in amino acid profiles in monocytes of patients with breast, lung, colorectal and ovarian cancers.
Proline Metabolism in WHO G4 Gliomas Is Altered as Compared to Unaffected Brain Tissue.
Enhanced glucose utilization of skeletal muscle after 4 weeks of intermittent hypoxia in a mouse model of type 2 diabetes.

ACS Chem Biol. 2024 Jan 25.

Forward Genetic Screens Identify Mechanisms of Resistance to Small-Molecule Lactate Dehydrogenase Inhibitors.

Anderson R Frank, Florentina Vandiver, David G McFadden.

Altered metabolism is a hallmark of cancer; however, it has been difficult to specifically target metabolism in cancer for therapeutic benefit. Cancers with genetically defined defects in metabolic enzymes constitute a subset of cancers where targeting metabolism is potentially accessible. Hürthle cell carcinoma of the thyroid (HTC) tumors frequently harbor deleterious mitochondrial DNA (mtDNA) mutations in subunits of complex I of the mitochondrial electron transport chain (ETC). Previous work has shown that HTC models with deleterious mtDNA mutations exhibit mitochondrial ETC defects that expose lactate dehydrogenase (LDH) as a therapeutic vulnerability. Here, we performed forward genetic screens to identify mechanisms of resistance to small-molecule LDH inhibitors. We identified two distinct mechanisms of resistance: upregulation of an LDH isoform and a compound-specific resistance mutation. Using these tools, we demonstrate that the anticancer activity of LDH inhibitors in cell line and xenograft models of complex I mutant HTC is through on-target LDH inhibition.

DOI: https://doi.org/10.1021/acschembio.3c00663
Nutrients. 2024 Jan 18. pii: 286. [Epub ahead of print]16(2):

Sucrose-Enriched and Carbohydrate-Free High-Fat Diets Distinctly Affect Substrate Metabolism in Oxidative and Glycolytic Muscles of Rats.

Daniel Da Eira, Shailee Jani, Mateja Stefanovic, Rolando B Ceddia.

  Skeletal muscle substrate preference for fuel is largely influenced by dietary macronutrient availability. The abundance of dietary carbohydrates promotes the utilization of glucose as a substrate for energy production, whereas an abundant dietary fat supply elevates rates of fatty acid (FA) oxidation. The objective of this study was to determine whether an obesogenic, high-fat, sucrose-enriched (HFS) diet or a carbohydrate-free ketogenic diet (KD) exert distinct effects on fat, glucose, and ketone metabolism in oxidative and glycolytic skeletal muscles. Male Wistar rats were fed either a HFS diet or a KD for 16 weeks. Subsequently, the soleus (Sol), extensor digitorum longus (EDL), and epitrochlearis (Epit) muscles were extracted to measure palmitate oxidation, insulin-stimulated glucose metabolism, and markers of mitochondrial biogenesis, ketolytic capacity, and cataplerotic and anaplerotic machinery. Sol, EDL, and Epit muscles from KD-fed rats preserved their ability to elevate glycogen synthesis and lactate production in response to insulin, whereas all muscles from rats fed with the HFS diet displayed blunted responses to insulin. The maintenance of metabolic flexibility with the KD was accompanied by muscle-fiber-type-specific adaptive responses. This was characterized by the Sol muscle in KD-fed rats enhancing mitochondrial biogenesis and ketolytic capacity without elevating its rates of FA oxidation in comparison with that in HFS feeding. Conversely, in the Epit muscle, rates of FA oxidation were increased, whereas the ketolytic capacity was markedly reduced by the KD in comparison with that by HFS feeding. In the EDL muscle, the KD also increased rates of FA oxidation, although it did so without altering its ketolytic capacity when compared to HFS feeding. In conclusion, even though obesogenic and ketogenic diets have elevated contents of fat and alter whole-body substrate partitioning, these two dietary interventions are associated with opposite outcomes with respect to skeletal muscle metabolic flexibility.

Keywords:  ACAT1; OXCT; PGC-1α; TFAM; anaplerosis; insulin resistance; ketogenic diet; ketolysis

DOI:  https://doi.org/10.3390/nu16020286
World J Oncol. 2024 Feb;15(1): 28-37

Oxygen and Iron Availability Shapes Metabolic Adaptations of Cancer Cells.

Rui Wang, Aashiq Hussain, Quan Quan Guo, Xiao Wei Jin, Miao Miao Wang.

  The dynamic changes between glycolysis and oxidative phosphorylation (OXPHOS) for adenosine triphosphate (ATP) output, along with glucose, glutamine, and fatty acid utilization, etc., lead to the maintenance and selection of growth advantageous to tumor cell subgroups in an environment of iron starvation and hypoxia. Iron plays an important role in the three major biochemical reactions in nature: photosynthesis, nitrogen fixation, and oxidative respiration, which all require the participation of iron-sulfur proteins, such as ferredoxin, cytochrome b, and the complex I, II, III in the electron transport chain, respectively. Abnormal iron-sulfur cluster synthesis process or hypoxia will directly affect the function of mitochondrial electron transfer and mitochondrial OXPHOS. More research results have indicated that iron metabolism, oxygen availability and hypoxia-inducible factor mutually regulate the shift between glycolysis and OXPHOS. In this article, we make a perspective review to provide novel opinions of the regulation of glycolysis and OXPHOS in tumor cells.

Keywords:  Glycolysis; Iron; Metabolism; OXPHOS; Oxygen; Tumor

DOI:  https://doi.org/10.14740/wjon1739
Biomedicines. 2024 Jan 17. pii: 211. [Epub ahead of print]12(1):

Targeting the Metabolic Paradigms in Cancer and Diabetes.

Mira Bosso, Dania Haddad, Ashraf Al Madhoun, Fahd Al-Mulla.

  Dysregulated metabolic dynamics are evident in both cancer and diabetes, with metabolic alterations representing a facet of the myriad changes observed in these conditions. This review delves into the commonalities in metabolism between cancer and type 2 diabetes (T2D), focusing specifically on the contrasting roles of oxidative phosphorylation (OXPHOS) and glycolysis as primary energy-generating pathways within cells. Building on earlier research, we explore how a shift towards one pathway over the other serves as a foundational aspect in the development of cancer and T2D. Unlike previous reviews, we posit that this shift may occur in seemingly opposing yet complementary directions, akin to the Yin and Yang concept. These metabolic fluctuations reveal an intricate network of underlying defective signaling pathways, orchestrating the pathogenesis and progression of each disease. The Warburg phenomenon, characterized by the prevalence of aerobic glycolysis over minimal to no OXPHOS, emerges as the predominant metabolic phenotype in cancer. Conversely, in T2D, the prevailing metabolic paradigm has traditionally been perceived in terms of discrete irregularities rather than an OXPHOS-to-glycolysis shift. Throughout T2D pathogenesis, OXPHOS remains consistently heightened due to chronic hyperglycemia or hyperinsulinemia. In advanced insulin resistance and T2D, the metabolic landscape becomes more complex, featuring differential tissue-specific alterations that affect OXPHOS. Recent findings suggest that addressing the metabolic imbalance in both cancer and diabetes could offer an effective treatment strategy. Numerous pharmaceutical and nutritional modalities exhibiting therapeutic effects in both conditions ultimately modulate the OXPHOS-glycolysis axis. Noteworthy nutritional adjuncts, such as alpha-lipoic acid, flavonoids, and glutamine, demonstrate the ability to reprogram metabolism, exerting anti-tumor and anti-diabetic effects. Similarly, pharmacological agents like metformin exhibit therapeutic efficacy in both T2D and cancer. This review discusses the molecular mechanisms underlying these metabolic shifts and explores promising therapeutic strategies aimed at reversing the metabolic imbalance in both disease scenarios.

Keywords:  cancer; glutaminolysis; insulin resistance; metabolic shift; mitochondria; nutritional adjuvants; oxidative phosphorylation; therapy; type 2 diabetes

DOI:  https://doi.org/10.3390/biomedicines12010211
Cancer Res. 2024 Jan 24.

The imipridone ONC213 targets α-ketoglutarate dehydrogenase to induce mitochondrial stress and suppress oxidative phosphorylation in acute myeloid leukemia.

Yongwei Su, Jenna L Carter, Xinyu Li, Yu Fukuda, Ashley Gray, John Lynch, Holly Edwards, Jun Ma, Patrick Schreiner, Lisa Polin, Juiwanna Kushner, Sijana H Dzinic, Steven A Buck, Shondra M Pruett-Miller, Katie Hege Hurrish, Camenzind Robinson, Xinan Qiao, Shuang Liu, Shuangshuang Wu, Guan Wang, Jing Li, Joshua E Allen, Varun V Prabhu, Aaron D Schimmer, Dhananjay Joshi, Shiva Kalhor-Monfared, Iain D G Watson, Richard Marcellus, Methvin B Isaac, Rima Al-Awar, Jeffrey W Taub, Hai Lin, John D Schuetz, Yubin Ge.

Eradication of acute myeloid leukemia (AML) is therapeutically challenging; many patients succumb to AML despite initially responding to conventional treatments. Here, we showed that the imipridone ONC213 elicits potent antileukemia activity in a subset of AML cell lines and primary patient samples, particularly in leukemia stem cells, while producing negligible toxicity in normal hematopoietic cells. ONC213 suppressed mitochondrial respiration and elevated alpha-ketoglutarate by suppressing alpha-ketoglutarate dehydrogenase (α-KGDH) activity. Deletion of OGDH, which encodes α-KGDH, suppressed AML fitness and impaired oxidative phosphorylation, highlighting the key role for α-KGDH inhibition in ONC213-induced death. ONC213 treatment induced a unique mitochondrial stress response and suppressed de novo protein synthesis in AML cells. Additionally, ONC213 reduced translation of MCL-1, which contributed to ONC213-induced apoptosis. Importantly, a patient-derived xenograft from a relapsed AML patient was sensitivity to ONC213 in vivo. Collectively these findings support further development of ONC213 for treating AML.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2659
Geroscience. 2024 Jan 25.

Mitochondrial complex I inhibition triggers NAD+-independent glucose oxidation via successive NADPH formation, "futile" fatty acid cycling, and FADH2 oxidation.

Roman Abrosimov, Marius W Baeken, Samuel Hauf, Ilka Wittig, Parvana Hajieva, Carmen E Perrone, Bernd Moosmann.

  Inhibition of mitochondrial complex I (NADH dehydrogenase) is the primary mechanism of the antidiabetic drug metformin and various unrelated natural toxins. Complex I inhibition can also be induced by antidiabetic PPAR agonists, and it is elicited by methionine restriction, a nutritional intervention causing resistance to diabetes and obesity. Still, a comprehensible explanation to why complex I inhibition exerts antidiabetic properties and engenders metabolic inefficiency is missing. To evaluate this issue, we have systematically reanalyzed published transcriptomic datasets from MPP-treated neurons, metformin-treated hepatocytes, and methionine-restricted rats. We found that pathways leading to NADPH formation were widely induced, together with anabolic fatty acid biosynthesis, the latter appearing highly paradoxical in a state of mitochondrial impairment. However, concomitant induction of catabolic fatty acid oxidation indicated that complex I inhibition created a "futile" cycle of fatty acid synthesis and degradation, which was anatomically distributed between adipose tissue and liver in vivo. Cofactor balance analysis unveiled that such cycling would indeed be energetically futile (-3 ATP per acetyl-CoA), though it would not be redox-futile, as it would convert NADPH into respirable FADH2 without any net production of NADH. We conclude that inhibition of NADH dehydrogenase leads to a metabolic shift from glycolysis and the citric acid cycle (both generating NADH) towards the pentose phosphate pathway, whose product NADPH is translated 1:1 into FADH2 by fatty acid cycling. The diabetes-resistant phenotype following hepatic and intestinal complex I inhibition is attributed to FGF21- and GDF15-dependent fat hunger signaling, which remodels adipose tissue into a glucose-metabolizing organ.

Keywords:  Diabetes; FGF21; Metformin; Methionine restriction; NADH dehydrogenase; Peroxisome proliferator-activated receptor

DOI:  https://doi.org/10.1007/s11357-023-01059-y
Magn Reson Med. 2024 Jan 25.

Distinguishing metabolic signals of liver tumors from surrounding liver cells using hyperpolarized 13 C MRI and gadoxetate.

Shubhangi Agarwal, Jeremy Gordon, Robert A Bok, Cornelius von Morze, Daniel B Vigneron, John Kurhanewicz, Michael A Ohliger.

   PURPOSE: To use the hepatocyte-specific gadolinium-based contrast agent gadoxetate combined with hyperpolarized (HP) [1-13 C]pyruvate MRI to selectively suppress metabolic signals from normal hepatocytes while preserving the signals arising from tumors.
METHODS: Simulations were performed to determine the expected changes in HP 13 C MR signal in liver and tumor under the influence of gadoxetate. CC531 colon cancer cells were implanted into the livers of five Wag/Rij rats. Liver and tumor metabolism were imaged at 3 T using HP [1-13 C] pyruvate chemical shift imaging before and 15 min after injection of gadoxetate. Area under the curve for pyruvate and lactate were measured from voxels containing at least 75% of normal-appearing liver or tumor.
RESULTS: Numerical simulations predicted a 36% decrease in lactate-to-pyruvate (L/P) ratio in liver and 16% decrease in tumor. In vivo, baseline L/P ratio was 0.44 ± 0.25 in tumors versus 0.21 ± 0.08 in liver (p = 0.09). Following administration of gadoxetate, mean L/P ratio decreased by an average of 0.11 ± 0.06 (p < 0.01) in normal-appearing liver. In tumors, mean L/P ratio post-gadoxetate did not show a statistically significant change from baseline. Compared to baseline levels, the relative decrease in L/P ratio was significantly greater in liver than in tumors (-0.52 ± 0.16 vs. -0.19 ± 0.25, p < 0.05).
CONCLUSIONS: The intracellular hepatobiliary contrast agent showed a greater effect suppressing HP 13 C MRI metabolic signals (through T1 shortening) in normal-appearing liver when compared to tumors. The combined use of HP MRI with selective gadolinium contrast agents may allow more selective imaging in HP 13 C MRI.

Keywords:  CC531; Eovist; carbon-13; colon cancer; gadolinium; gadoxetate; hyperpolarized MRI; liver

DOI:  https://doi.org/10.1002/mrm.29918
bioRxiv. 2024 Jan 09. pii: 2024.01.08.574722. [Epub ahead of print]

A mouse model to study glutathione limitation in vivo.

Rebecca C Timson, Artem Khan, Beste Uygur, Marwa Saad, Hsi-Wen Yeh, Nicole DelGaudio, Ross Weber, Hanan Alwaseem, Jing Gao, Chingwen Yang, Kıvanç Birsoy.

Glutathione (GSH) is a highly abundant tripeptide thiol that performs diverse protective and biosynthetic functions in cells. While changes in GSH availability are linked to many diseases, including cancer and neurodegenerative disorders, determining the function of GSH in physiology and disease has been challenging due to its tight regulation. To address this, we generated cell and mouse models that express a bifunctional glutathione-synthesizing enzyme from Streptococcus Thermophilus (GshF). GshF expression allows efficient production of GSH in the cytosol and mitochondria and prevents cell death in response to GSH depletion, but not ferroptosis, indicating that GSH is not a limiting factor under lipid peroxidation. CRISPR screens using engineered enzymes revealed metabolic liabilities under compartmentalized GSH depletion. Finally, GshF expression in mice is embryonically lethal but sustains postnatal viability when restricted to adulthood. Overall, our work identifies a conditional mouse model to investigate the role of GSH availability in physiology and disease.

DOI: https://doi.org/10.1101/2024.01.08.574722
Foods. 2024 Jan 12. pii: 248. [Epub ahead of print]13(2):

Methodological Challenges and Confounders in Research on the Effects of Ketogenic Diets: A Literature Review of Meta-Analyses.

Katalin Szendi, Edit Murányi, Nicole Hunter, Balázs Németh.

  Several meta-analyses have found a positive association between a popular type of "fad diet", ketogenic diets, and their effect on anthropometric and blood parameters. However, the non-specific inclusion criteria for meta-analyses may lead to incorrect conclusions. The aim of this literature review is to highlight the main confounders and methodological pitfalls of meta-analyses on ketogenic diets by inspecting the presence of key inclusion criteria. The PubMed, Embase, and Web of Science databases and the Cochrane Database of Systematic Reviews were searched for meta-analyses. Most meta-analyses did not define the essential parameters of a ketogenic diet (i.e., calories, macronutrient ratio, types of fatty acids, ketone bodies, etc.) as inclusion criteria. Of the 28 included meta-analyses, few addressed collecting real, re-measured nutritional data from the ketogenic diet and control groups in parallel with the pre-designed nutritional data. Most meta-analyses reported positive results in favor of ketogenic diets, which can result in erroneous conclusions considering the numerous methodological pitfalls and confounders. Well-designed clinical trials with comparable results and their meta-analyses are needed. Until then, medical professionals should not recommend ketogenic diets as a form of weight loss when other well-known dietary options have been shown to be healthy and effective.

Keywords:  caloric intake; confounder; fad diet; ketogenic diet; ketone bodies; literature review; meta-analysis; types of fatty acids

DOI:  https://doi.org/10.3390/foods13020248
NMR Biomed. 2024 Jan 23. e5102

Transmembrane pH gradient imaging in rodent glioma models.

Sandeep Kumar Mishra, Jessica Gois Santana, Jelena Mihailovic, Fahmeed Hyder, Daniel Coman.

  A unique feature of the tumor microenvironment is extracellular acidosis in relation to intracellular milieu. Metabolic reprogramming in tumors results in overproduction of H+ ions (and lactate), which are extruded from the cells to support tumor survival and progression. As a result, the transmembrane pH gradient (ΔpH), representing the difference between intracellular pH (pHi ) and extracellular pH (pHe ), is posited to be larger in tumors compared with normal tissue. Controlling the transmembrane pH difference has promise as a potential therapeutic target in cancer as it plays an important role in regulating drug delivery into cells. The current study shows successful development of an MRI/MRSI-based technique that provides ΔpH imaging at submillimeter resolution. We applied this technique to image ΔpH in rat brains with RG2 and U87 gliomas, as well as in mouse brains with GL261 gliomas. pHi was measured with Amine and Amide Concentration-Independent Detection (AACID), while pHe was measured with Biosensor Imaging of Redundant Deviation in Shifts (BIRDS). The results indicate that pHi was slightly higher in tumors (7.40-7.43 in rats, 7.39-7.47 in mice) compared with normal brain (7.30-7.38 in rats, 7.32-7.36 in mice), while pHe was significantly lower in tumors (6.62-6.76 in rats, 6.74-6.84 in mice) compared with normal tissue (7.17-7.22 in rats, 7.20-7.21 in mice). As a result, ΔpH was higher in tumors (0.64-0.81 in rats, 0.62-0.65 in mice) compared with normal brain (0.13-0.16 in rats, 0.13-0.16 in mice). This work establishes an MRI/MRSI-based platform for ΔpH imaging at submillimeter resolution in gliomas.

Keywords:  AACID; BIRDS; MRI; MRSI; extracellular pH; glioma; intracellular pH; transmembrane pH

DOI:  https://doi.org/10.1002/nbm.5102
Nat Metab. 2024 Jan 24.

Metabolic heterogeneity in cancer.

Margherita Demicco, Xiao-Zheng Liu, Katharina Leithner, Sarah-Maria Fendt.

Cancer cells rewire their metabolism to survive during cancer progression. In this context, tumour metabolic heterogeneity arises and develops in response to diverse environmental factors. This metabolic heterogeneity contributes to cancer aggressiveness and impacts therapeutic opportunities. In recent years, technical advances allowed direct characterisation of metabolic heterogeneity in tumours. In addition to the metabolic heterogeneity observed in primary tumours, metabolic heterogeneity temporally evolves along with tumour progression. In this Review, we summarize the mechanisms of environment-induced metabolic heterogeneity. In addition, we discuss how cancer metabolism and the key metabolites and enzymes temporally and functionally evolve during the metastatic cascade and treatment.

DOI: https://doi.org/10.1038/s42255-023-00963-z
Elife. 2024 Jan 22. pii: e84282. [Epub ahead of print]13

Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms.

Yeyun Ouyang, Mi-Young Jeong, Corey N Cunningham, Jordan A Berg, Ashish G Toshniwal, Casey E Hughes, Kristina Seiler, Jonathan G Van Vranken, Ahmad A Cluntun, Geanette Lam, Jacob M Winter, Emel Akdoǧan, Katja K Dove, Sara M Nowinski, Matthew West, Greg Odorizzi, Steven P Gygi, Cory D Dunn, Dennis R Winge, Jared Rutter.

  Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential, both through inducing the electron transport chain and the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited simply by phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of mitochondrial membrane potential is observed in primary and immortalized mammalian cells as well as in Drosophila. These data suggest that mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement of mitochondrial function even in defective mitochondria.

Keywords:  D. melanogaster; S. cerevisiae; cell biology; human

DOI:  https://doi.org/10.7554/eLife.84282
bioRxiv. 2024 Jan 08. pii: 2024.01.07.573662. [Epub ahead of print]

Reprogramming neuroblastoma by diet-enhanced polyamine depletion.

Sarah Cherkaoui, Lifeng Yang, Matthew McBride, Christina S Turn, Wenyun Lu, Caroline Eigenmann, George E Allen, Olesya O Panasenko, Lu Zhang, Annette Vu, Kangning Liu, Yimei Li, Om H Gandhi, Lea Surrey, Michael Wierer, Eileen White, Joshua D Rabinowitz, Michael D Hogarty, Raphael J Morscher.

Neuroblastoma is a highly lethal childhood tumor derived from differentiation-arrested neural crest cells 1,2 . Like all cancers, its growth is fueled by metabolites obtained from either circulation or local biosynthesis 3,4 . Neuroblastomas depend on local polyamine biosynthesis, with the inhibitor difluoromethylornithine showing clinical activity 5 . Here we show that such inhibition can be augmented by dietary restriction of upstream amino acid substrates, leading to disruption of oncogenic protein translation, tumor differentiation, and profound survival gains in the TH- MYCN mouse model. Specifically, an arginine/proline-free diet decreases the polyamine precursor ornithine and augments tumor polyamine depletion by difluoromethylornithine. This polyamine depletion causes ribosome stalling, unexpectedly specifically at adenosine-ending codons. Such codons are selectively enriched in cell cycle genes and low in neuronal differentiation genes. Thus, impaired translation of these codons, induced by the diet-drug combination, favors a pro-differentiation proteome. These results suggest that the genes of specific cellular programs have evolved hallmark codon usage preferences that enable coherent translational rewiring in response to metabolic stresses, and that this process can be targeted to activate differentiation of pediatric cancers.
Highlights: - Extra-tumoral conversion of arginine feeds tumor ornithine via uptake from circulation in MYCN-neuroblastoma.- A proline and arginine free diet enhances pharmacological polyamine depletion via reduced ornithine substrate availability.- Polyamine depletion disrupts oncogenic translation to induce a pro-differentiation proteome causing neuroblast differentiation and prolonged survival in the TH-MYCN mouse model.- Genes of specific cellular programs have evolved codon usage preferences that enable coherent translational rewiring in response to metabolic stress, such as polyamine depletion.

DOI: https://doi.org/10.1101/2024.01.07.573662
Obesity (Silver Spring). 2024 Jan 23.

A ketogenic diet lowers myocardial fatty acid oxidation but does not affect oxygen consumption: a study in overweight humans.

Thien Vinh Luong, Mette Glavind Bülow Pedersen, Caroline Bruun Abild, Stephen C Cunnane, Etienne Croteau, Katrine Meyer Lauritsen, Mette Louise Gram Kjaerulff, Lars Poulsen Tolbod, Niels Møller, Esben Søndergaard, Lars Christian Gormsen.

OBJECTIVE: A ketogenic diet (KD) characterized by very low carbohydrate intake and high fat consumption may simultaneously induce weight loss and be cardioprotective. The "thrifty substrate hypothesis" posits that ketone bodies are more energy efficient compared with other cardiac oxidative substrates such as fatty acids. This work aimed to study whether a KD with presumed increased myocardial ketone body utilization reduces cardiac fatty acid uptake and oxidation, resulting in decreased myocardial oxygen consumption (MVO2 ).
METHODS: This randomized controlled crossover trial examined 11 individuals with overweight or obesity on two occasions: (1) after a KD and (2) after a standard diet. Myocardial free fatty acid (FFA) oxidation, uptake, and esterification rate were measured using dynamic [11 C]palmitate positron emission tomography (PET)/computed tomography, whereas MVO2 and myocardial external efficiency (MEE) were measured using dynamic [11 C]acetate PET.
RESULTS: The KD increased plasma β-hydroxybutyrate, reduced myocardial FFA oxidation (p < 0.01) and uptake (p = 0.03), and increased FFA esterification (p = 0.03). No changes were observed in MVO2 (p = 0.2) or MEE (p = 0.87).
CONCLUSIONS: A KD significantly reduced myocardial FFA uptake and oxidation, presumably by increasing ketone body oxidation. However, this change in cardiac substrate utilization did not improve MVO2 , speaking against the thrifty substrate hypothesis.

DOI: https://doi.org/10.1002/oby.23967
bioRxiv. 2024 Jan 01. pii: 2023.12.31.573774. [Epub ahead of print]

A genetically-encoded fluorescent biosensor for visualization of acetyl-CoA in live cells.

Joseph J Smith, Taylor R Valentino, Austin H Ablicki, Riddhidev Banerjee, Adam R Colligan, Debra M Eckert, Gabrielle A Desjardins, Katharine L Diehl.

Acetyl-coenzyme A is a central metabolite that participates in many cellular pathways. Evidence suggests that acetyl-CoA production and consumption are highly compartmentalized in mammalian cells. Yet methods to measure acetyl-CoA in living cells are lacking. In this work, we engineer an acetyl-CoA biosensor from the bacterial protein PanZ and circularly permuted green fluorescent protein (cpGFP). We biochemically characterize the sensor and demonstrate its selectivity for acetyl-CoA over other CoA species. We then deploy the biosensor in E. coli and HeLa cells to demonstrate its utility in living cells. In E. coli , we show that the biosensor enables detection of rapid changes in acetyl-CoA levels. In human cells, we show that the biosensor enables subcellular detection and reveals the compartmentalization of acetyl-CoA metabolism.

DOI: https://doi.org/10.1101/2023.12.31.573774
Biosensors (Basel). 2024 Jan 15. pii: 46. [Epub ahead of print]14(1):

Recent Advances in Electrochemical Detection of Cell Energy Metabolism.

Kyeong-Mo Koo, Chang-Dae Kim, Tae-Hyung Kim.

  Cell energy metabolism is a complex and multifaceted process by which some of the most important nutrients, particularly glucose and other sugars, are transformed into energy. This complexity is a result of dynamic interactions between multiple components, including ions, metabolic intermediates, and products that arise from biochemical reactions, such as glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), the two main metabolic pathways that provide adenosine triphosphate (ATP), the main source of chemical energy driving various physiological activities. Impaired cell energy metabolism and perturbations or dysfunctions in associated metabolites are frequently implicated in numerous diseases, such as diabetes, cancer, and neurodegenerative and cardiovascular disorders. As a result, altered metabolites hold value as potential disease biomarkers. Electrochemical biosensors are attractive devices for the early diagnosis of many diseases and disorders based on biomarkers due to their advantages of efficiency, simplicity, low cost, high sensitivity, and high selectivity in the detection of anomalies in cellular energy metabolism, including key metabolites involved in glycolysis and mitochondrial processes, such as glucose, lactate, nicotinamide adenine dinucleotide (NADH), reactive oxygen species (ROS), glutamate, and ATP, both in vivo and in vitro. This paper offers a detailed examination of electrochemical biosensors for the detection of glycolytic and mitochondrial metabolites, along with their many applications in cell chips and wearable sensors.

Keywords:  cell chip; electrochemical biosensor; glycolytic metabolites; mitochondrial metabolites; wearable sensor

DOI:  https://doi.org/10.3390/bios14010046
Nucl Med Commun. 2024 Jan 22.

In-vivo correlations of fluorescent or radioisotope glucose-analogs in imaging cancer metabolism.

Hongchang Lin, Mariko Kobayashi, Keiichiro Kushiro, Hironobu Yanagie, Kenji Shimazoe, Hiroyuki Takahashi.

OBJECTIVE: To investigate the impact of different tracer modifications on the imaging of cancer metabolism, focusing on the comparison of fluorescent glucose-analog tracers (2-NBDG and 2-DG-750) and the radiolabeled tracer 18F-FDG in both in-vitro and in-vivo settings.
METHODS: We conducted an in-vitro comparative study using four cancer cell lines, each with unique glucose uptake characteristics. The study involved direct comparison of three tracers: 2-NBDG, 2-DG-750 and 18F-FDG, examining their internalization behaviors, metabolic functionality and localization effects in cancer metabolism imaging.
RESULTS: The study revealed that each tracer exhibits distinct internalization behaviors correlated with imaging label size and type. 18F-FDG showed the highest uptake efficiency. Fluorescent molecules were found to accumulate in tumors primarily due to hydrophobic interactions and possible aggregation, indicating inefficiency in metabolism and suitability for imaging metabolic phenomena when compared to radiolabeled biomolecules.
CONCLUSION: Our findings demonstrate that despite certain impracticalities, nuclear imaging, particularly using radiolabeled biomolecules like 18F-FDG, offers significant potential for accurately capturing biological phenomena. This is crucial for future advancements in both clinical and research settings. The study emphasizes the limitations of fluorescent molecules in imaging metabolic activities due to their inefficient metabolism and aggregation tendencies.

DOI: https://doi.org/10.1097/MNM.0000000000001812
Blood Cancer Discov. 2024 Jan 23. OF1-OF18

IDH1-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation.

Niklas Landberg, Thomas Köhnke, Yang Feng, Yusuke Nakauchi, Amy C Fan, Miles H Linde, Daiki Karigane, Kelly Lim, Rahul Sinha, Luca Malcovati, Daniel Thomas, Ravindra Majeti.

Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at the time of acute myeloid leukemia (AML) diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSC). We confirm that IDH1-driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in the complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wild-type HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent the development and relapse of leukemia.
SIGNIFICANCE: A high burden of pHSCs is associated with worse overall survival in AML. Using single-cell sequencing, metabolic assessment, and gene-edited human models, we find human pHSCs with IDH1 mutations to be metabolically vulnerable and sensitive to eradication by complex I inhibition. See related commentary by Steensma.

DOI: https://doi.org/10.1158/2643-3230.BCD-23-0195
J Clin Med. 2024 Jan 18. pii: 549. [Epub ahead of print]13(2):

Venetoclax Combined with Intensive Chemotherapy: A New Hope for Refractory and/or Relapsed Acute Myeloid Leukemia?

Ramy Rahmé, Thorsten Braun.

  Background. Primary resistance of acute myeloid leukemia (AML) to the conventional 3 + 7 intensive chemotherapy and relapses after first-line chemotherapy are two highly challenging clinical scenarios. In these cases, when allogeneic stem cell transplantation is feasible, patients are usually retreated with other chemotherapeutic regimens, as transplantation is still considered, nowadays, the only curative option. Methods. We discuss the mechanisms behind resistance to chemotherapy and offer a comprehensive review on current treatments of refractory/relapsed AML with a focus on novel approaches incorporating the BCL-2 inhibitor venetoclax. Results. Alas, complete remission rates after salvage chemotherapy remain relatively low, between 30 and 60% at best. More recently, the BCL-2 inhibitor venetoclax was combined either with hypomethylating agents or chemotherapy in refractory/relapsed patients. In particular, its combination with chemotherapy offered promising results by achieving higher rates of remission and bridging a substantial number of patients to transplantation. Conclusions. Venetoclax-based approaches might become, in the near future, the new standard of care for refractory/relapsed AML.

Keywords:  AML; chemotherapy; leukemia; refractory; relapsed; venetoclax

DOI:  https://doi.org/10.3390/jcm13020549
bioRxiv. 2024 Jan 04. pii: 2024.01.03.573955. [Epub ahead of print]

Spatially resolved quantification of oxygen consumption rate in ex vivo lymph node slices.

Parastoo Anbaei, Marissa G Stevens, Alexander G Ball, Timothy N J Bullock, Rebecca R Pompano.

Cellular metabolism has been closely linked to activation state in cells of the immune system, and the oxygen consumption rate (OCR) in particular serves as a valuable metric for assessing metabolic activity. Several oxygen sensing assays have been reported for cells in standard culture conditions. However, none have provided a spatially resolved, optical measurement of local oxygen consumption in intact tissue samples, making it challenging to understand regional dynamics of consumption. Therefore, here we established a system to monitor the rates of oxygen consumption in ex vivo tissue slices, using murine lymphoid tissue as a case study. By integrating an optical oxygen sensor into a sealed perfusion chamber and incorporating appropriate correction for photobleaching of the sensor and of tissue autofluorescence, we were able to visualize and quantify rates of oxygen consumption in tissue. This method revealed for the first time that the rate of oxygen consumption in naïve lymphoid tissue was higher in the T cell region compared to the B cell and cortical regions. To validate the method, we measured OCR in the T cell regions of naïve lymph node slices using the optical assay and estimated the consumption rate per cell. The predictions from the optical assay were similar to reported values and were not significantly different from those of the Seahorse metabolic assay, a gold standard method for measuring OCR in cell suspensions. Finally, we used this method to quantify the rate of onset of tissue hypoxia for lymph node slices cultured in a sealed chamber and showed that continuous perfusion was sufficient to maintain oxygenation. In summary, this work establishes a method to monitor oxygen consumption with regional resolution in intact tissue explants, suitable for future use to compare tissue culture conditions and responses to stimulation.
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DOI: https://doi.org/10.1101/2024.01.03.573955
Res Sq. 2024 Jan 08. pii: rs.3.rs-3837925. [Epub ahead of print]

Glutathione peroxidase 4 suppresses manganese-dependent oxidative stress to reduce colorectal tumorigenesis.

Xiang Xue, Zhaoli Liu, Yanshan Liang, Young-Yon Kwon, Rui Liu, David Martin, Sheng Hui.

The role of glutathione peroxidase 4 (GPX4) in ferroptosis and various cancers is well-established; however, its specific contribution to colorectal cancer has been unclear. Surprisingly, in a genetic mouse model of colon tumors, the deletion of GPX4 specifically in colon epithelial cells increased tumor burden but decreased oxidized glutathione. Notably, this specific GPX4 deletion did not enhance susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice with varied iron diets but showed vulnerability in mice with a vitamin E-deficient diet. Additionally, a high manganese diet heightened susceptibility, while a low manganese diet reduced DSS-induced colitis in colon epithelial-specific GPX4-deficient mice. Strikingly, the low manganese diet also significantly reduced colorectal cancer formation in both colon epithelial-specific GPX4-deficient and wildtype mice. Mechanistically, antioxidant proteins, especially manganese-dependent superoxide dismutase (MnSOD or SOD2), correlated with disease severity. Treatment with tempol, a superoxide dismutase mimetic radical scavenger, suppressed GPX4 deficiency-induced colorectal tumors. In conclusion, the study elucidates the critical role of GPX4 in inhibiting colorectal cancer progression by regulating oxidative stress in a manganese-dependent manner. The findings underscore the intricate interactions between GPX4, dietary factors, and their collective influence on colorectal cancer development, providing potential insights for personalized therapeutic strategies.

DOI: https://doi.org/10.21203/rs.3.rs-3837925/v1
NMR Biomed. 2024 Jan 26. e5107

A continuous flow bioreactor system for high-throughput hyperpolarized metabolic flux analysis.

Nichlas Vous Christensen, Rikke Holm, Juan D Sanchez, Esben S S Hansen, Mathilde H Lerche, Jan Henrik Ardenkjaer-Larsen, Christoffer Laustsen, Lotte Bonde Bertelsen.

  Hyperpolarized carbon-13 labeled compounds are increasingly being used in medical MR imaging (MRI) and MR imaging (MRI) and spectroscopy (MRS) research, due to its ability to monitor tissue and cell metabolism in real-time. Although radiological biomarkers are increasingly being considered as clinical indicators, biopsies are still considered the gold standard for a large variety of indications. Bioreactor systems can play an important role in biopsy examinations because of their ability to provide a physiochemical environment that is conducive for therapeutic response monitoring ex vivo. We demonstrate here a proof-of-concept bioreactor and microcoil receive array setup that allows for ex vivo preservation and metabolic NMR spectroscopy on up to three biopsy samples simultaneously, creating an easy-to-use and robust way to simultaneously run multisample carbon-13 hyperpolarization experiments. Experiments using hyperpolarized [1-13 C]pyruvate on ML-1 leukemic cells in the bioreactor setup were performed and the kinetic pyruvate-to-lactate rate constants ( kPL$$ {k}_{PL} $$ ) extracted. The coefficient of variation of the experimentally found kPL$$ {k}_{PL} $$ s for five repeated experiments was CV=35%$$ {C}_V=35\% $$ . With this statistical power, treatment effects of 30%-40% change in lactate production could be easily differentiable with only a few hyperpolarization dissolutions on this setup. Furthermore, longitudinal experiments showed preservation of ML-1 cells in the bioreactor setup for at least 6 h. Rat brain tissue slices were also seen to be preserved within the bioreactor for at least 1 h. This validation serves as the basis for further optimization and upscaling of the setup, which undoubtedly has huge potential in high-throughput studies with various biomarkers and tissue types.

Keywords:  bioreactor; carbon-13; ex vivo metabolism; hyperpolarization; leukemia; microcoil

DOI:  https://doi.org/10.1002/nbm.5107
Mol Biol Rep. 2024 Jan 22. 51(1): 168

Targeting apoptosis and unfolded protein response: the impact of β-hydroxybutyrate in clear cell renal cell carcinoma under glucose-deprived conditions.

Fatemeh Roohy, Morvarid Siri, Kiarash Kohansal, Afsane Ghalandari, Roya Rezaei, Mohammad Hasan Maleki, Mesbah Shams, Alireza Monsef, Sanaz Dastghaib.

   BACKGROUND: Clear cell renal cell carcinoma (ccRCC) plays a significant role in the mortality associated with kidney cancer. Targeting biological processes that inhibit cancer growth opens up new treatment possibilities. The unfolded protein response (UPR) and apoptosis have crucial roles in RCC progression. This study investigates the impact of β-hydroxybutyrate (BHB) on ccRCC cells under glucose deprivation resembling as a ketogenic diet.
METHOD: Caki-1 ccRCC cells were exposed to decreasing glucose concentrations alone or in combination with 10 or 25 mM BHB during 48 and 72 h. Cell viability was determined using MTT assay. The mRNA expression level of apoptosis-and UPR-related markers (Bcl-2, Bax, caspase 3, XBP1s, BIP, CHOP, ATF4, and ATF6) were assayed by qRT-PCR.
RESULTS: Cell viability experiments demonstrated that combining different doses of BHB with decreasing glucose levels initially improved cell viability after 48 h. Nevertheless, this trend reversed after 72 h, with higher impacts disclosed at 25 mM BHB. Apoptosis was induced in BHB-treated cells as caspase-3 and Bax were increased and Bcl-2 was downregulated. BHB supplementation reduced UPR-related gene expression (XBP1s, BIP, CHOP, ATF4, and ATF6), revealing a possible mechanism by which BHB affects cell survival.
CONCLUSION: This research emphasizes the dual effect of BHB, initially suppressing cell- survival under glucose deprivation but eventually triggering apoptosis and suppressing UPR signaling. These data highlight the intricate connection between metabolic reprogramming and cellular stress response in ccRCC. Further research is recommended to explore the potential of BHB as a therapeutic strategy for managing ccRCC.

Keywords:  Apoptosis; Clear cell renal cell carcinoma; Ketone metabolism; UPR; β-hydroxybutyrate

DOI:  https://doi.org/10.1007/s11033-023-08977-2
Nat Cancer. 2024 Jan 25.

Lipids as mediators of cancer progression and metastasis.

Felix C E Vogel, Adriano B Chaves-Filho, Almut Schulze.

Metastasis formation is a complex process, involving multiple crucial steps, which are controlled by different regulatory mechanisms. In this context, the contribution of cancer metabolism to the metastatic cascade is being increasingly recognized. This Review focuses on changes in lipid metabolism that contribute to metastasis formation in solid tumors. We discuss the molecular mechanisms by which lipids induce a pro-metastatic phenotype and explore the role of lipids in response to oxidative stress and as signaling molecules. Finally, we reflect on potential avenues to target lipid metabolism to improve the treatment of metastatic cancers.

DOI: https://doi.org/10.1038/s43018-023-00702-z
Physiology (Bethesda). 2024 Jan 23.

Emerging pathophysiological roles of ketone bodies.

Hiroaki Tsuruta, Kosuke Yamahara, Mako Yasuda-Yamahara, Shinji Kume.

  The discovery of insulin approximately a century ago greatly improved the management of diabetes, including many of its life-threatening acute complications like ketoacidosis. This breakthrough saved many lives and extended the healthy lifespan of many patients with diabetes. However, there is still a negative perception of ketone bodies stemming from ketoacidosis. Originally, ketone bodies were thought of as a vital source of energy during fasting and exercise. Furthermore, in recent years, research on calorie restriction and its potential impact on extending healthy lifespans, as well as studies on ketone bodies, have gradually led to a reevaluation of the significance of ketone bodies in promoting longevity. Thus, in this review we discuss the emerging and hidden roles of ketone bodies in various organs, including the heart, kidneys, skeletal muscles, and brain, as well as their potential impact on malignancies and lifespan.

Keywords:  Fuel metabolism; HMGCS2; Ketone bodies; Ketongenic diet; Longevity

DOI:  https://doi.org/10.1152/physiol.00031.2023
Gastroenterology. 2024 Jan 23. pii: S0016-5085(24)00064-7. [Epub ahead of print]

Oncogenic fatty acid metabolism rewires energy supply chain in gastric carcinogenesis.

Yoonkyung Won, Bogun Jang, Su-Hyung Lee, Michelle L Reyzer, Kimberly S Presentation, Hyesung Kim, Brianna Caldwell, Changqing Zhang, Hye Seung Lee, Cheol Lee, Vincent Q Trinh, Marcus C B Tan, Kwangho Kim, Richard M Caprioli, Eunyoung Choi.

   BACKGROUND & AIMS: Gastric carcinogenesis develops within a sequential carcinogenic cascade from pre-cancerous metaplasia to dysplasia and adenocarcinoma, and oncogenic gene activation can drive the process. Metabolic reprogramming is considered a key mechanism for cancer cell growth and proliferation. However, it remains unclear how metabolic changes contribute to the progression of metaplasia to dysplasia. We have examined metabolic dynamics during gastric carcinogenesis using a novel mouse model that induces Kras activation in zymogen-secreting chief cells.
METHODS: We generated a Gif-rtTA;TetO-Cre;KrasG12D (GCK) mouse model which continuously induces active Kras expression in chief cells following doxycycline treatment. Histological examination and imaging mass spectrometry were performed in the GCK mouse stomachs at 2 to 14 weeks after doxycycline treatment. Mouse and human gastric organoids were used for metabolic enzyme inhibitor treatment. The GCK mice were treated with a stearoyl-CoA desaturase (SCD) inhibitor to inhibit the fatty acid desaturation. Tissue microarrays were used to assess the SCD expression in human gastrointestinal cancers.
RESULTS: The GCK mice developed metaplasia and high-grade dysplasia within 4 months. Metabolic reprogramming from glycolysis to fatty acid metabolism occurred during metaplasia progression to dysplasia. Altered fatty acid desaturation through SCD produces a novel Eicosenoic acid, which fuels dysplastic cell hyperproliferation and survival. The SCD inhibitor killed both mouse and human dysplastic organoids and selectively targeted dysplastic cells in vivo. SCD was upregulated during carcinogenesis in human gastrointestinal cancers.
CONCLUSIONS: Active Kras expression only in gastric chief cells drives the full spectrum of gastric carcinogenesis. Also, oncogenic metabolic rewiring is an essential adaptation for high energy demand in dysplastic cells.

Keywords:  Carcinogenesis; Fatty acid metabolism; Imaging mass spectrometry; Kras; Stearoyl-CoA desaturase

DOI:  https://doi.org/10.1053/j.gastro.2024.01.027
Genes (Basel). 2023 Dec 31. pii: 63. [Epub ahead of print]15(1):

A Comprehensive Metabolism-Related Gene Signature Predicts the Survival of Patients with Acute Myeloid Leukemia.

Yujia Zhai, Heng Shen, Hui Wei.

  (1) Background: Acute myeloid leukemia (AML) is a clonal malignancy with heterogeneity in genomics and clinical outcome. Metabolism reprogramming has been increasingly recognized to play an important role in the leukemogenesis and prognosis in AML. A comprehensive prognostic model based on metabolism signatures has not yet been developed. (2) Methods: We applied Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) normalization to establish a metabolism-related prognostic gene signature based on glycolysis, fatty acid metabolism, and the tricarboxylic acid cycle gene signatures. The Cancer Genome Atlas-Acute Myeloid Leukemia-like (TCGA-LAML) cohort was set as the training dataset for model construction. Three independent AML cohorts (GSE37642, GSE10358, and GSE12417) combined from Gene Expression Omnibus (GEO) datasets and the Beat-AML dataset were retrieved as two validation sets to test the robustness of the model. The transcriptome data and clinic information of the cohorts were enrolled for the analysis. (3) Results: Divided by the median value of the metabolism risk score, the five-year overall survival (OS) of the high-risk and low-risk groups in the training set were 8.2% and 41.3% (p < 0.001), respectively. The five-year OS of the high-risk and low-risk groups in the combined GEO cohort were 25.5% and 37.3% (p = 0.002), respectively. In the Beat-AML cohort, the three-year OS of the high-risk and low-risk groups were 16.2% and 40.2% (p = 0.0035), respectively. The metabolism risk score showed a significantly negative association with the long-term survival of AML. Furthermore, this metabolism risk score was an independent unfavorable factor for OS by univariate analysis and multivariate analysis. (4) Conclusions: Our study constructed a comprehensive metabolism-related signature with twelve metabolism-related genes for the risk stratification and outcome prediction of AML. This novel signature might contribute to a better use of metabolism reprogramming factors as prognostic markers and provide novel insights into potential metabolism targets for AML treatment.

Keywords:  RNA-seq analysis; acute myeloid leukemia; metabolism-related gene; prognostic model; survival analysis

DOI:  https://doi.org/10.3390/genes15010063
Acta Physiol (Oxf). 2024 Jan 25. e14081

Erythrocyte metabolism.

Panagiotis N Chatzinikolaou, Nikos V Margaritelis, Vassilis Paschalis, Anastasios A Theodorou, Ioannis S Vrabas, Antonios Kyparos, Angelo D'Alessandro, Michalis G Nikolaidis.

  Our aim is to present an updated overview of the erythrocyte metabolism highlighting its richness and complexity. We have manually collected and connected the available biochemical pathways and integrated them into a functional metabolic map. The focus of this map is on the main biochemical pathways consisting of glycolysis, the pentose phosphate pathway, redox metabolism, oxygen metabolism, purine/nucleoside metabolism, and membrane transport. Other recently emerging pathways are also curated, like the methionine salvage pathway, the glyoxalase system, carnitine metabolism, and the lands cycle, as well as remnants of the carboxylic acid metabolism. An additional goal of this review is to present the dynamics of erythrocyte metabolism, providing key numbers used to perform basic quantitative analyses. By synthesizing experimental and computational data, we conclude that glycolysis, pentose phosphate pathway, and redox metabolism are the foundations of erythrocyte metabolism. Additionally, the erythrocyte can sense oxygen levels and oxidative stress adjusting its mechanics, metabolism, and function. In conclusion, fine-tuning of erythrocyte metabolism controls one of the most important biological processes, that is, oxygen loading, transport, and delivery.

Keywords:  2,3-BPG; free radicals; haemoglobin; mathematical modelling; red blood cell

DOI:  https://doi.org/10.1111/apha.14081
Front Immunol. 2023 ;14 1332043

Specific changes in amino acid profiles in monocytes of patients with breast, lung, colorectal and ovarian cancers.

Vitaliy Chagovets, Natalia Starodubtseva, Alisa Tokareva, Anastasia Novoselova, Marina Patysheva, Irina Larionova, Elizaveta Prostakishina, Militsa Rakina, Anna Kazakova, Evgenii Topolnitskiy, Nikolay Shefer, Julia Kzhyshkowska, Vladimir Frankevich, Gennadiy Sukhikh.

   Introduction: Immunometabolism is essential factor of tumor progression, and tumor-associated macrophages are characterized by substantial changes in their metabolic status. In this study for the first time, we applied targeted amino acid LC-MS/MS analysis to compare amino acid metabolism of circulating monocytes isolated from patients with breast, ovarian, lung, and colorectal cancer.
Methods: Monocyte metabolomics was analyzed by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/ MS) analysis of amino acid extracts. The targeted analysis of 26 amino acids was conducted by LCMS/MS on an Agilent 6460 triple quadrupole mass spectrometer equipped with an electrospray ionization source and an Agilent 1260 II liquid chromatograph.
Results: Comparison of monocytes of cancer patients with monocytes of healthy control individuals demonstrated that in breast cancer most pronounced changes were identified for tryptophan (AUC = 0.76); for ovarian cancer, aminobutyric acid was significantly elevated (AUC= 1.00); for lung cancer significant changes we indented for citrulline (AUC = 0.70). In order to identify key amino acids that are characteristic for monocytes in specific cancer types, we compared each individual cancer with other 3 types of cancer. We found, that aspartic acid and citrulline are specific for monocytes of patients with colorectal cancer (p<0.001, FC = 1.40 and p=0.003, FC = 1.42 respectively). Citrulline, sarcosine and glutamic acid are ovarian cancer-specific amino acids (p = 0.003, FC = 0.78, p = 0.003, FC = 0.62, p = 0.02, FC = 0.78 respectively). Glutamine, methionine and phenylalanine (p = 0.048, FC = 1.39. p = 0.03, FC = 1.27 and p = 0.02, FC = 1.41) are lung cancer-specific amino acids. Ornithine in monocytes demonstrated strong positive correlation (r = 0.63) with lymph node metastasis incidence in breast cancer patients. Methyl histidine and cysteine in monocytes had strong negative correlation with lymph node metastasis in ovarian cancer patients (r = -0.95 and r = -0.95 respectively). Arginine, citrulline and ornithine have strong negative correlation with tumor size (r = -0.78, citrulline) and lymph node metastasis (r = -0.63 for arginine and r = -0.66 for ornithine).
Discussion: These alterations in monocyte amino acid metabolism can reflect the reaction of systemic innate immunity on the growing tumor. Our data indicate that this metabolic programming is cancer specific and can be inhibiting cancer progression. Cancer-specific differences in citrulline, as molecular link between metabolic pathways and epigenetic programing, provide new option for the development and validation of anti-cancer therapies using inhibitors of enzymes catalyzing citrullination.

Keywords:  mass spectrometry; metabolomics; monocytes; oncology; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2023.1332043
Cancers (Basel). 2024 Jan 21. pii: 456. [Epub ahead of print]16(2):

Proline Metabolism in WHO G4 Gliomas Is Altered as Compared to Unaffected Brain Tissue.

Magdalena M Sawicka, Karol Sawicki, Marek Jadeszko, Katarzyna Bielawska, Elżbieta Supruniuk, Joanna Reszeć, Izabela Prokop-Bielenia, Barbara Polityńska, Mateusz Jadeszko, Magdalena Rybaczek, Eryk Latoch, Krzysztof Gorbacz, Tomasz Łysoń, Wojciech Miltyk.

  Proline metabolism has been identified as a significant player in several neoplasms, but knowledge of its role in gliomas is limited despite it providing a promising line of pursuit. Data on proline metabolism in the brain are somewhat historical. This study aims to investigate alterations of proline metabolism in gliomas of WHO grade 4 (GG4) in the context of the brain. A total of 20 pairs of samples were studied, consisting of excised tumor and unaffected brain tissue, obtained when partial brain resection was required to reach deep-seated lesions. Levels of proline oxidase/proline dehydrogenase (POX/PRODH), Δ1-pyrroline-5-carboxylate reductases (PYCR1/2/3), prolidase (PEPD), and metalloproteinases (MMP-2, MMP-9) were assessed, along with the concentration of proline and proline-related metabolites. In comparison to normal brain tissue, POX/PRODH expression in GG4 was found to be suppressed, while PYCR1 expression and activity of PEPD, MMP-2, and -9 were upregulated. The GG4 proline concentration was 358% higher. Hence, rewiring of the proline metabolism in GG4 was confirmed for the first time, with a low-POX/PRODH/high-PYCR profile. High PEPD and MMPs activity is in keeping with GG4-increased collagen turnover and local aggressiveness. Further studies on the mechanisms of the interplay between altered proline metabolism and the GG4 microenvironment are warranted.

Keywords:  glioblastoma; glioma; prolidase; proline dehydrogenase; proline metabolism; proline oxidase; Δ1-pyrroline-5-carboxylate reductases

DOI:  https://doi.org/10.3390/cancers16020456
PLoS One. 2024 ;19(1): e0296815

Enhanced glucose utilization of skeletal muscle after 4 weeks of intermittent hypoxia in a mouse model of type 2 diabetes.

Yuqi Zhao, Chaoqun Li, Shi Zhou, Youyu He, Yun Wang, Yuan Zhang, Li Wen.

BACKGROUND: Intermittent hypoxia intervention (IHI) has been shown to reduces blood glucose and improves insulin resistance in type 2 diabetes (T2D) and has been suggested as a complementary or alternative intervention to exercise for individuals with limited mobility. Previous research on IHI has assessed cellular glucose uptake rather than utilization. The purpose of this study was to determine the effect of a 4-week IHI, with or without an aerobic exercise, on skeletal muscle glucose utilization as indicated by the changes in pyruvate, lactate, NAD+, and NADH, using a mouse model of diet-induced T2D. In addition, the effects of one exposure to hypoxia (acute) and of a 4-week IHI (chronic) were compared to explore their relationship.
METHODS: C57BL/6J mice were randomly assigned to normal control and high-fat-diet groups, and the mice that developed diet-induced diabetes were assigned to diabetes control, and intervention groups with 1 hour (acute) or 4 weeks (1 hour/day, 6 days/week) exposure to a hypoxic envrionment (0.15 FiO2), exercise (treadmill run) in normoxia, and exercise in hypoxia, respectively, with N = 7 in each group. The effects of the interventions on concentrations of fasting blood glucose, muscle glucose, GLUT4, lactate, pyruvate, nicotinamide adenine dinucleotide (NAD+), and NADH were measured, and statistically compared between the groups.
RESULTS: Compared with diabetes control group, the mice treated in the hypoxic environment for 4 weeks showed a significantly higher pyruvate levels and lower lactate/pyruvate ratios in the quadriceps muscle, and the mice exposed to hypoxia without or with aerobic exercise for either for 4 weeks or just 1 hour showed higher NAD+ levels and lower NADH/NAD+ ratios.
CONCLUSIONS: Exposure to moderate hypoxia for either one bout or 4 weeks significantly increased the body's mitochondrial NAD cyclethe in diabetic mice even in the absence of aerobic exercise. The hypoxia and exercise interventions exhibited synergistic effects on glycolysis. These findings provide mechanistic insights into the effects of IHI in respect of the management of hyperglycemia.

DOI: https://doi.org/10.1371/journal.pone.0296815