bims-medica 2024-03-24 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024‒03‒24
thirty-six papers selected by
Brett Chrest, East Carolina University

Metabolic Fluxes in the Renal Cortex are Dysregulated In Vivo in Response to High-Fat Diet.
Activation of polyamine catabolism promotes glutamine metabolism and creates a targetable vulnerability in lung cancer.
Exploiting the Achilles' heel of cancer: disrupting glutamine metabolism for effective cancer treatment.
Serine synthesis and catabolism in starved lung cancer and primary bronchial epithelial cells.
Knowledge-Based Therapeutics for Tricarboxylic Acid (TCA) Cycle-Deficient Cancers.
SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis.
Tracing the Diverse Paths of One-Carbon Metabolism in Cancer and Beyond.
Cancer cells hijack physiological metabolic signals to seed liver metastasis.
Monocarboxylate transporter 4 deficiency enhances high-intensity interval training-induced metabolic adaptations in skeletal muscle.
A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.
Structures of 3-acetylpyridine adenine dinucleotide and ADP-ribose bound to the electron input module of respiratory complex I.
Modeling of Mouse Experiments Suggests that Optimal Anti-Hormonal Treatment for Breast Cancer is Diet-Dependent.
CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction.
Chemical proteomics to study metabolism, a reductionist approach applied at the systems level.
The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.
Weight-centric prevention of cancer.
Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1.
Live-cell biosensors based on the fluorescence lifetime of environment-sensing dyes.
Synchronized assembly of the oxidative phosphorylation system controls mitochondrial respiration in yeast.
Discovery of Alternative Binding Poses through Fragment-Based Identification of DHODH Inhibitors.
Mitochondrial Raf1 Regulates Glutamine Catabolism.
A comparison between different human hepatocyte models reveals profound differences in net glucose production, lipid composition and metabolism in vitro.
Association of glucose-lowering drug target and risk of gastrointestinal cancer: a mendelian randomization study.
Substitution of dietary monounsaturated fatty acids from olive oil for saturated fatty acids from lard increases LDL apolipoprotein B-100 fractional catabolic rate in subjects with dyslipidemia associated with insulin resistance: a randomized controlled trial.
Assessing cell viability with dynamic optical coherence microscopy.
Fasting as a precursor to high-fat diet enhances mitochondrial resilience in Drosophila melanogaster.
Structural determinants of mitochondrial STAT3 targeting and function.
Hepatic insulin resistance and muscle insulin resistance are characterized by distinct postprandial plasma metabolite profiles: a cross-sectional study.
Lipid-Restricted Culture Media Reveal Unexpected Cancer Cell Sensitivities.
Novel Therapeutic Targets in Acute Myeloid Leukemia (AML).
GALDAR: A genetically encoded galactose sensor for visualizing sugar metabolism in vivo.
Next Generation Weight Loss Drugs for the Prevention of Cancer?
Use of tryptic peptide MALDI mass spectrometry imaging to identify the spatial proteomic landscape of colorectal cancer liver metastases.
Future perspectives on the roles of mitochondrial dynamics in the heart in obesity and aging.
Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival.
Effects of High-protein and High-fiber Diets on Weight and Glucose Regulation in Spiny Mice (Acomys cahirinus).

Diabetes. 2024 Mar 19. pii: db230710. [Epub ahead of print]

Metabolic Fluxes in the Renal Cortex are Dysregulated In Vivo in Response to High-Fat Diet.

Clinton M Hasenour, Deveena R Banerjee, Jamey D Young.

Diabetes and obesity are risk factors for kidney disease. While renal glucose production increases in diabetes, recent data suggest that gluconeogenic and oxidative capacity decline in kidney disease. Thus, metabolic dysregulation caused by diet-induced insulin resistance may sensitize the kidney for a loss in function. Here we examined how diet-induced insulin resistance disrupts mitochondrial metabolic fluxes in the renal cortex in vivo. C57Bl/6J mice were rendered insulin resistant through high-fat (HF) feeding; anaplerotic, cataplerotic, and oxidative metabolic fluxes in the cortex were quantified through 13C-isotope tracing during a hyperinsulinemic-euglycemic clamp. As expected, HF-fed mice exhibited increased body weight, gluconeogenesis, and systemic insulin resistance compared to chow-fed mice. Relative to the citric acid cycle, HF-feeding increased metabolic flux through pyruvate carboxylation (anaplerosis) and phosphoenolpyruvate carboxykinase (cataplerosis) while decreasing flux through the pyruvate dehydrogenase complex in the cortex. Furthermore, the relative flux from non-pyruvate sources of acetyl-CoA profoundly increased in the cortex of HF-fed mice, correlating with a marker of oxidative stress. The data demonstrate that HF-feeding spares pyruvate from dehydrogenation at the expense of increasing cataplerosis, which may underpin renal gluconeogenesis during insulin resistance; the results also support the hypothesis that dysregulated oxidative metabolism in the kidney contributes to metabolic disease.

DOI: https://doi.org/10.2337/db23-0710
Proc Natl Acad Sci U S A. 2024 Mar 26. 121(13): e2319429121

Activation of polyamine catabolism promotes glutamine metabolism and creates a targetable vulnerability in lung cancer.

Xinlu Han, Deyu Wang, Liao Yang, Ning Wang, Jianliang Shen, Jinghan Wang, Lei Zhang, Li Chen, Shenglan Gao, Wei-Xing Zong, Yongbo Wang.

  Polyamines are a class of small polycationic alkylamines that play essential roles in both normal and cancer cell growth. Polyamine metabolism is frequently dysregulated and considered a therapeutic target in cancer. However, targeting polyamine metabolism as monotherapy often exhibits limited efficacy, and the underlying mechanisms are incompletely understood. Here we report that activation of polyamine catabolism promotes glutamine metabolism, leading to a targetable vulnerability in lung cancer. Genetic and pharmacological activation of spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme of polyamine catabolism, enhances the conversion of glutamine to glutamate and subsequent glutathione (GSH) synthesis. This metabolic rewiring ameliorates oxidative stress to support lung cancer cell proliferation and survival. Simultaneous glutamine limitation and SAT1 activation result in ROS accumulation, growth inhibition, and cell death. Importantly, pharmacological inhibition of either one of glutamine transport, glutaminase, or GSH biosynthesis in combination with activation of polyamine catabolism synergistically suppresses lung cancer cell growth and xenograft tumor formation. Together, this study unveils a previously unappreciated functional interconnection between polyamine catabolism and glutamine metabolism and establishes cotargeting strategies as potential therapeutics in lung cancer.

Keywords:  SAT1; glutamine metabolism; lung cancer; polyamine catabolism

DOI:  https://doi.org/10.1073/pnas.2319429121
Front Pharmacol. 2024 ;15 1345522

Exploiting the Achilles' heel of cancer: disrupting glutamine metabolism for effective cancer treatment.

Yuxin Fan, Han Xue, Zhimin Li, Mingge Huo, Hongxia Gao, Xingang Guan.

  Cancer cells have adapted to rapid tumor growth and evade immune attack by reprogramming their metabolic pathways. Glutamine is an important nitrogen resource for synthesizing amino acids and nucleotides and an important carbon source in the tricarboxylic acid (TCA) cycle and lipid biosynthesis pathway. In this review, we summarize the significant role of glutamine metabolism in tumor development and highlight the vulnerabilities of targeting glutamine metabolism for effective therapy. In particular, we review the reported drugs targeting glutaminase and glutamine uptake for efficient cancer treatment. Moreover, we discuss the current clinical test about targeting glutamine metabolism and the prospective direction of drug development.

Keywords:  cancer therapy; combination therapy; glutamine; glutamine metabolism; glutamine uptake

DOI:  https://doi.org/10.3389/fphar.2024.1345522
Cancer Metab. 2024 Mar 21. 12(1): 9

Serine synthesis and catabolism in starved lung cancer and primary bronchial epithelial cells.

Theresa Haitzmann, Katharina Schindlmaier, Tobias Frech, Ayusi Mondal, Visnja Bubalo, Barbara Konrad, Gabriele Bluemel, Philipp Stiegler, Stefanie Lackner, Andelko Hrzenjak, Thomas Eichmann, Harald C Köfeler, Katharina Leithner.

  Serine and glycine give rise to important building blocks in proliferating cells. Both amino acids are either synthesized de novo or taken up from the extracellular space. In lung cancer, serine synthesis gene expression is variable, yet, expression of the initial enzyme, phosphoglycerate dehydrogenase (PHGDH), was found to be associated with poor prognosis. While the contribution of de novo synthesis to serine pools has been shown to be enhanced by serine starvation, the impact of glucose deprivation, a commonly found condition in solid cancers is poorly understood. Here, we utilized a stable isotopic tracing approach to assess serine and glycine de novo synthesis and uptake in different lung cancer cell lines and normal bronchial epithelial cells in variable serine, glycine, and glucose conditions. Under low glucose supplementation (0.2 mM, 3-5% of normal plasma levels), serine de novo synthesis was maintained or even activated. As previously reported, also gluconeogenesis supplied carbons from glutamine to serine and glycine under these conditions. Unexpectedly, low glucose treatment consistently enhanced serine to glycine conversion, along with an up-regulation of the mitochondrial one-carbon metabolism enzymes, serine hydroxymethyltransferase (SHMT2) and methylenetetrahydrofolate dehydrogenase (MTHFD2). The relative contribution of de novo synthesis greatly increased in low serine/glycine conditions. In bronchial epithelial cells, adaptations occurred in a similar fashion as in cancer cells, but serine synthesis and serine to glycine conversion, as assessed by label enrichments and gene expression levels, were generally lower than in (PHGDH positive) cancer cells. In summary, we found a variable contribution of glucose or non-glucose carbon sources to serine and glycine and a high adaptability of the downstream one-carbon metabolism pathway to variable glucose supply.

Keywords:  Glycine; Lung cancer; Metabolism; Serine; Starvation

DOI:  https://doi.org/10.1186/s40170-024-00337-3
Cold Spring Harb Perspect Med. 2024 Mar 19. pii: a041536. [Epub ahead of print]

Knowledge-Based Therapeutics for Tricarboxylic Acid (TCA) Cycle-Deficient Cancers.

Daniel Peled, Ruth Casey, Eyal Gottlieb.

With the foundation pre-laid, research in the new millennium has readily excavated and expanded upon the architectural framework laid out by Otto Warburg's seminal work in a new wave of "westward expansion," ever widening our understanding of cancer metabolism beyond the telescopic vision seen over a century ago. On this path, the unique circuitry of the cancer metabolic program has been elucidated, illuminating mutations of conserved cellular pathways implicated in tumorigenesis. Paramount among these are mutations in tricarboxylic acid cycle enzymes, succinate dehydrogenase, and fumarate hydratase, leading to deleterious accumulations in metabolic intermediates, "oncometabolites," the pilots of the disease process. In this work, we seek to reflect on the advancements in the field in recent years, updating knowledge on the exact biochemical mechanisms at the helm of the tumor, providing rationale for clinical trials currently underway, and anticipating directions for the future on this expansive frontier.

DOI: https://doi.org/10.1101/cshperspect.a041536
Cell Rep. 2024 Mar 19. pii: S2211-1247(24)00303-6. [Epub ahead of print]43(4): 113975

SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis.

Sarah A Tucker, Song-Hua Hu, Sejal Vyas, Albert Park, Shakchhi Joshi, Aslihan Inal, Tiffany Lam, Emily Tan, Kevin M Haigis, Marcia C Haigis.

  The intestine is a highly metabolic tissue, but the metabolic programs that influence intestinal crypt proliferation, differentiation, and regeneration are still emerging. Here, we investigate how mitochondrial sirtuin 4 (SIRT4) affects intestinal homeostasis. Intestinal SIRT4 loss promotes cell proliferation in the intestine following ionizing radiation (IR). SIRT4 functions as a tumor suppressor in a mouse model of intestinal cancer, and SIRT4 loss drives dysregulated glutamine and nucleotide metabolism in intestinal adenomas. Intestinal organoids lacking SIRT4 display increased proliferation after IR stress, along with increased glutamine uptake and a shift toward de novo nucleotide biosynthesis over salvage pathways. Inhibition of de novo nucleotide biosynthesis diminishes the growth advantage of SIRT4-deficient organoids after IR stress. This work establishes SIRT4 as a modulator of intestinal metabolism and homeostasis in the setting of DNA-damaging stress.

Keywords:  CP: Cancer; SIRT4; glutamine; intestinal organoids; irradiation; nucleotide biosynthesis; nucleotide metabolism; sirtuin

DOI:  https://doi.org/10.1016/j.celrep.2024.113975
Cold Spring Harb Perspect Med. 2024 Mar 19. pii: a041533. [Epub ahead of print]

Tracing the Diverse Paths of One-Carbon Metabolism in Cancer and Beyond.

Esther W Lim, Christian M Metallo.

One-carbon (1C) metabolism is a network of biochemical reactions distributed across organelles that delivers folate-activated 1C units to support macromolecule synthesis, methylation, and reductive homeostasis. Fluxes through these pathways are up-regulated in highly proliferative cancer cells, and anti-folates, which target enzymes within the 1C pathway, have long been used in the treatment of cancer. In this work, we review fundamental aspects of 1C metabolism and place it in context with other biosynthetic and redox pathways, such that 1C metabolism acts to bridge pathways across compartments. We further discuss the importance of stable-isotope-tracing techniques combined with mass spectrometry analysis to study 1C metabolism and conclude by highlighting therapeutic approaches that could exploit cancer cells' dependency on 1C metabolism.

DOI: https://doi.org/10.1101/cshperspect.a041533
Cancer Res. 2024 Mar 19.

Cancer cells hijack physiological metabolic signals to seed liver metastasis.

Andres Rettig, Karuna Ganesh.

Metastasis arises from cancer-cell intrinsic adaptations and permissive tumor microenvironments (TME) that are distinct across different organs. Deciphering the mechanisms underpinning organotropism could provide novel preventive and therapeutic strategies for cancer patients. Rogava and colleagues identified Pip4kc as a driver of liver metastasis, acting by sensitizing cancer cells to insulin-dependent PI3K/AKT signaling, which could be reversed by dual pharmacological inhibition of PI3K and SGLT2 or a ketogenic diet. The study highlights the importance of tumor: microenvironment communication in the context of systemic physiology and points towards potential combination therapies.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0835
J Physiol. 2024 Mar 21.

Monocarboxylate transporter 4 deficiency enhances high-intensity interval training-induced metabolic adaptations in skeletal muscle.

Yuki Tamura, Eunbin Jee, Karina Kouzaki, Takaya Kotani, Koichi Nakazato.

  High-intensity exercise stimulates glycolysis, subsequently leading to elevated lactate production within skeletal muscle. While lactate produced within the muscle is predominantly released into the circulation via the monocarboxylate transporter 4 (MCT4), recent research underscores lactate's function as an intercellular and intertissue signalling molecule. However, its specific intracellular roles within muscle cells remains less defined. In this study, our objective was to elucidate the effects of increased intramuscular lactate accumulation on skeletal muscle adaptation to training. To achieve this, we developed MCT4 knockout mice and confirmed that a lack of MCT4 indeed results in pronounced lactate accumulation in skeletal muscle during high-intensity exercise. A key finding was the significant enhancement in endurance exercise capacity at high intensities when MCT4 deficiency was paired with high-intensity interval training (HIIT). Furthermore, metabolic adaptations supportive of this enhanced exercise capacity were evident with the combination of MCT4 deficiency and HIIT. Specifically, we observed a substantial uptick in the activity of glycolytic enzymes, notably hexokinase, glycogen phosphorylase and pyruvate kinase. The mitochondria also exhibited heightened pyruvate oxidation capabilities, as evidenced by an increase in oxygen consumption when pyruvate served as the substrate. This mitochondrial adaptation was further substantiated by elevated pyruvate dehydrogenase activity, increased activity of isocitrate dehydrogenase - the rate-limiting enzyme in the TCA cycle - and enhanced function of cytochrome c oxidase, pivotal to the electron transport chain. Our findings provide new insights into the physiological consequences of lactate accumulation in skeletal muscle during high-intensity exercises, deepening our grasp of the molecular intricacies underpinning exercise adaptation. KEY POINTS: We pioneered a unique line of monocarboxylate transporter 4 (MCT4) knockout mice specifically tailored to the ICR strain, an optimal background for high-intensity exercise studies. A deficiency in MCT4 exacerbates the accumulation of lactate in skeletal muscle during high-intensity exercise. Pairing MCT4 deficiency with high-intensity interval training (HIIT) results in a synergistic boost in high-intensity exercise capacity, observable both at the organismal level (via a treadmill running test) and at the muscle tissue level (through an ex vivo muscle contractile function test). Coordinating MCT4 deficiency with HIIT enhances both the glycolytic enzyme activities and mitochondrial capacity to oxidize pyruvate.

Keywords:  exercise; glycolysis; high‐intensity interval training; lactate; metabolism; mitochondria; monocarboxylate transporter; skeletal muscle

DOI:  https://doi.org/10.1113/JP285719
bioRxiv. 2024 Mar 07. pii: 2024.03.05.583623. [Epub ahead of print]

A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.

Eugene V Mosharov, Ayelet M Rosenberg, Anna S Monzel, Corey A Osto, Linsey Stiles, Gorazd B Rosoklija, Andrew J Dwork, Snehal Bindra, Ya Zhang, Masashi Fujita, Madeline B Mariani, Mihran Bakalian, David Sulzer, Philip L De Jager, Vilas Menon, Orian S Shirihai, J John Mann, Mark Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard.

Mitochondrial oxidative phosphorylation (OxPhos) powers brain activity 1,2 , and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders 3,4 , underscoring the need to define the brain's molecular energetic landscape 5-10 . To bridge the cognitive neuroscience and cell biology scale gap, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3×3×3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes including OxPhos enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains a diversity of mitochondrial phenotypes driven by both topology and cell types. Compared to white matter, grey matter contains >50% more mitochondria. We show that the more abundant grey matter mitochondria also are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backward linear regression model integrating several neuroimaging modalities 11 , thereby generating a brain-wide map of mitochondrial distribution and specialization that predicts mitochondrial characteristics in an independent brain region of the same donor brain. This new approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain functions, relating it to neuroimaging data, and defining the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders.

DOI: https://doi.org/10.1101/2024.03.05.583623
Structure. 2024 Mar 15. pii: S0969-2126(24)00052-2. [Epub ahead of print]

Structures of 3-acetylpyridine adenine dinucleotide and ADP-ribose bound to the electron input module of respiratory complex I.

Daniel Wohlwend, Luca Mérono, Sarah Bucka, Kevin Ritter, Henning J Jessen, Thorsten Friedrich.

  Energy-converting NADH:ubiquinone oxidoreductase, respiratory complex I, is a major enzyme of energy metabolism that couples NADH oxidation and ubiquinone reduction with proton translocation. The NADH oxidation site features different enzymatic activities with various nucleotides. While the kinetics of these reactions are well described, only binding of NAD+ and NADH have been structurally characterized. Here, we report the structures of the electron input module of Aquifex aeolicus complex I with bound ADP-ribose and 3-acetylpyridine adenine dinucleotides at resolutions better than 2.0 Å. ADP-ribose acts as inhibitor by blocking the "ADP-handle" motif essential for nucleotide binding. The pyridine group of APADH is minimally offset from flavin, which could contribute to its poorer suitability as substrate. A comparison with other nucleotide co-structures surprisingly shows that the adenine ribose and the pyrophosphate moiety contribute most to nucleotide binding, thus all adenine dinucleotides share core binding modes to the unique Rossmann-fold in complex I.

Keywords:  3-acetylpyridine dinucleotide; ADP-ribose; NADH dehydrogenase; bioenergetics; cellular respiration; crystal structures; flavin mononucleotide; respiratory complex I

DOI:  https://doi.org/10.1016/j.str.2024.02.013
Bull Math Biol. 2024 Mar 18. 86(4): 42

Modeling of Mouse Experiments Suggests that Optimal Anti-Hormonal Treatment for Breast Cancer is Diet-Dependent.

Tuğba Akman, Lisa M Arendt, Jürgen Geisler, Vessela N Kristensen, Arnoldo Frigessi, Alvaro Köhn-Luque.

  Estrogen receptor positive breast cancer is frequently treated with anti-hormonal treatment such as aromatase inhibitors (AI). Interestingly, a high body mass index has been shown to have a negative impact on AI efficacy, most likely due to disturbances in steroid metabolism and adipokine production. Here, we propose a mathematical model based on a system of ordinary differential equations to investigate the effect of high-fat diet on tumor growth. We inform the model with data from mouse experiments, where the animals are fed with high-fat or control (normal) diet. By incorporating AI treatment with drug resistance into the model and by solving optimal control problems we found differential responses for control and high-fat diet. To the best of our knowledge, this is the first attempt to model optimal anti-hormonal treatment for breast cancer in the presence of drug resistance. Our results underline the importance of considering high-fat diet and obesity as factors influencing clinical outcomes during anti-hormonal therapies in breast cancer patients.

Keywords:  Aromatase inhibitors; Differential equations; Drug resistance; Estrogen receptor positive breast cancer; High-fat diet; Optimal control

DOI:  https://doi.org/10.1007/s11538-023-01253-1
Aging (Albany NY). 2024 Mar 20. 16

CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction.

Alcir L Dafre, Saadia Zahid, Jessica Jorge Probst, Antonio Currais, Jingting Yu, David Schubert, Pamela Maher.

  BACKGROUND: Modulated by differences in genetic and environmental factors, laboratory mice often show progressive weight gain, eventually leading to obesity and metabolic dyshomeostasis. Since the geroneuroprotector CMS121 has a positive effect on energy metabolism in a mouse model of type 2 diabetes, we investigated the potential of CMS121 to counteract the metabolic changes observed during the ageing process of wild type mice.METHODS: Control or CMS121-containing diets were supplied ad libitum for 6 months, and mice were sacrificed at the age of 7 months. Blood, adipose tissue, and liver were analyzed for glucose, lipids, and protein markers of energy metabolism.
RESULTS: The CMS121 diet induced a 40% decrease in body weight gain and improved both glucose and lipid indexes. Lower levels of hepatic caspase 1, caspase 3, and NOX4 were observed with CMS121 indicating a lower liver inflammatory status. Adipose tissue from CMS121-treated mice showed increased levels of the transcription factors Nrf1 and TFAM, as well as markers of mitochondrial electron transport complexes, levels of GLUT4 and a higher resting metabolic rate. Metabolomic analysis revealed elevated plasma concentrations of short chain acylcarnitines and butyrate metabolites in mice treated with CMS121.
CONCLUSIONS: The diminished de novo lipogenesis, which is associated with increased acetyl-CoA, acylcarnitine, and butyrate metabolite levels, could contribute to safeguarding not only the peripheral system but also the aging brain. By mimicking the effects of ketogenic diets, CMS121 holds promise for metabolic diseases such as obesity and diabetes, since these diets are hard to follow over the long term.

Keywords:  diabetes; geroneuroprotection; ketogenic diet; metabolic disorders; obesity

DOI:  https://doi.org/10.18632/aging.205673
Cell Chem Biol. 2024 Mar 21. pii: S2451-9456(24)00089-8. [Epub ahead of print]31(3): 446-451

Chemical proteomics to study metabolism, a reductionist approach applied at the systems level.

Md Yousuf Ali, Liron Bar-Peled.

Cellular metabolism encompasses a complex array of interconnected biochemical pathways that are required for cellular homeostasis. When dysregulated, metabolism underlies multiple human pathologies. At the heart of metabolic networks are enzymes that have been historically studied through a reductionist lens, and more recently, using high throughput approaches including genomics and proteomics. Merging these two divergent viewpoints are chemical proteomic technologies, including activity-based protein profiling, which combines chemical probes specific to distinct enzyme families or amino acid residues with proteomic analysis. This enables the study of metabolism at the network level with the precision of powerful biochemical approaches. Herein, we provide a primer on how chemical proteomic technologies custom-built for studying metabolism have unearthed fundamental principles in metabolic control. In parallel, these technologies have leap-frogged drug discovery through identification of novel targets and drug specificity. Collectively, chemical proteomics technologies appear to do the impossible: uniting systematic analysis with a reductionist approach.

DOI: https://doi.org/10.1016/j.chembiol.2024.02.015
J Cell Biol. 2024 May 06. pii: e202302069. [Epub ahead of print]223(5):

The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.

Tianyao Xiao, Alyssa M English, Zachary N Wilson, J Alan Maschek, James E Cox, Adam L Hughes.

Cells utilize multiple mechanisms to maintain mitochondrial homeostasis. We recently characterized a pathway that remodels mitochondria in response to metabolic alterations and protein overload stress. This remodeling occurs via the formation of large membranous structures from the mitochondrial outer membrane called mitochondrial-derived compartments (MDCs), which are eventually released from mitochondria and degraded. Here, we conducted a microscopy-based screen in budding yeast to identify factors that regulate MDC formation. We found that two phospholipids, cardiolipin (CL) and phosphatidylethanolamine (PE), differentially regulate MDC biogenesis. CL depletion impairs MDC biogenesis, whereas blocking mitochondrial PE production leads to constitutive MDC formation. Additionally, in response to metabolic MDC activators, cellular and mitochondrial PE declines, and overexpressing mitochondrial PE synthesis enzymes suppress MDC biogenesis. Altogether, our data indicate a requirement for CL in MDC biogenesis and suggest that PE depletion may stimulate MDC formation downstream of MDC-inducing metabolic stress.

DOI: https://doi.org/10.1083/jcb.202302069
Obes Pillars. 2024 Jun;10 100106

Weight-centric prevention of cancer.

Diego Anazco, Andres Acosta, Elizabeth J Cathcart-Rake, Stacy D D'Andre, Maria D Hurtado.

  Background: The link between excess adiposity and carcinogenesis has been well established for multiple malignancies, and cancer is one of the main contributors to obesity-related mortality. The potential role of different weight-loss interventions on cancer risk modification has been assessed, however, its clinical implications remain to be determined. In this clinical review, we present the data assessing the effect of weight loss interventions on cancer risk.Methods: In this clinical review, we conducted a comprehensive search of relevant literature using MEDLINE, Embase, Web of Science, and Google Scholar databases for relevant studies from inception to January 20, 2024. In this clinical review, we present systematic reviews and meta-analysis, randomized clinical trials, and prospective and retrospective observational studies that address the effect of different treatment modalities for obesity in cancer risk. In addition, we incorporate the opinions from experts in the field of obesity medicine and oncology regarding the potential of weight loss as a preventative intervention for cancer.
Results: Intentional weight loss achieved through different modalities has been associated with a reduced cancer incidence. To date, the effect of weight loss on the postmenopausal women population has been more widely studied, with multiple reports indicating a protective effect of weight loss on hormone-dependent malignancies. The effect of bariatric interventions as a protective intervention for cancer has been studied extensively, showing a significant reduction in cancer incidence and mortality, however, data for the effect of bariatric surgery on certain specific types of cancer is conflicting or limited.
Conclusion: Medical nutrition therapy, exercise, antiobesity medication, and bariatric interventions, might lead to a reduction in cancer risk through weight loss-dependent and independent factors. Further evidence is needed to better determine which population might benefit the most, and the amount of weight loss required to provide a clinically significant preventative effect.

Keywords:  Bariatric surgery; Cancer; Obesity; Prevention; Weight loss

DOI:  https://doi.org/10.1016/j.obpill.2024.100106
Mol Cell. 2024 Mar 11. pii: S1097-2765(24)00176-X. [Epub ahead of print]

Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1.

Tristen Wright, Meghan E Turnis, Christy R Grace, Xiao Li, Lauren A Brakefield, Yong-Dong Wang, Haiyan Xu, Ewa Kaminska, Leslie K Climer, Tresor O Mukiza, Chi-Lun Chang, Tudor Moldoveanu, Joseph T Opferman.

  MCL-1 is essential for promoting the survival of many normal cell lineages and confers survival and chemoresistance in cancer. Beyond apoptosis regulation, MCL-1 has been linked to modulating mitochondrial metabolism, but the mechanism(s) by which it does so are unclear. Here, we show in tissues and cells that MCL-1 supports essential steps in long-chain (but not short-chain) fatty acid β-oxidation (FAO) through its binding to specific long-chain acyl-coenzyme A (CoA) synthetases of the ACSL family. ACSL1 binds to the BH3-binding hydrophobic groove of MCL-1 through a non-conventional BH3-domain. Perturbation of this interaction, via genetic loss of Mcl1, mutagenesis, or use of selective BH3-mimetic MCL-1 inhibitors, represses long-chain FAO in cells and in mouse livers and hearts. Our findings reveal how anti-apoptotic MCL-1 facilitates mitochondrial metabolism and indicate that disruption of this function may be associated with unanticipated cardiac toxicities of MCL-1 inhibitors in clinical trials.

Keywords:  MCL-1; acyl-coenzyme A synthetase; apoptosis; fatty acid; metabolism; mitochondria; β-oxidation

DOI:  https://doi.org/10.1016/j.molcel.2024.02.035
Cell Rep Methods. 2024 Mar 14. pii: S2667-2375(24)00059-6. [Epub ahead of print] 100734

Live-cell biosensors based on the fluorescence lifetime of environment-sensing dyes.

Brian P Mehl, Pothiappan Vairaprakash, Li Li, Elizabeth Hinde, Christopher J MacNevin, Chia-Wen Hsu, Enrico Gratton, Bei Liu, Klaus M Hahn.

  In this work, we examine the use of environment-sensitive fluorescent dyes in fluorescence lifetime imaging microscopy (FLIM) biosensors. We screened merocyanine dyes to find an optimal combination of environment-induced lifetime changes, photostability, and brightness at wavelengths suitable for live-cell imaging. FLIM was used to monitor a biosensor reporting conformational changes of endogenous Cdc42 in living cells. The ability to quantify activity using phasor analysis of a single fluorophore (e.g., rather than ratio imaging) eliminated potential artifacts. We leveraged these properties to determine specific concentrations of activated Cdc42 across the cell.

Keywords:  CP: Imaging; Cdc42; FLIM; biosensor; cell; dye; fluorescence; merocyanine; phasor; solvatochromic

DOI:  https://doi.org/10.1016/j.crmeth.2024.100734
Dev Cell. 2024 Mar 18. pii: S1534-5807(24)00110-2. [Epub ahead of print]

Synchronized assembly of the oxidative phosphorylation system controls mitochondrial respiration in yeast.

Daiana N Moretti-Horten, Carlotta Peselj, Asli Aras Taskin, Lisa Myketin, Uwe Schulte, Oliver Einsle, Friedel Drepper, Marcin Luzarowski, F-Nora Vögtle.

  Control of protein stoichiometry is essential for cell function. Mitochondrial oxidative phosphorylation (OXPHOS) presents a complex stoichiometric challenge as the ratio of the electron transport chain (ETC) and ATP synthase must be tightly controlled, and assembly requires coordinated integration of proteins encoded in the nuclear and mitochondrial genome. How correct OXPHOS stoichiometry is achieved is unknown. We identify the MitochondrialRegulatory hub for respiratoryAssembly (MiRA) platform, which synchronizes ETC and ATP synthase biogenesis in yeast. Molecularly, this is achieved by a stop-and-go mechanism: the uncharacterized protein Mra1 stalls complex IV assembly. Two "Go" signals are required for assembly progression: binding of the complex IV assembly factor Rcf2 and Mra1 interaction with an Atp9-translating mitoribosome induce Mra1 degradation, allowing synchronized maturation of complex IV and the ATP synthase. Failure of the stop-and-go mechanism results in cell death. MiRA controls OXPHOS assembly, ensuring correct stoichiometry of protein machineries encoded by two different genomes.

Keywords:  complex stoichiometry; mitochondria; mitoribosome; protein complex assembly; protein import; protein quality control; respiratory chain

DOI:  https://doi.org/10.1016/j.devcel.2024.02.011
ACS Med Chem Lett. 2024 Mar 14. 15(3): 381-387

Discovery of Alternative Binding Poses through Fragment-Based Identification of DHODH Inhibitors.

Lindsey G DeRatt, E Christine Pietsch, Justin S Cisar, Edgar Jacoby, Faraz Kazmi, Rosalie Matico, Paul Shaffer, Alexandra Tanner, Weixue Wang, Ricardo Attar, James P Edwards, Scott D Kuduk.

Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that affects many aspects essential to cell proliferation and survival. Recently, DHODH has been identified as a potential target for acute myeloid leukemia therapy. Herein, we describe the identification of potent DHODH inhibitors through a scaffold hopping approach emanating from a fragment screen followed by structure-based drug design to further improve the overall profile and reveal an unexpected novel binding mode. Additionally, these compounds had low P-gp efflux ratios, allowing for applications where exposure to the brain would be required.

DOI: https://doi.org/10.1021/acsmedchemlett.3c00543
bioRxiv. 2024 Mar 09. pii: 2024.03.08.581297. [Epub ahead of print]

Mitochondrial Raf1 Regulates Glutamine Catabolism.

Ronald L Shanderson, Ian D Ferguson, Zurab Siprashvili, Luca Ducoli, Albert M Li, Weili Miao, Suhas Srinivasan, Mary Grace Velasco, Yang Li, Jiangbin Ye, Paul A Khavari.

Raf kinases play vital roles in normal mitogenic signaling and cancer, however, the identities of functionally important Raf-proximal proteins throughout the cell are not fully known. Raf1 proximity proteomics/BioID in Raf1-dependent cancer cells unexpectedly identified Raf1-adjacent proteins known to reside in the mitochondrial matrix. Inner-mitochondrial localization of Raf1 was confirmed by mitochondrial purification and super-resolution microscopy. Inside mitochondria, Raf1 associated with glutaminase (GLS) in diverse human cancers and enabled glutaminolysis, an important source of biosynthetic precursors in cancer. These impacts required Raf1 kinase activity and were independent of canonical MAP kinase pathway signaling. Kinase-dead mitochondrial matrix-localized Raf1 impaired glutaminolysis and tumorigenesis in vivo. These data indicate that Raf1 localizes inside mitochondria where it interacts with GLS to engage glutamine catabolism and support tumorigenesis.

DOI: https://doi.org/10.1101/2024.03.08.581297
Exp Cell Res. 2024 Mar 16. pii: S0014-4827(24)00099-5. [Epub ahead of print] 114008

A comparison between different human hepatocyte models reveals profound differences in net glucose production, lipid composition and metabolism in vitro.

Flavio Bonanini, Madhulika Singh, Hong Yang, Dorota Kurek, Amy C Harms, Adil Mardinoglu, Thomas Hankemeier.

  Hepatocytes are responsible for maintaining a stable blood glucose concentration during periods of nutrient scarcity. The breakdown of glycogen and de novo synthesis of glucose are crucial metabolic pathways deeply interlinked with lipid metabolism. Alterations in these pathways are often associated with metabolic diseases with serious clinical implications. Studying energy metabolism in human cells is challenging. Primary hepatocytes are still considered the golden standard for in vitro studies and have been instrumental in elucidating key aspects of energy metabolism found in vivo. As a result of several limitations posed by using primary cells, a multitude of alternative hepatocyte cellular models emerged as potential substitutes. Yet, there remains a lack of clarity regarding the precise applications for which these models accurately reflect the metabolic competence of primary hepatocytes. In this study, we compared primary hepatocytes, stem cell-derived hepatocytes, adult donor-derived liver organoids, immortalized Upcyte-hepatocytes and the hepatoma cell line HepG2s in their response to a glucose production challenge. We observed the highest net glucose production in primary hepatocytes, followed by organoids, stem-cell derived hepatocytes, Upcyte-hepatocytes and HepG2s. Glucogenic gene induction was observed in all tested models, as indicated by an increase in G6PC and PCK1 expression. Lipidomic analysis revealed considerable differences across the models, with organoids showing the closest similarity to primary hepatocytes in the common lipidome, comprising 347 lipid species across 19 classes. Changes in lipid profiles as a result of the glucose production challenge showed a variety of, and in some cases opposite, trends when compared to primary hepatocytes.

Keywords:  Energy metabolism; Hepatocytes; In vitro glucose production; Lipidomics; Organoids

DOI:  https://doi.org/10.1016/j.yexcr.2024.114008
Cell Biosci. 2024 Mar 19. 14(1): 36

Association of glucose-lowering drug target and risk of gastrointestinal cancer: a mendelian randomization study.

Yi Yang, Bo Chen, Chongming Zheng, Hao Zeng, Junxi Zhou, Yaqing Chen, Qing Su, Jingxian Wang, Juejin Wang, Yurong Wang, Hongli Wang, Ruxue Jin, Zhiyuan Bo, Gang Chen, Yi Wang.

  BACKGROUND & AIMS: Glucose-lowering drug is associated with various cancers, but the causality with gastrointestinal cancer risk is rarely reported. We aimed to explore the causality between them in this Mendelian randomization (MR) study.METHODS: Two-sample MR, summary-data-based (SMR), mediation MR, and colocalization analyses was employed. Ten glucose-lowering drug targets (PPARG, DPP4, GLP1R, INSR, SLC5A2, ABCC8, KCNJ11, ETFDH, GPD2, PRKAB1) and seven types of gastrointestinal cancer (anal carcinoma, cardia cancer, gastric cancer, hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), pancreatic cancer, rectum cancer) were included. Patients with gastrointestinal cancers from six different large GWAS databases, including the UK Biobank and Finnish cohorts were incorporated, for discovery and external validation. Meta-analysis was employed to integrate the results from both discovery and validation cohorts, thereby ensuring the reliability of findings.
RESULTS: ABCC8/KCNJ11 were associated with pancreatic cancer risk in both two-sample MR (odds ratio (OR): 15.058, per standard deviation unit (SD) change of glucose-lowering durg target perturbation equivalent to 1 SD unit of HbA1c lowering; 95% confidence interval (95% CI): 3.824-59.295; P-value = 0.0001) and SMR (OR: 1.142; 95% CI: 1.013-1.287; P-value = 0.030) analyses. The mediation effect of body mass index (OR: 0.938; 95% CI: 0.884-0.995; proportion of mediation effect: 3.001%; P-value = 0.033) on ABCC8/KCNJ11 and pancreatic cancer was uncovered. Strong connections of DPP4 with anal carcinoma (OR: 0.123; 95% CI: 0.020-0.745; P-value = 0.023) and ICC (OR: 7.733; 95% CI: 1.743-34.310; P-value = 0.007) were detected. PPARG was associated with anal carcinoma (OR: 12.909; 95% CI: 3.217-51.795; P-value = 0.0003), HCC (OR: 36.507; 95% CI: 8.929-149.259; P-value < 0.0001), and pancreatic cancer (OR: 0.110; 95% CI: 0.071-0.172; P-value < 0.0001). SLC5A2 was connected with pancreatic cancer (OR: 8.096; 95% CI: 3.476-18.857; P-value < 0.0001). Weak evidence indicated the connections of GLP1R, GPD2, and PRKAB1 with anal carcinoma, cardia cancer, ICC, and rectum cancer. In addition, the corresponding results were consistently validated in both the validation cohorts and the integrated outcomes.
CONCLUSIONS: Some glucose-lowering drugs were associated with gastrointestinal cancer risk, which might provide new ideas for gastrointestinal cancer treatment.

Keywords:  Causality; Gastrointestinal cancer risk; Glucose-lowering drug target; Mendelian randomization

DOI:  https://doi.org/10.1186/s13578-024-01214-8
Am J Clin Nutr. 2024 Mar 20. pii: S0002-9165(24)00382-4. [Epub ahead of print]

Substitution of dietary monounsaturated fatty acids from olive oil for saturated fatty acids from lard increases LDL apolipoprotein B-100 fractional catabolic rate in subjects with dyslipidemia associated with insulin resistance: a randomized controlled trial.

Louis-Charles Desjardins, Francis Brière, André J Tremblay, Maryka Rancourt-Bouchard, Jean-Philippe Drouin-Chartier, Jacques Corbeil, Valéry Lemelin, Amélie Charest, Ernst J Schaefer, Benoît Lamarche, Patrick Couture.

  BACKGROUND: The substitution of monounsaturated acids (MUFAs) for saturated fatty acids (SFAs) is recommended for cardiovascular disease prevention but its impact on lipoprotein metabolism in subjects with dyslipidemia associated with insulin resistance (IR) remains largely unknown.OBJECTIVE: This study aimed to evaluate the impact of substituting MUFAs for SFAs on the in vivo kinetics of apolipoprotein (apo)B-containing lipoproteins and on the plasma lipidomic profile in adults with IR-induced dyslipidemia.
DESIGN: Males and females with dyslipidemia associated with IR (n = 18) were recruited for this crossover double-blind randomized controlled trial. Subjects consumed, in random order, a diet rich in SFAs (SFAs: 13.4%E; MUFAs: 14.4%E) and a diet rich in MUFAs (SFAs: 7.1%E; MUFAs: 20.7%E) in fully controlled feeding conditions for periods of 4 wk each, separated by a 4-wk washout. At the end of each diet, fasting plasma samples were taken together with measurements of the in vivo kinetics of apoB-containing lipoproteins.
RESULTS: Substituting MUFAs for SFAs had no impact on TRL apoB-48 fractional catabolic rate (FCR) (Δ = -8.9%, P = 0.4) and production rate (PR) (Δ = 0.0%, P = 0.9), although it decreased VLDL apoB-100 pool size (PS) (Δ = -22.5%; P = 0.01). This substitution also reduced LDL-C (Δ = -7.0%; P = 0.01), non-HDL cholesterol (Δ = -2.5%; P = 0.04) and LDL apoB-100 PS (Δ = -6.0%; P = 0.05). These differences were partially attributed to an increase in LDL apoB-100 FCR (Δ = +1.6%; P = 0.05). The MUFA diet showed reduced sphingolipid concentrations and elevated glycerophospholipid levels compared with the SFA diet.
CONCLUSIONS: This study demonstrated that substituting dietary MUFAs for SFAs decreases LDL-C levels and LDL PS by increasing LDL apoB-100 FCR and results in an overall improved plasma lipidomic profile in individuals with IR-induced lipidemia.
TRIAL REGISTRATION: clinicaltrials.gov NCT03872349.

Keywords:  insulin resistance; lipidomics; lipoprotein metabolism; monounsaturated fatty acids; saturated fatty acids

DOI:  https://doi.org/10.1016/j.ajcnut.2024.03.015
Biomed Opt Express. 2024 Mar 01. 15(3): 1408-1417

Assessing cell viability with dynamic optical coherence microscopy.

Chao J Liu, Jason T Smith, Yuanbo Wang, Jonathan N Ouellette, Jeremy D Rogers, Jonathan D Oliner, Michael Szulczewski, Eric Wait, William Brown, Adam Wax, Kevin W Eliceiri, John Rafter.

Assessing cell viability is important in many fields of research. Current optical methods to assess cell viability typically involve fluorescent dyes, which are often less reliable and have poor permeability in primary tissues. Dynamic optical coherence microscopy (dOCM) is an emerging tool that provides label-free contrast reflecting changes in cellular metabolism. In this work, we compare the live contrast obtained from dOCM to viability dyes, and for the first time to our knowledge, demonstrate that dOCM can distinguish live cells from dead cells in murine syngeneic tumors. We further demonstrate a strong correlation between dOCM live contrast and optical redox ratio by metabolic imaging in primary mouse liver tissue. The dOCM technique opens a new avenue to apply label-free imaging to assess the effects of immuno-oncology agents, targeted therapies, chemotherapy, and cell therapies using live tumor tissues.

DOI: https://doi.org/10.1364/BOE.509835
Insect Sci. 2024 Mar 21.

Fasting as a precursor to high-fat diet enhances mitochondrial resilience in Drosophila melanogaster.

Florence Hunter-Manseau, Simon B Cormier, Rebekah Strang, Nicolas Pichaud.

  Changes in diet type and nutrient availability can impose significant environmental stress on organisms, potentially compromising physiological functions and reproductive success. In nature, dramatic fluctuations in dietary resources are often observed and adjustments to restore cellular homeostasis are crucial to survive this type of stress. In this study, we exposed male Drosophila melanogaster to two modulated dietary treatments: one without a fasting period before exposure to a high-fat diet and the other with a 24-h fasting period. We then investigated mitochondrial metabolism and molecular responses to these treatments. Exposure to a high-fat diet without a preceding fasting period resulted in disrupted mitochondrial respiration, notably at the level of complex I. On the other hand, a short fasting period before the high-fat diet maintained mitochondrial respiration. Generally, transcript abundance of genes associated with mitophagy, heat-shock proteins, mitochondrial biogenesis, and nutrient sensing pathways increased either slightly or significantly following a fasting period and remained stable when flies were subsequently put on a high-fat diet, whereas a drastic decrease of almost all transcript abundances was observed for all these pathways when flies were exposed directly to a high-fat diet. Moreover, mitochondrial enzymatic activities showed less variation after the fasting period than the treatment without a fasting period. Overall, our study sheds light on the mechanistic protective effects of fasting prior to a high-fat diet and highlights the metabolic flexibility of Drosophila mitochondria in response to abrupt dietary changes and have implication for adaptation of species to their changing environment.

Keywords:  dietary modulation; fasting; high‐fat diet; metabolic flexibility; mitochondrial metabolism; stress response

DOI:  https://doi.org/10.1111/1744-7917.13355
Mitochondrial Commun. 2024 ;2 1-13

Structural determinants of mitochondrial STAT3 targeting and function.

Isabelle J Marié, Tanaya Lahiri, Özlem Önder, Kojo S J Elenitoba-Johnson, David E Levy.

  Signal transducer and activator of transcription (STAT) 3 has been found within mitochondria in addition to its canonical role of shuttling between cytoplasm and nucleus during cytokine signaling. Mitochondrial STAT3 has been implicated in modulation of cellular metabolism, largely through effects on the respiratory electron transport chain. However, the structural requirements underlying mitochondrial targeting and function have remained unclear. Here, we show that mitochondrial STAT3 partitions between mitochondrial compartments defined by differential detergent solubility, suggesting that mitochondrial STAT3 is membrane associated. The majority of STAT3 was found in an SDS soluble fraction copurifying with respiratory chain proteins, including numerous components of the complex I NADH dehydrogenase, while a minor component was found with proteins of the mitochondrial translation machinery. Mitochondrial targeting of STAT3 required the amino-terminal domain, and an internal linker domain motif also directed mitochondrial translocation. However, neither the phosphorylation of serine 727 nor the presence of mitochondrial DNA was required for the mitochondrial localization of STAT3. Two cysteine residues in the STAT3 SH2 domain, which have been previously suggested to be targets for protein palmitoylation, were also not required for mitochondrial translocation, but were required for its function as an enhancer of complex I activity. These structural determinants of STAT3 mitochondrial targeting and function provide potential therapeutic targets for disrupting the activity of mitochondrial STAT3 in diseases such as cancer.

Keywords:  Electron transport chain; Mitochondrial import; Stat3

DOI:  https://doi.org/10.1016/j.mitoco.2024.01.001
Cardiovasc Diabetol. 2024 Mar 16. 23(1): 97

Hepatic insulin resistance and muscle insulin resistance are characterized by distinct postprandial plasma metabolite profiles: a cross-sectional study.

Anouk Gijbels, Balázs Erdős, Inez Trouwborst, Kelly M Jardon, Michiel E Adriaens, Gijs H Goossens, Ellen E Blaak, Edith J M Feskens, Lydia A Afman.

  BACKGROUND: Tissue-specific insulin resistance (IR) predominantly in muscle (muscle IR) or liver (liver IR) has previously been linked to distinct fasting metabolite profiles, but postprandial metabolite profiles have not been investigated in tissue-specific IR yet. Given the importance of postprandial metabolic impairments in the pathophysiology of cardiometabolic diseases, we compared postprandial plasma metabolite profiles in response to a high-fat mixed meal between individuals with predominant muscle IR or liver IR.METHODS: This cross-sectional study included data from 214 women and men with BMI 25-40 kg/m2, aged 40-75 years, and with predominant muscle IR or liver IR. Tissue-specific IR was assessed using the muscle insulin sensitivity index (MISI) and hepatic insulin resistance index (HIRI), which were calculated from the glucose and insulin responses during a 7-point oral glucose tolerance test. Plasma samples were collected before (T = 0) and after (T = 30, 60, 120, 240 min) consumption of a high-fat mixed meal and 247 metabolite measures, including lipoproteins, cholesterol, triacylglycerol (TAG), ketone bodies, and amino acids, were quantified using nuclear magnetic resonance spectroscopy. Differences in postprandial plasma metabolite iAUCs between muscle and liver IR were tested using ANCOVA with adjustment for age, sex, center, BMI, and waist-to-hip ratio. P-values were adjusted for a false discovery rate (FDR) of 0.05 using the Benjamini-Hochberg method.
RESULTS: Sixty-eight postprandial metabolite iAUCs were significantly different between liver and muscle IR. Liver IR was characterized by greater plasma iAUCs of large VLDL (p = 0.004), very large VLDL (p = 0.002), and medium-sized LDL particles (p = 0.026), and by greater iAUCs of TAG in small VLDL (p = 0.025), large VLDL (p = 0.003), very large VLDL (p = 0.002), all LDL subclasses (all p < 0.05), and small HDL particles (p = 0.011), compared to muscle IR. In liver IR, the postprandial plasma fatty acid (FA) profile consisted of a higher percentage of saturated FA (p = 0.013), and a lower percentage of polyunsaturated FA (p = 0.008), compared to muscle IR.
CONCLUSION: People with muscle IR or liver IR have distinct postprandial plasma metabolite profiles, with more unfavorable postprandial metabolite responses in those with liver IR compared to muscle IR.

Keywords:  Dyslipidemia; Glucose homeostasis; Insulin resistance; Lipid metabolism; Lipoproteins; Meal challenge test; Metabolomics; Postprandial lipemia; Postprandial metabolism; Triglycerides

DOI:  https://doi.org/10.1186/s12933-024-02188-0
ACS Chem Biol. 2024 Mar 20.

Lipid-Restricted Culture Media Reveal Unexpected Cancer Cell Sensitivities.

Ralston B Goldfarb, Matthew J Atala Pleshinger, David F Yan, Drew J Adams.

Cancer cell culture models frequently rely on fetal bovine serum as a source of protein and lipid factors that support cell survival and proliferation; however, serum-containing media imperfectly mimic the in vivo cancer environment. Recent studies suggest that typical serum-containing cell culture conditions can mask cancer dependencies, for example, on cholesterol biosynthesis enzymes, that exist in vivo and emerge when cells are cultured in media that provide more realistic levels of lipids. Here, we describe a high-throughput screen that identified fenretinide and ivermectin as small molecules whose cytotoxicity is greatly enhanced in lipid-restricted media formulations. The mechanism of action studies indicates that ivermectin-induced cell death involves oxidative stress, while fenretinide likely targets delta 4-desaturase, sphingolipid 1, a lipid desaturase necessary for ceramide synthesis, to induce cell death. Notably, both fenretinide and ivermectin have previously demonstrated in vivo anticancer efficacy despite their low cytotoxicity under typical cell culture conditions. These studies suggest ceramide synthesis as a targetable vulnerability of cancer cells cultured under lipid-restricted conditions and reveal a general screening strategy for identifying additional cancer dependencies masked by the superabundance of medium lipids.

DOI: https://doi.org/10.1021/acschembio.3c00699
Curr Oncol Rep. 2024 Mar 19.

Novel Therapeutic Targets in Acute Myeloid Leukemia (AML).

Michael Wysota, Marina Konopleva, Shane Mitchell.

  PURPOSE OF REVIEW: This review seeks to identify and describe novel genetic and protein targets and their associated therapeutics currently being used or studied in the treatment of acute myeloid leukemia (AML).RECENT FINDINGS: Over the course of the last 5-6 years, several targeted therapies have been approved by the FDA, for the treatment of both newly diagnosed as well as relapsed/refractory AML. These novel therapeutics, as well as several others currently under investigation, have demonstrated activity in AML and have improved outcomes for many patients. Patient outcomes in AML have slowly improved over time, though for many patients, particularly elderly patients or those with relapsed/refractory disease, mortality remains very high. With the identification of several molecular/genetic drivers and protein targets and development of therapeutics which leverage those mechanisms to target leukemic cells, outcomes for patients with AML have improved and continue to improve significantly.

Keywords:  AML; Acute myeloid leukemia; Immune therapy; Molecular targets; Novel therapeutics

DOI:  https://doi.org/10.1007/s11912-024-01503-y
PLoS Biol. 2024 Mar;22(3): e3002549

GALDAR: A genetically encoded galactose sensor for visualizing sugar metabolism in vivo.

Uğurcan Sakizli, Tomomi Takano, Sa Kan Yoo.

Sugar metabolism plays a pivotal role in sustaining life. Its dynamics within organisms is less understood compared to its intracellular metabolism. Galactose, a hexose stereoisomer of glucose, is a monosaccharide transported via the same transporters with glucose. Galactose feeds into glycolysis and regulates protein glycosylation. Defects in galactose metabolism are lethal for animals. Here, by transgenically implementing the yeast galactose sensing system into Drosophila, we developed a genetically encoded sensor, GALDAR, which detects galactose in vivo. Using this heterologous system, we revealed dynamics of galactose metabolism in various tissues. Notably, we discovered that intestinal stem cells do not uptake detectable levels of galactose or glucose. GALDAR elucidates the role for galactokinase in metabolism of galactose and a transition of galactose metabolism during the larval period. This work provides a new system that enables analyses of in vivo sugar metabolism.

DOI: https://doi.org/10.1371/journal.pbio.3002549
Cancer Control. 2024 Jan-Dec;31:31 10732748241241158

Next Generation Weight Loss Drugs for the Prevention of Cancer?

Chantelle Carbonell, Mariet Mathew Stephen, Yibing Ruan, Matthew T Warkentin, Darren R Brenner.

  Background: Western populations are losing the battle over healthy weight management, and excess body weight is a notable cancer risk factor at the population level. There is ongoing interest in pharmacological interventions aimed at promoting weight loss, including GLP-1 receptor agonists (GLP-1RA), which may be a useful tool to stem the rising tide of obesity-related cancers. Purpose: To investigate the potential of next generation weight loss drugs (NGWLD) like GLP-1RA in population-level chemoprevention.Research Design: We used the OncoSim microsimulation tool to estimate the population-level reductions in obesity and the potentially avoidable obesity-related cancers in Canada over the next 25 years.Results: We estimated a total of 71 281 preventable cancers by 2049, with 36 235 and 35 046 cancers prevented for females and males, respectively. Among the 327 254 total projected cancer cases in 2049, 1.3% are estimated to be preventable through intervention with NGWLD.Conclusions: Pharmacologic intervention is not the ideal solution for the obesity-related cancer crisis. However, these agents and subsequent generations provide an additional tool to rapidly reduce body weight and adiposity in populations that have been extremely challenging to reduce weight with standard diet and exercise approaches. Additional research is needed around approaches to prevent initial weight gain and maintain long-term weight loss.

Keywords:  Glucagon-like peptide-1 receptor agonists; cancer prevention; chemoprevention; pharmacology; weight loss

DOI:  https://doi.org/10.1177/10732748241241158
Clin Exp Med. 2024 Mar 16. 24(1): 53

Use of tryptic peptide MALDI mass spectrometry imaging to identify the spatial proteomic landscape of colorectal cancer liver metastases.

Celine Man Ying Li, Matthew T Briggs, Yea-Rin Lee, Teresa Tin, Clifford Young, John Pierides, Gurjeet Kaur, Paul Drew, Guy J Maddern, Peter Hoffmann, Manuela Klingler-Hoffmann, Kevin Fenix.

  Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. CRC liver metastases (CRLM) are often resistant to conventional treatments, with high rates of recurrence. Therefore, it is crucial to identify biomarkers for CRLM patients that predict cancer progression. This study utilised matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to spatially map the CRLM tumour proteome. CRLM tissue microarrays (TMAs) of 84 patients were analysed using tryptic peptide MALDI-MSI to spatially monitor peptide abundances across CRLM tissues. Abundance of peptides was compared between tumour vs stroma, male vs female and across three groups of patients based on overall survival (0-3 years, 4-6 years, and 7+ years). Peptides were then characterised and matched using LC-MS/MS. A total of 471 potential peptides were identified by MALDI-MSI. Our results show that two unidentified m/z values (1589.876 and 1092.727) had significantly higher intensities in tumours compared to stroma. Ten m/z values were identified to have correlation with biological sex. Survival analysis identified three peptides (Histone H4, Haemoglobin subunit alpha, and Inosine-5'-monophosphate dehydrogenase 2) and two unidentified m/z values (1305.840 and 1661.060) that were significantly higher in patients with shorter survival (0-3 years relative to 4-6 years and 7+ years). This is the first study using MALDI-MSI, combined with LC-MS/MS, on a large cohort of CRLM patients to identify the spatial proteome in this malignancy. Further, we identify several protein candidates that may be suitable for drug targeting or for future prognostic biomarker development.

Keywords:  Biomarkers; Colorectal cancer; Colorectal cancer liver metastasis; Drug targets; LC-MS/MS; MALDI-MSI

DOI:  https://doi.org/10.1007/s10238-024-01311-5
Life Sci. 2024 Mar 14. pii: S0024-3205(24)00164-4. [Epub ahead of print]344 122575

Future perspectives on the roles of mitochondrial dynamics in the heart in obesity and aging.

Chayodom Maneechote, Siriporn C Chattipakorn, Nipon Chattipakorn.

  Increasing global obesity rates and an aging population are independently linked to cardiac complications. Consequently, it is crucial to comprehensively understand the mechanisms behind these conditions to advance innovative therapies for age-related diseases. Mitochondrial dysfunction, specifically defects in mitochondrial fission/fusion processes, has emerged as a central regulator of cardiac complications in aging and age-related diseases (e.g., obesity). Since excessive fission and impaired fusion of cardiac mitochondria lead to disruptions in mitochondrial dynamics and cellular metabolism in aging and obesity, modulating mitochondrial dynamics with either fission inhibitors or fusion promoters has offered cardioprotection against these pathological conditions in preclinical models. This review explores the molecular mechanisms governing mitochondrial dynamics as well as the disturbances observed in aging and obesity. Additionally, pharmaceutical interventions that specifically target the processes of mitochondrial fission and fusion are presented and discussed. By establishing a connection between mitochondrial dynamism through fission and fusion and the advancement or mitigation of age-related diseases, particularly obesity, this review provides valuable insights into the progression and potential prevention strategies for such conditions.

Keywords:  Aging; Cardiovascular disease; Mitochondria; Mitochondrial dynamics; Obesity

DOI:  https://doi.org/10.1016/j.lfs.2024.122575
World J Gastroenterol. 2024 Feb 21. 30(7): 714-727

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival.

Pui-Yin Leung, Wenjing Chen, Anissa N Sari, Poojitha Sitaram, Pui-Kei Wu, Susan Tsai, Jong-In Park.

  BACKGROUND: Pancreatic cancer is a leading cause of cancer-related deaths. Increased activity of the epidermal growth factor receptor (EGFR) is often observed in pancreatic cancer, and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration. Nevertheless, erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes. We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential (Δψm), facilitate tumor cell uptake of Δψm-sensitive agents, disrupt mitochondrial homeostasis, and subsequently trigger tumor cell death. Erlotinib has not been tested for this effect.AIM: To determine whether erlotinib can elevate Δψm and increase tumor cell uptake of Δψm-sensitive agents, subsequently triggering tumor cell death.
METHODS: Δψm-sensitive fluorescent dye was used to determine how erlotinib affects Δψm in pancreatic adenocarcinoma (PDAC) cell lines. The viability of conventional and patient-derived primary PDAC cell lines in 2D- and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone (MitoQ), a Δψm-sensitive MitoQ. The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0. The preclinical efficacy of the two-drug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts.
RESULTS: Erlotinib elevated Δψm in PDAC cells, facilitating tumor cell uptake and mitochondrial enrichment of Δψm-sensitive agents. MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses, while erlotinib pretreatment potentiated low doses of MitoQ. SynergyFinder suggested that these drugs synergistically induced tumor cell lethality. Consistent with in vitro data, erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent.
CONCLUSION: Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.

Keywords:  Combination therapy; Erlotinib; Mitochondria; Mitochondria-targeted ubiquinone; Pancreatic cancer

DOI:  https://doi.org/10.3748/wjg.v30.i7.714
J Am Assoc Lab Anim Sci. 2024 Mar 19.

Effects of High-protein and High-fiber Diets on Weight and Glucose Regulation in Spiny Mice (Acomys cahirinus).

Joette W Crews, Ammar A Rashied, Tamas Nagy, Cristin E Roach.

Despite the long-term contributions of the spiny mouse (Acomys cahirinus) to research, basic knowledge of appropriate nutrition is lacking for this species. In the wild, spiny mice eat a high-fiber, high-protein food source. In the research setting, spiny mice are prone to obesity that can lead to diabetes mellitus. Common dietary modifications for weight control in humans with diabetes mellitus consist of increased fiber and protein. We hypothesized that increasing the dietary protein or fiber of spiny mice would reduce weight gain and improve their glycemic control, whereas the combination of protein and fiber in the diet would achieve optimal weight management and glycemic control without diet-related pathologic changes. We randomly assigned cages of young adult spiny mice (n = 34) to one of 4 diets: high protein (HP), high fiber (HF), a combination of both high protein and high fiber (HPF), or the base (control) diet (BD). Over the 8-wk study, spiny mice given HF diets maintained baseline weights despite the elevated dietary protein. None of the diets altered blood glucose levels; all diet groups maintained mean blood glucose levels within normal ranges. Spiny mice seem particularly sensitive to changes within their environment, as seen by increased food waste and transient elevated blood glucose levels when the spiny mice were transitioned to novel diets. The short-term elevations in protein and fiber that we tested were well tolerated by spiny mice. Although HF was effective in controlling weight, the ideal percentage of fiber still needs to be determined. The combination diet (HPF) maintained weight and body condition scores and showed a nonsignificant elevation of blood glucose that warrants a longer diet trial before our recommending this specific combination.

DOI: https://doi.org/10.30802/AALAS-JAALAS-23-000112