bims-medica 2024-09-29 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024‒09‒29
27 papers selected by
Brett Chrest, Wake Forest University

Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.
Identifying targetable metabolic dependencies across colorectal cancer progression.
Metabolic Reprogramming in Glioblastoma Multiforme: A Review of Pathways and Therapeutic Targets.
Mitochondrial metabolism: A moving target in hepatocellular carcinoma therapy.
Redox remodeling of central metabolism as a driving force for cellular protection, proliferation, differentiation, and dysfunction.
Mitochondria-targeted cancer analysis using survival and expression: Prioritizing mitochondrial targets that alleviate pancreatic cancer cell phenotypes.
Anticancer effects of high-dose extracellular citrate treatment in pancreatic cancer cells under different glucose concentrations.
BMP receptor 2 inhibition regulates mitochondrial bioenergetics to induce synergistic cell death with BCL-2 inhibitors in leukemia and NSLC cells.
Three-dimensional analysis of mitochondria in a patient-derived xenograft model of triple negative breast cancer reveals mitochondrial network remodeling following chemotherapy treatments.
Metabolic landscape of the healthy pancreas and pancreatic tumor microenvironment.
Quizartinib: a new hope in acute myeloid leukemia, an applied comprehensive review.
Differentiating leukemia subtypes based on metabolic signatures using hyperpolarized 13C NMR.
Mitochondrial lipid peroxidation is necessary but not sufficient for induction of ferroptosis.
Uncovering the Links Between Dietary Sugar and Cancer: A Narrative Review Exploring the Impact of Dietary Sugar and Fasting on Cancer Risk and Prevention.
A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
Cholesterol synthesis is essential for the growth of liver metastasis-prone colorectal cancer cells.
What to Eat for Cancer Prevention: The Total Dietary Pattern as a Combination Treatment for Prevention.
A secondary β-hydroxybutyrate metabolic pathway linked to energy balance.
Protocol to monitor live-cell, real-time, mitochondrial respiration in mouse muscle cells using the Resipher platform.
Dietary Patterns and Breast Cancer Risk: A KCPS-II Cohort Study.
Association of metabolic obesity phenotypes with risk of overall and site-specific cancers: a systematic review and meta-analysis of cohort studies.
Diagnostic performance of serum metabolites biomarker associated with colorectal adenoma: a systematic review.
Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway.
Combinations of HDAC inhibitor and PPAR agonist induce ferroptosis of leukemic stem cell-like cells in acute myeloid leukemia.
Improvement of substrate specificity of the direct electron transfer type FAD-dependent glucose dehydrogenase catalytic subunit.
Beyond MitoCarta-expanding the list of candidate proteins involved in mitochondrial functions using a biological network approach.
Hematopoietic cells emerging from hemogenic endothelium exhibit lineage-specific oxidative stress responses.

Cell Rep. 2024 Sep 20. pii: S2211-1247(24)01126-4. [Epub ahead of print]43(10): 114775

Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.

Cara Abecunas, Audrey D Kidd, Ying Jiang, Hui Zong, Mohammad Fallahi-Sichani.

  Targeting the distinct metabolic needs of tumor cells has recently emerged as a promising strategy for cancer therapy. The heterogeneous, context-dependent nature of cancer cell metabolism, however, poses challenges to identifying effective therapeutic interventions. Here, we utilize various unsupervised and supervised multivariate modeling approaches to systematically pinpoint recurrent metabolic states within hundreds of cancer cell lines, elucidate their association with tumor lineage and growth environments, and uncover vulnerabilities linked to their metabolic states across diverse genetic and tissue contexts. We validate key findings via analysis of data from patient-derived tumors and pharmacological screens and by performing genetic and pharmacological experiments. Our analysis uncovers synthetically lethal associations between the tumor metabolic state (e.g., oxidative phosphorylation), driver mutations (e.g., loss of tumor suppressor PTEN), and actionable biological targets (e.g., mitochondrial electron transport chain). Investigating the mechanisms underlying these relationships can inform the development of more precise and context-specific, metabolism-targeted cancer therapies.

Keywords:  CP: Cancer; CP: Metabolism; PTEN; cancer metabolism; cancer therapies; glioma; metabolic state vulnerabilities; mitochondrial electron transport chain; multivariate modeling; oxidative phosphorylation; synthetic lethality

DOI:  https://doi.org/10.1016/j.celrep.2024.114775
Mol Metab. 2024 Sep 25. pii: S2212-8778(24)00168-6. [Epub ahead of print] 102037

Identifying targetable metabolic dependencies across colorectal cancer progression.

Danny N Legge, Tracey J Collard, Ewelina Stanko, Ashley J Hoskin, Amy K Holt, Caroline J Bull, Madhu Kollareddy, Jake Bellamy, Sarah Groves, Eric H Ma, Emma Hazelwood, David Qualtrough, Borko Amulic, Karim Malik, Ann C Williams, Nicholas Jones, Emma E Vincent.

  Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system - comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease.

Keywords:  Colorectal cancer; adenocarcinoma; adenoma; asparagine; asparagine synthetase; oncometabolism

DOI:  https://doi.org/10.1016/j.molmet.2024.102037
Cells. 2024 Sep 19. pii: 1574. [Epub ahead of print]13(18):

Metabolic Reprogramming in Glioblastoma Multiforme: A Review of Pathways and Therapeutic Targets.

Ashley Irin Cortes Ballen, Maryam Amosu, Surya Ravinder, Joey Chan, Emre Derin, Hasan Slika, Betty Tyler.

  Glioblastoma (GBM) is an aggressive and highly malignant primary brain tumor characterized by rapid growth and a poor prognosis for patients. Despite advancements in treatment, the median survival time for GBM patients remains low. One of the crucial challenges in understanding and treating GBMs involves its remarkable cellular heterogeneity and adaptability. Central to the survival and proliferation of GBM cells is their ability to undergo metabolic reprogramming. Metabolic reprogramming is a process that allows cancer cells to alter their metabolism to meet the increased demands of rapid growth and to survive in the often oxygen- and nutrient-deficient tumor microenvironment. These changes in metabolism include the Warburg effect, alterations in several key metabolic pathways including glutamine metabolism, fatty acid synthesis, and the tricarboxylic acid (TCA) cycle, increased uptake and utilization of glutamine, and more. Despite the complexity and adaptability of GBM metabolism, a deeper understanding of its metabolic reprogramming offers hope for developing more effective therapeutic interventions against GBMs.

Keywords:  Warburg effect; glioblastoma multiforme; glycolysis; metabolic reprogramming; therapeutic drugs; tumor microenvironment

DOI:  https://doi.org/10.3390/cells13181574
J Cell Physiol. 2024 Sep 26. e31441

Mitochondrial metabolism: A moving target in hepatocellular carcinoma therapy.

Monika Komza, Jerry Edward Chipuk.

  Mitochondria are pivotal contributors to cancer mechanisms due to their homeostatic and pathological roles in cellular bioenergetics, biosynthesis, metabolism, signaling, and survival. During transformation and tumor initiation, mitochondrial function is often disrupted by oncogenic mutations, leading to a metabolic profile distinct from precursor cells. In this review, we focus on hepatocellular carcinoma, a cancer arising from metabolically robust and nutrient rich hepatocytes, and discuss the mechanistic impact of altered metabolism in this setting. We provide distinctions between normal mitochondrial activity versus disease-related function which yielded therapeutic opportunities, along with highlighting recent preclinical and clinical efforts focused on targeting mitochondrial metabolism. Finally, several novel strategies for exploiting mitochondrial programs to eliminate hepatocellular carcinoma cells in metabolism-specific contexts are presented to integrate these concepts and gain foresight into the future of mitochondria-focused therapeutics.

Keywords:  cancer; hepatocytes; metabolism; mitochondria; oncogenes; therapeutics

DOI:  https://doi.org/10.1002/jcp.31441
Free Radic Res. 2024 Sep 24. 1-24

Redox remodeling of central metabolism as a driving force for cellular protection, proliferation, differentiation, and dysfunction.

Junichi Fujii.

  The production of reactive oxygen species (ROS) is elevated via metabolic hyperactivation in response to a variety of stimuli such as growth factors and inflammation. Tolerable amounts of ROS moderately inactivate enzymes via oxidative modification, which can be reversed back to the native form in a redox-dependent manner. The excessive production of ROS, however, causes cell dysfunction and death. Redox-reactive enzymes are present in primary metabolic pathways such as glycolysis and the tricarboxylic acid cycle, and these act as floodgates for carbon flux. Oxidation of a specific form of cysteine inhibits glyceraldehyde-3-phosphate dehydrogenase, which is reversible, and causes an accumulation of upstream intermediary compounds that increases the flux of glucose-6-phosphate to the pentose phosphate pathway. These reactions increase the NADPH and ribose-5-phosphate that are available for reductive reactions and nucleotide synthesis, respectively. On the other hand, oxidative inactivation of mitochondrial aconitase increases citrate, which is then recruited to synthesize fatty acids in the cytoplasm. Decreases in the use of carbohydrate for ATP production can be compensated via amino acid catabolism, and this metabolic change makes nitrogen available for nucleic acid synthesis. Coupling of the urea cycle also converts nitrogen to urea and polyamine, the latter of which supports cell growth. This metabolic remodeling stimulates the proliferation of tumor cells and fibrosis in oxidatively damaged tissues. Oxidative modification of these enzymes is generally reversible in the early stages of oxidizing reactions, which suggests that early treatment with appropriate antioxidants promotes the maintenance of natural metabolism.

Keywords:  Glycolysis; TCA cycle; metabolic remodeling; reactive sulfhydryl; urea cycle

DOI:  https://doi.org/10.1080/10715762.2024.2407147
iScience. 2024 Sep 20. 27(9): 110880

Mitochondria-targeted cancer analysis using survival and expression: Prioritizing mitochondrial targets that alleviate pancreatic cancer cell phenotypes.

Daisuke Murata, Fumiya Ito, Gongyu Tang, Wakiko Iwata, Nelson Yeung, Junior J West, Andrew J Ewald, Xiaowei Wang, Miho Iijima, Hiromi Sesaki.

  Substantial changes in energy metabolism are a hallmark of pancreatic cancer. To adapt to hypoxic and nutrient-deprived microenvironments, pancreatic cancer cells remodel their bioenergetics from oxidative phosphorylation to glycolysis. This bioenergetic shift makes mitochondria an Achilles' heel. Since mitochondrial function remains essential for pancreatic cancer cells, further depleting mitochondrial energy production is an appealing treatment target. However, identifying effective mitochondrial targets for treatment is challenging. Here, we developed an approach, mitochondria-targeted cancer analysis using survival and expression (mCAUSE), to prioritize target proteins from the entire mitochondrial proteome. Selected proteins were further tested for their impact on pancreatic cancer cell phenotypes. We discovered that targeting a dynamin-related GTPase, OPA1, which controls mitochondrial fusion and cristae, effectively suppresses pancreatic cancer activities. Remarkably, when combined with a mutation-specific KRAS inhibitor, OPA1 inhibition showed a synergistic effect. Our findings offer a therapeutic strategy against pancreatic cancer by simultaneously targeting mitochondria dynamics and KRAS signaling.

Keywords:  Cancer; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.110880
Heliyon. 2024 Sep 30. 10(18): e37917

Anticancer effects of high-dose extracellular citrate treatment in pancreatic cancer cells under different glucose concentrations.

Wonjin Kim, Sanghee Park, Taehyun Park, Seunghwan Kim, Jimin Kim, Ji-Hong Bong, Misu Lee.

  Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive solid tumor. Recently, the uptake of extracellular citrate by the sodium-dependent citrate transporter (NaCT), encoded by SLC13A5, has been demonstrated to exert profound effects on cancer cell metabolism. However, research on the function of extracellular citrate in PDAC pathogenesis and the relationship between NaCT expression and the tumor metabolic microenvironment is limited. Therefore, we aimed to evaluate the expression of citrate transporters across a spectrum of glucose concentrations in pancreatic cancer and systematically explore the effects of sodium citrate treatment on pancreatic cancer cells at different glucose concentrations. We observed a positive correlation between glucose concentration and NaCT expression in PDAC cell lines. Extracellular sodium citrate significantly reduced cell viability partially due to reduction in intracellular Ca2+ levels and decreased the migration of human PDAC cells. Furthermore, we observed a decrease in the levels of the stem cell marker prominin I (CD133) following sodium citrate treatment. Notably, the combination treatment of gemcitabine and extracellular sodium citrate exhibited a synergistic anticancer effect in both two-dimensional (2D) and three-dimensional (3D) culture systems. Additionally, we confirmed that pH slightly increased upon administration of sodium citrate, indicating that this could potentially augment the efficacy of gemcitabine. Altogether, these findings suggest that exogenous sodium citrate treatment, particularly in combination with gemcitabine, may represent a novel therapeutic strategy for treating PDAC. This approach holds promise for disrupting PDAC cell metabolism and inhibiting tumor progression.

Keywords:  Extracellular citrate; Glucose; Pancreatic ductal adenocarcinoma; Sodium citrate; Synergistic anticancer effect

DOI:  https://doi.org/10.1016/j.heliyon.2024.e37917
Res Sq. 2024 Sep 12. pii: rs.3.rs-5065904. [Epub ahead of print]

BMP receptor 2 inhibition regulates mitochondrial bioenergetics to induce synergistic cell death with BCL-2 inhibitors in leukemia and NSLC cells.

Ashley Toussaint, Manohar Singh, Guoquiang Wang, Monica Driscoll, Vrushank Bhatt, Jean De La Croix Ndong, Sahil Shuaib, Harrison Zoltowski, John Gilleran, Youyi Peng, Anastassiia Tsymbal, Dongxuan Jia, Jacques Roberge, Hellen Chiou, Jessie Yanxiang Guo, Daniel Herranz, John Langenfeld.

Background Bone morphogenetic protein (BMP) signaling cascade is a phylogenetically conserved stem cell regulator that is aberrantly expressed in non-small cell lung cancer (NSLC) and leukemias. BMP signaling negatively regulates mitochondrial bioenergetics in lung cancer cells. The impact of inhibiting BMP signaling on mitochondrial bioenergetics and the effect this has on the survival of NSLC and leukemia cells are not known. Methods Utilizing the BMP type 2 receptor (BMPR2) JL189, BMPR2 knockout (KO) in cancer cells, and BMP loss of function mutants in C elegans , we determined the effects of BMPR2 inhibition (BMPR2i) on TCA cycle metabolic intermediates, mitochondrial respiration, and the regulation of mitochondrial superoxide anion (SOA) and Ca ++ levels. We also examined whether BMPR2i altered the threshold cancer therapeutics induce cell death in NSLC and leukemia cell lines. KO of the mitochondria uniporter (MCU) was used to determine the mechanism BMPR2i regulates the uptake of Ca ++ into the mitochondria, mitochondrial bioenergetics, and cell death. Results BMPR2i increases mtCa ++ levels and enhances mitochondrial bioenergetics in both NSLC and leukemia cell lines that is conserved in C elegans. BMPR2i induced increase in mtCa ++ levels is regulated through the MCU, effecting mitochondria mass and cell survival. BMPR2i synergistically induced cell death when combined with BCL-2 inhibitors or microtubule targeting agents in both NSLC and leukemia cells. Cell death is caused by synergistic increase in mitochondrial ROS and Ca ++ levels. BMPR2i enhances Ca ++ uptake into the mitochondria induced by reactive oxygen species (ROS) produced by cancer therapeutics. Both acute myeloid leukemia (AML) and T-cell lymphoblastic leukemia cells lines were more responsive to the JL189 alone and when combined with venetoclax or navitoclax compared to NSLC.

DOI: https://doi.org/10.21203/rs.3.rs-5065904/v1
bioRxiv. 2024 Sep 09. pii: 2024.09.09.611245. [Epub ahead of print]

Three-dimensional analysis of mitochondria in a patient-derived xenograft model of triple negative breast cancer reveals mitochondrial network remodeling following chemotherapy treatments.

Mariah J Berner, Heather K Beasley, Zer Vue, Audra Lane, Larry Vang, Mokryun L Baek, Andrea G Marshall, Mason Killion, Faben Zeleke, Bryanna Shao, Dominque Parker, Autumn Peterson, Julie Sterling Rhoades, Estevão Scudese, Lacey E Dobrolecki, Michael T Lewis, Antentor Hinton, Gloria V Echeverria.

Mitochondria are hubs of metabolism and signaling and play an important role in tumorigenesis, therapeutic resistance, and metastasis in many cancer types. Various laboratory models of cancer demonstrate the extraordinary dynamics of mitochondrial structure, but little is known about the role of mitochondrial structure in resistance to anticancer therapy. We previously demonstrated the importance of mitochondrial structure and oxidative phosphorylation in the survival of chemotherapy-refractory triple negative breast cancer (TNBC) cells. As TNBC is a highly aggressive breast cancer subtype with few targeted therapy options, conventional chemotherapies remain the backbone of early TNBC treatment. Unfortunately, approximately 45% of TNBC patients retain substantial residual tumor burden following chemotherapy, associated with abysmal prognoses. Using an orthotopic patient-derived xenograft mouse model of human TNBC, we compared mitochondrial structures between treatment-naïve tumors and residual tumors after conventional chemotherapeutics were administered singly or in combination. We reconstructed 1,750 mitochondria in three dimensions from serial block-face scanning electron micrographs, providing unprecedented insights into the complexity and intra-tumoral heterogeneity of mitochondria in TNBC. Following exposure to carboplatin or docetaxel given individually, residual tumor mitochondria exhibited significant increases in mitochondrial complexity index, area, volume, perimeter, width, and length relative to treatment-naïve tumor mitochondria. In contrast, residual tumors exposed to those chemotherapies given in combination exhibited diminished mitochondrial structure changes. Further, we document extensive intra-tumoral heterogeneity of mitochondrial structure, especially prior to chemotherapeutic exposure. These results highlight the potential for structure-based monitoring of chemotherapeutic responses and reveal potential molecular mechanisms that underlie chemotherapeutic resistance in TNBC.

DOI: https://doi.org/10.1101/2024.09.09.611245
JCI Insight. 2024 Aug 13. pii: e180114. [Epub ahead of print]9(18):

Metabolic landscape of the healthy pancreas and pancreatic tumor microenvironment.

Monica E Bonilla, Megan D Radyk, Matthew D Perricone, Ahmed M Elhossiny, Alexis C Harold, Paola I Medina-Cabrera, Padma Kadiyala, Jiaqi Shi, Timothy L Frankel, Eileen S Carpenter, Michael D Green, Cristina Mitrea, Costas A Lyssiotis, Marina Pasca di Magliano.

  Pancreatic cancer, one of the deadliest human malignancies, is characterized by a fibro-inflammatory tumor microenvironment and wide array of metabolic alterations. To comprehensively map metabolism in a cell type-specific manner, we harnessed a unique single-cell RNA-sequencing dataset of normal human pancreata. This was compared with human pancreatic cancer samples using a computational pipeline optimized for this study. In the cancer cells we observed enhanced biosynthetic programs. We identified downregulation of mitochondrial programs in several immune populations, relative to their normal counterparts in healthy pancreas. Although granulocytes, B cells, and CD8+ T cells all downregulated oxidative phosphorylation, the mechanisms by which this occurred were cell type specific. In fact, the expression pattern of the electron transport chain complexes was sufficient to identify immune cell types without the use of lineage markers. We also observed changes in tumor-associated macrophage (TAM) lipid metabolism, with increased expression of enzymes mediating unsaturated fatty acid synthesis and upregulation in cholesterol export. Concurrently, cancer cells exhibited upregulation of lipid/cholesterol receptor import. We thus identified a potential crosstalk whereby TAMs provide cholesterol to cancer cells. We suggest that this may be a new mechanism boosting cancer cell growth and a therapeutic target in the future.

Keywords:  Bioinformatics; Cancer; Macrophages; Oncology

DOI:  https://doi.org/10.1172/jci.insight.180114
Future Oncol. 2024 Sep 19. 1-20

Quizartinib: a new hope in acute myeloid leukemia, an applied comprehensive review.

Fatemeh Esmaeilpour Moallem, Mohammad Sadra Gholami Chahkand, Parisa Alsadat Dadkhah, Eftekhar Azarm, Mehregan Shahrokhi, Mitra Sadat Deyhimi, Mohammad Amin Karimi.

  Acute myeloid leukemia (AML) is caused by a defective precursor leading to malignant clonal expansion, often with FMS-like tyrosine kinase-3 receptor (FLT3) mutations, particularly internal tandem duplication (ITD), which has a poor prognosis. Quizartinib, a second-generation FLT3 inhibitor, has FDA approval for relapsed/refractory AML with FLT3/ITD mutation. It has shown promise in clinical studies since 2013 due to its excellent oral absorption and potent activity on FLT3. This review explores Quizartinib's mechanism of action, efficacy in monotherapy or combination with chemotherapy, drug interactions, adverse events, resistance mechanisms and future research directions.

Keywords:  AML; FLT3 inhibitor; FLT3-ITD mutation; malignancy; quizartinib

DOI:  https://doi.org/10.1080/14796694.2024.2399425
NMR Biomed. 2024 Sep 25. e5264

Differentiating leukemia subtypes based on metabolic signatures using hyperpolarized 13C NMR.

Nichlas Vous Christensen, Christoffer Laustsen, Lotte Bonde Bertelsen.

  Leukemia is a group of blood cancers that are classified in four major classes. Within these four classes, many different subtypes exists with similar origin, genetic mutations, and level of maturity, which can make them difficult to distinguish. Despite their similarities, they might respond differently to treatment, and therefore distinguishing between them is of crucial importance. A deranged metabolic phenotype (Warburg effect) is often seen in cancer cells, leukemia cells included, and is increasingly a target for improved diagnosis and treatment. In this study, hyperpolarized 13C NMR spectroscopy was used to characterize the metabolic signatures of the six leukemia cell lines ML-1, CCRF-CEM, THP-1, MOLT-4, HL-60, and K562. This was done using [1-13C]pyruvate and [1-13C]alanine as bioprobes for downstream metabolite quantification and kinetic analysis on cultured cells with and without 2-deoxy-D-glucose treatment. The metabolic signatures of similar leukemia subtypes could be readily distinguished. This includes ML-1 and THP-1, which are of the similar M4 and M5 AML subtypes, CCRF-CEM and MOLT-4, which are of the similar T-ALL lineage at different maturation states, and HL-60 and K562, which are of the closely related M1 and M2 AML subtypes. The data presented here demonstrate the potential of hyperpolarized 13C NMR spectroscopy as a method to differentiate between leukemia subtypes of similar origin. Combining this method with bioreactor setups could potentially allow for better leukemia disease management as metabolic signatures could be acquired from a single biopsy through repeated experimentation and intervention.

Keywords:  13C NMR; 2‐DG treatment; ALL; AML; hyperpolarization; leukemia

DOI:  https://doi.org/10.1002/nbm.5264
Front Cell Dev Biol. 2024 ;12 1452824

Mitochondrial lipid peroxidation is necessary but not sufficient for induction of ferroptosis.

He Huan, Konstantin G Lyamzaev, Alisa A Panteleeva, Boris V Chernyak.

  Ferroptosis, a form of regulated cell death mediated by lipid peroxidation (LPO), has become the subject of intense research due to its potential therapeutic applications in cancer chemotherapy as well as its pathophysiological role in ischemic organ injury. The role of mitochondrial lipid peroxidation (LPO) in ferroptosis remains poorly understood. We show that supplementation of exogenous iron in the form of ferric ammonium citrate (FAC) in combination with buthionine sulfoximine (BSO, an inhibitor of glutathione biosynthesis) induces mitochondrial lipid peroxidation that precedes ferroptosis in normal human fibroblasts. The mitochondrial-targeted antioxidant SkQ1 and the redox mediator methylene blue, which inhibits the production of reactive oxygen species (ROS) in complex I of the mitochondrial electron transport chain, prevent both mitochondrial lipid peroxidation and ferroptosis, but do not affect the cytosolic ROS accumulation. These data indicate that mitochondrial lipid peroxidation is required for ferroptosis induced by exogenous iron. FAC in the absence of BSO stimulates mitochondrial peroxidation without reducing cell viability. Glutathione depletion by BSO does not affect FAC-induced mitochondrial LPO but strongly stimulates the accumulation of ROS in the cytosol. These data allow us to conclude that mitochondrial LPO is not sufficient for ferroptosis and that cytosolic ROS mediates additional oxidative events that stimulate ferroptosis in conjunction with mitochondrial LPO.

Keywords:  buthionine sulfoximine (BSO); ferric ammonium citrate (FAC); ferroptosis; mitochondrial lipid peroxidation; mitochondrial-targeted antioxidants

DOI:  https://doi.org/10.3389/fcell.2024.1452824
Cureus. 2024 Aug;16(8): e67434

Uncovering the Links Between Dietary Sugar and Cancer: A Narrative Review Exploring the Impact of Dietary Sugar and Fasting on Cancer Risk and Prevention.

Ashik Anil, Ronak Raheja, Diya Gibu, Aravind S Raj, S Spurthi.

  Over the last several years, the scientific community has grown concerned about the relationship between dietary sugar intake and cancer development. The main causes of concern are the increasing intake of processed foods rich in sugar and the rising incidence of cancer cases. This study aims to uncover the complex relationship between sugar consumption and cancer development and its progression, with a particular focus on investigating whether fasting can protect against this condition. Our review provides a detailed discussion of the molecular aspects of the sugar-cancer relationship and an analysis of the existing literature. It explains how sugar affects cell signaling, inflammation, and hormonal pathways associated with the development of cancer. We also explored the new role of fasting in the prevention of cancer and its impact on cancer patients. This encompasses fasting-triggered autophagy, metabolic alterations, and possible health benefits, which form the major concern of this paper. Thus, by deepening the knowledge of these relations and providing the results of the analysis accompanied by concise and meaningful illustrations to facilitate the understanding of the data, we open the door to the further development of ideas to minimize the rates of cancer and improve overall well-being.

Keywords:  cancer cell metabolism; cancer prevention; fasting; obesity and cancer; sugar and cancer

DOI:  https://doi.org/10.7759/cureus.67434
Cell. 2024 Sep 17. pii: S0092-8674(24)00974-7. [Epub ahead of print]

A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.

Pablo Hernansanz-Agustín, Carmen Morales-Vidal, Enrique Calvo, Paolo Natale, Yolanda Martí-Mateos, Sara Natalia Jaroszewicz, José Luis Cabrera-Alarcón, Rebeca Acín-Pérez, Iván López-Montero, Jesús Vázquez, José Antonio Enríquez.

  Eukaryotic cell function and survival rely on the use of a mitochondrial H+ electrochemical gradient (Δp), which is composed of an inner mitochondrial membrane (IMM) potential (ΔΨmt) and a pH gradient (ΔpH). So far, ΔΨmt has been assumed to be composed exclusively of H+. Here, using a rainbow of mitochondrial and nuclear genetic models, we have discovered that a Na+ gradient equates with the H+ gradient and controls half of ΔΨmt in coupled-respiring mammalian mitochondria. This parallelism is controlled by the activity of the long-sought Na+-specific Na+/H+ exchanger (mNHE), which we have identified as the P-module of complex I (CI). Deregulation of this mNHE function, without affecting the canonical enzymatic activity or the assembly of CI, occurs in Leber's hereditary optic neuropathy (LHON), which has profound consequences in ΔΨmt and mitochondrial Ca2+ homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.

Keywords:  LHON; Na(+) gradient; complex I; mitochondrial Na(+)/H(+) antiporter; ΔΨmt

DOI:  https://doi.org/10.1016/j.cell.2024.08.045
Cancer Sci. 2024 Sep 22.

Cholesterol synthesis is essential for the growth of liver metastasis-prone colorectal cancer cells.

Kumiko Taniguchi, Kei Sugihara, Takashi Miura, Daisuke Hoshi, Susumu Kohno, Chiaki Takahashi, Eishu Hirata, Etsuko Kiyokawa.

  Metastasis to the liver is a leading cause of death in patients with colorectal cancer. To investigate the characteristics of cancer cells prone to metastasis, we utilized an isogenic model of BALB/c and colon tumor 26 (C26) cells carrying an active KRAS mutation. Liver metastatic (LM) 1 cells were isolated from mice following intrasplenic transplantation of C26 cells. Subsequent injections of LM1 cells generated LM2 cells, and after four cycles, LM4 cells were obtained. In vitro, using a perfusable capillary network system, we found comparable extravasation frequencies between C26 and LM4 cells. Both cell lines showed similar growth rates in vitro. However, C26 cells showed higher glucose consumption, whereas LM4 cells incorporated more fluorescent fatty acids (FAs). Biochemical analysis revealed that LM4 cells had higher cholesterol levels than C26 cells. A correlation was observed between fluorescent FAs and cholesterol levels detected using filipin III. LM4 cells utilized FAs as a source for cholesterol synthesis through acetyl-CoA metabolism. In cellular analysis, cholesterol accumulated in punctate regions, and upregulation of NLRP3 and STING proteins, but not mTOR, was observed in LM4 cells. Treatment with a cholesterol synthesis inhibitor (statin) induced LM4 cell death in vitro and suppressed LM4 cell growth in the livers of nude mice. These findings indicate that colorectal cancer cells prone to liver metastasis show cholesterol-dependent growth and that statin therapy could help treat liver metastasis in immunocompromised patients.

Keywords:  cholesterol; colorectal cancer; extravasation; fatty acid; liver metastasis

DOI:  https://doi.org/10.1111/cas.16331
Cancer J. 2024 Sep-Oct 01;30(5):30(5): 307-312

What to Eat for Cancer Prevention: The Total Dietary Pattern as a Combination Treatment for Prevention.

Yiwen Zhang, Edward L Giovannucci.

ABSTRACT: Over the past 2 decades, the search for dietary factors for developing cancer prevention guidelines has led to a significant expansion in the study of dietary patterns and their relation to cancer. Dietary patterns, which consider the types, amounts, variety, and combination of consumed foods, may encompass additive, synergistic, or interactive effects on human health, compared with individual nutrients or foods. In this review, we discuss the history and methodologies of dietary pattern research, describe common dietary indices used in cancer research, and summarize the existing evidence on dietary patterns and cancer risk. Current evidence supports the beneficial role of dietary patterns that are rich in vegetables, legumes, whole fruit, and whole grains and limited in added sugars, refined grains, processed foods, and red and processed meat in preventing various cancers, including breast, colorectal, and prostate cancers. Additionally, emerging evidence suggests that dietary patterns based on biological mechanisms, such as hyperinsulinemic diet and inflammatory diet, hold promise and may be priority areas for future research.

DOI: https://doi.org/10.1097/PPO.0000000000000741
bioRxiv. 2024 Sep 09. pii: 2024.09.09.612087. [Epub ahead of print]

A secondary β-hydroxybutyrate metabolic pathway linked to energy balance.

Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine Ward, Lichao Liu, Katrin J Svensson, Emily L Goldberg, Christopher D Gardner, Jonathan P Little, Steven M Banik, Yong Xu, Jonathan Z Long.

β-hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve interconversion of BHB and primary energy intermediates. Here we show that CNDP2 controls a previously undescribed secondary BHB metabolic pathway via enzymatic conjugation of BHB and free amino acids. This BHB-ylation reaction produces a family of endogenous ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. Administration of BHB-Phe, the most abundant BHB-amino acid, to obese mice activates neural populations in the hypothalamus and brainstem and suppresses feeding and body weight. Conversely, CNDP2-KO mice exhibit increased food intake and body weight upon ketosis stimuli. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, the metabolic pathways of BHB extend beyond primary metabolism and include secondary ketone metabolites linked to energy balance.

DOI: https://doi.org/10.1101/2024.09.09.612087
STAR Protoc. 2024 Sep 20. pii: S2666-1667(24)00495-7. [Epub ahead of print]5(4): 103330

Protocol to monitor live-cell, real-time, mitochondrial respiration in mouse muscle cells using the Resipher platform.

Matthew Triolo, Mireille Khacho.

  Mitochondrial function is typically assessed by measuring oxygen consumption at a given time point. However, this approach cannot monitor respiratory changes that occur over time. Here, we present a protocol to measure mitochondrial respiration in freshly isolated muscle stem cells, primary skeletal muscle, and immortalized C2C12 myoblasts in real time using the Resipher platform. We describe steps for preparing and plating cells, performing media changes, setting up the software and device, and analyzing data. This method can be adapted to other cell types. For complete details on the use and execution of this protocol, please refer to Triolo et al.1.

Keywords:  Cell Biology; Metabolism; Stem Cells

DOI:  https://doi.org/10.1016/j.xpro.2024.103330
Eur J Breast Health. 2024 Sep 26. 20(4): 262-269

Dietary Patterns and Breast Cancer Risk: A KCPS-II Cohort Study.

Ji-Young Lee, Hae In Cho, Heejin Kimm.

  Objective: There have been inconsistencies in the evidence for a role of dietary patterns in the development of breast cancer. In this study, we used a large-scale cohort [Korean Cancer Prevention Study-II (KCPS-II)] to examine the association between dietary patterns and breast cancer risk in Korean women.Materials and Methods: The dietary patterns of 14,807 women from the KCPS-II were derived by factor analysis and 135 cases of breast cancer were diagnosed during the follow-up period. Cox proportional models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of breast cancer.
Results: The following three major dietary patterns were identified: "Korean dietary pattern" (high intake of Kimchi, vegetables, and rice); "sweet dietary pattern" (high intake of soda and sugar); and "new (Western-like) dietary pattern" (high intake of dairy products, eggs, oil, fruits, and bread). After adjusting for potential confounders, neither the Korean (HR for the highest compared with the lowest tertile, 1.04; 95% CI 0.53-2.06) nor the sweet dietary patterns were associated with the risk of breast cancer. In contrast, the new (Western-like) dietary pattern was found to be significantly associated with an increased risk of breast cancer with an HR (95% CI) of 1.01 (0.65-1.60) for the second tertile and 1.61 (1.04-2.50) for the third tertile as compared with the lowest tertile. After stratifying by menopausal status, these effects were only statistically significant among premenopausal women for the third tertile, compared with those in the bottom tertile (HR 1.69; 95% CI 1.06-2.68; p = 0.028). No significant association was observed between the Korean or sweet dietary pattern and breast cancer among either pre- or postmenopausal women.
Conclusion: Our findings revealed that a greater consumption of a new (Western-like) diet was associated with an increased breast cancer risk and consequently offer a potential prevention strategy for Korean women.

Keywords:  Dietary pattern; KCPS-II cohort; Korean women; breast cancer

DOI:  https://doi.org/10.4274/ejbh.galenos.2024.2024-3-4
Br J Cancer. 2024 Sep 24.

Association of metabolic obesity phenotypes with risk of overall and site-specific cancers: a systematic review and meta-analysis of cohort studies.

Yahya Mahamat-Saleh, Dagfinn Aune, Heinz Freisling, Sheetal Hardikar, Rola Jaafar, Sabina Rinaldi, Marc J Gunter, Laure Dossus.

BACKGROUND: Adiposity is a known risk factor for certain cancers; however, it is not clear whether the risk of cancer differs between individuals with high adiposity but different metabolic health status. The aim of this systematic literature review and meta-analysis of cohort studies was to evaluate associations between metabolic obesity phenotypes and overall and site-specific cancer risk.METHODS: PubMed and Embase databases were used to identify relevant cohort studies up to the 6th of June 2023. Random-effects models were used to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs) for the association between metabolic obesity phenotypes and cancer risk. Certainty of evidence was assessed using the Cochrane methods and the GRADE tool. This study is registered with PROSPERO, number CRD42024549511.
RESULTS: A total of 15,556 records were screened, and 31 publications covering 15 unique cohort studies were included in this analysis. Of these studies, 22 were evaluated as being at low risk of bias and 9 at moderate risk of bias. Compared to metabolically healthy normal-weight individuals (MHNW), metabolically unhealthy overweight/obese (MUOW/OB) individuals had a higher risk of overall (SRR = 1.21, 95% CI = 1.02-1.44, n = 3 studies, high certainty) and obesity-related cancers (SRR = 1.42, 95% CI = 1.15-1.74, n = 3, very low certainty). Specifically, MUOW/OB individuals were at higher risk of cancers of the postmenopausal breast (SRR = 1.32, 95% CI = 1.17-1.48, n = 7, low certainty), colorectum (SRR = 1.24, 95% CI = 1.16-1.31, n = 6, moderate certainty), endometrium (SRR = 2.31, 95% CI = 2.08-2.57, n = 4, high certainty), thyroid (SRR = 1.42, 95% CI = 1.29-1.57, n = 4, moderate certainty), kidney (SRR = 1.71, 95% CI = 1.40-2.10, n = 3, low certainty), pancreas (SRR = 1.35, 95% CI = 1.24-1.47, n = 3, high certainty), liver (SRR = 1.81, 95% CI = 1.36-2.42, n = 2, moderate certainty), gallbladder (SRR = 1.42, 95% CI = 1.17-1.73, n = 2, high certainty), bladder (SRR = 1.36, 95% CI = 1.19-1.56, n = 2, moderate certainty), and stomach (SRR = 1.50, 95% CI = 1.12-2.01, n = 2, high certainty). In addition, we found elevated risks of most of these cancers among individuals classified as MUNW and MHOW/OB phenotypes compared to those with MHNW phenotype. Our stratified analyses according to metabolic obesity phenotypes suggested that the elevated risks of some cancers were stronger in individuals with MUOW/OB versus those with MHOW/OB or MUNW phenotypes.
CONCLUSION: These findings suggest that both higher adiposity and metabolic dysfunction were independently associated with increased risk of several cancers, with the strongest associations generally observed among those with both metabolic dysfunction and obesity.

DOI: https://doi.org/10.1038/s41416-024-02857-7
PeerJ. 2024 ;12 e18043

Diagnostic performance of serum metabolites biomarker associated with colorectal adenoma: a systematic review.

Maryam Fatimah Abu Bakar, Siok Fong Chin, Suzana Makpol, Jen Kit Tan, Azmawati Mohammed Nawi.

  Evidence on serum biomarkers as a non-invasive tool to detect colorectal adenoma (CRA) in the general population is quite promising. However, the sensitivity and specificity of these serum biomarkers in detecting disease are still questionable. This study aimed to systematically review the evidence on the diagnostic performance of serum biomarkers associated with CRA. Database searches on PubMed, Scopus, and WoS from January 2014 to December 2023 using PRISMA guidelines resulted in 4,380 citations, nine of which met inclusion criteria. The quality of these studies was assessed using the QUADOMICS tool. These studies reported on 77 individual/panel biomarkers which were further analysed to find associated altered pathways using MetaboAnlyst 5.0. Diagnostic accuracy analysis of these biomarkers was conducted by constructing a receiver operating characteristic (ROC) curve using their reported sensitivity and specificity. This review identified six potential serum metabolite biomarkers with 0.7<AUC<1. Benzoic acid, acetate, and lactate significantly differentiate CRA vs. normal, while adenosine, pentothenate, and linoleic acid are highly remarkable for CRA vs. CRC. The five most affected pathways for CRA vs. normal are glycoxylate and dicarboxylate metabolism; alanine, aspartate, and glutamate metabolism; aminoacyl-tRNA biosynthesis; D-glutamine and D-glutamate metabolism; and nitrogen metabolism. Meanwhile, pyruvate metabolism, glycolysis/gluconeogenesis, glycerolipid metabolism, citrate/TCA cycle, and alanine, aspartate, and glutamate metabolism were found to be altered in CRA vs. CRC. However, the association of suggested serum metabolites and altered pathways is still unknown. Despite promising emerging evidence, further validation studies in a diverse population with standardized methodology are needed to validate the findings.

Keywords:  Accuracy; Colorectal polyps; Metabolomics; Serum biomarker

DOI:  https://doi.org/10.7717/peerj.18043
Cell Rep. 2024 Sep 19. pii: S2211-1247(24)01097-0. [Epub ahead of print]43(10): 114746

Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway.

Weiwei Xu, Dongyan Zhang, Yumin Ma, Rafael C Gaspar, Mario Kahn, Ali Nasiri, Sue Murray, Varman T Samuel, Gerald I Shulman.

  Inhibition of the ceramide synthetic pathway with myriocin or an antisense oligonucleotide (ASO) targeting dihydroceramide desaturase (DES1) both improved hepatic insulin sensitivity in rats fed either a saturated or unsaturated fat diet and was associated with reductions in both hepatic ceramide and plasma membrane (PM)-sn-1,2-diacylglycerol (DAG) content. The insulin sensitizing effects of myriocin and Des1 ASO were abrogated by acute treatment with an ASO against DGAT2, which increased hepatic PM-sn-1,2-DAG but not hepatic C16 ceramide content. Increased PM-sn-1,2-DAG content was associated with protein kinase C (PKC)ε activation, increased insulin receptor (INSR)T1150 phosphorylation leading to reduced insulin-stimulated INSRY1152/AktS473 phosphorylation, and impaired insulin-mediated suppression of endogenous glucose production. These results demonstrate that inhibition of de novo ceramide synthesis by either myriocin treatment or DES1 knockdown protects against lipid-induced hepatic insulin resistance through a C16 ceramide-independent mechanism and that they mediate their effects to protect from lipid-induced hepatic insulin resistance via the PM-sn-1,2-DAG-PKCε-INSRT1150 phosphorylation pathway.

Keywords:  CP: Metabolism; CP: Molecular biology; antisense oligonucleotides; ceramides; diacylglycerols (DAG); fatty acids; insulin resistance; lipid metabolism; metabolic dysfunction-associated steatotic disease (MASLD); protein kinase C epsilon

DOI:  https://doi.org/10.1016/j.celrep.2024.114746
Clin Cancer Res. 2024 Sep 25.

Combinations of HDAC inhibitor and PPAR agonist induce ferroptosis of leukemic stem cell-like cells in acute myeloid leukemia.

Hui Zhou, Dongmei Qin, Chendi Xie, Jie Zhou, Shuman Jia, Ziwei Zhou, Yi Qiu, Bing Xu, Jie Zha.

PURPOSE: Leukemia stem cells (LSCs) are responsible for leukemia initiation, relapse, and therapeutic resistance. Therefore, the development of novel therapeutic approaches targeting LSCs is urgently needed for patients with AML.METHODS: The LSCs-like cell lines (KG-1α and Kasumi-1), CD34+ primary AML cells purified from AML patients (n=23) treated with CS055 and/or chiglitazar and were analyzed for viability, death, and colony formation assay. We performed RNA-seq, Glutamate-Release, Intracellular-GSH, Lipid-ROS, transmission-electron-microscopy, Western-Blotting assay, and confirmed ferroptosis in LSCs-like cells. The luciferase-reporter, co-immunoprecipitation, HDAC3-shRNA/HDAC3/deacetylase-deficient LSCs-like cell lines, His-pull-down, and chromatin-immunoprecipitation assays performed to clarify the molecular mechanism of CS055/chiglitazar in LSCs-like cells. We also established CDX and PDX mouse models to evaluate the therapeutic efficacy of CS055/chiglitazar against-AML in vivo.
RESULTS: We report that the histone deacetylase inhibitor CS055, in combination with peroxisome proliferator-activated receptor (PPAR) pan-agonist (chiglitazar), synergistically targets leukemia stem-like cells from leukemia cell lines and patient samples, while sparing normal hematopoietic progenitor cells. Mechanistically, chiglitazar enhances the inhibitory effect of CS055 on HDAC3 and induces ferroptosis in LSCs-like cells by down-regulating the expression of ferroptosis suppressor SLC7A11. In fact, the inhibition of HDAC3 increases H3K27AC levels in the promoter region of activating transcription factor 3 (ATF3), a transcriptional repressor of the SLC7A11 gene, and upregulates the expression of ATF3. In contrast, ATF4, a SLC7A11 activator, is suppressed by HDAC3 inhibition.
CONCLUSIONS: Our findings suggest that treatment with CS055 combined with chiglitazar, will target LSCs by inducing ferroptosis and may confer an effective approach for the treatment of AML.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-0796
J Biotechnol. 2024 Sep 24. pii: S0168-1656(24)00256-6. [Epub ahead of print]

Improvement of substrate specificity of the direct electron transfer type FAD-dependent glucose dehydrogenase catalytic subunit.

Joseph A Kerrigan, Hiromi Yoshida, Junko Okuda-Shimazaki, Brenda Temple, Katsuhiro Kojima, Koji Sode.

  The heterotrimeric flavin adenine dinucleotide (FAD) dependent glucose dehydrogenase derived from Burkholderia cepacia (BcGDH) has many exceptional features for its use in glucose sensing-including that this enzyme is capable of direct electron transfer with an electrode in its heterotrimeric configuration. However, this enzyme's high catalytic activity towards not only glucose but also galactose presents an engineering challenge. To increase the substrate specificity of this enzyme, it must be engineered to reduce its specificity towards galactose while maintaining its activity towards glucose. To aid in these mutagenesis studies, the crystal structure composed of BcGDH's small subunit and catalytic subunit (BcGDHγα), in complex with D-glucono-1,5-lactone was elucidated and used to construct the three-dimensional model for targeted site-directed mutagenesis. BcGDHγα was then mutated at three different residues, glycine 322, asparagine 474 and asparagine 475.The single mutations that showed the greatest glucose selectivity were combined to create the resulting mutant, α-G322Q-N474S-N475S. The α-G322Q-N474S-N475S mutant and BcGDHγα wild type were then characterized with dye-mediated dehydrogenase activity assays to determine their kinetic parameters. The α-G322Q-N474S-N475S mutant showed more than a 2-fold increase in Vmax towards glucose and this mutant showed a lower activity towards galactose in the physiological range (5mM) of 4.19 U mg-1, as compared to the wild type, 86.6 U mg-1. This resulting increase in specificity lead to an 81.7gal/glc % activity for the wild type while the α-G322Q-N474S-N475S mutant had just 10.9gal/glc % activity at 5mM. While the BcGDHγα wild type has high specificity towards galactose, our engineering α-G322Q-N474S-N475S mutant showed concentration dependent response to glucose and was not affected by galactose.

Keywords:  direct electron transfer; galactose; glucose dehydrogenase; glucose sensors; substrate specificity, X-ray structure

DOI:  https://doi.org/10.1016/j.jbiotec.2024.09.013
NAR Genom Bioinform. 2023 Dec;5(4): lqad107

Beyond MitoCarta-expanding the list of candidate proteins involved in mitochondrial functions using a biological network approach.

Dmitriy Leyfer, Jessica L Fetterman.

Mitochondrial diseases are the result of pathogenic variants in genes involved in the diverse functions of the mitochondrion. A comprehensive list of mitochondrial genes is needed to improve gene prioritization in the diagnosis of mitochondrial diseases and development of therapeutics that modulate mitochondrial function. MitoCarta is an experimentally derived catalog of proteins localized to mitochondria. We sought to expand this list of mitochondrial proteins to identify proteins that may not be localized to the mitochondria yet perform important mitochondrial functions. We used a computational approach to assign statistical significance to the overlap between STRING database gene network neighborhoods and MitoCarta proteins. Using a data-driven stringent significance threshold, 2059 proteins that were not located in MitoCarta were identified, which we termed mitochondrial proximal (MitoProximal) proteins. We identified all of the oxidative phosphorylation complex subunits and 90% of 149 genes that contain confirmed oxidative phosphorylation disease causal variants, lending validation to our methodology. Among the MitoProximal proteins, 134 are annotated to be localized to mitochondria but are not in the MitoCarta 3.0 database. We extend MitoCarta nearly 3-fold, generating a more comprehensive list of mitochondrial genes, a resource to facilitate the identification of pathogenic variants in mitochondrial and metabolic diseases.

DOI: https://doi.org/10.1093/nargab/lqad107
J Biol Chem. 2024 Sep 24. pii: S0021-9258(24)02316-0. [Epub ahead of print] 107815

Hematopoietic cells emerging from hemogenic endothelium exhibit lineage-specific oxidative stress responses.

Harmke Biezeman, Martina Nubiè, Leal Oburoglu.

During human embryogenesis, distinct waves of hematopoiesis give rise to various blood cell types, originating from hemogenic endothelial (HE) cells. As HE cells reside in hypoxic conditions in the embryo, we investigated the role of hypoxia in human EHT and subsequent hematopoiesis. Using single-cell RNA sequencing we describe hypoxia-related transcriptional changes in different HE-derived blood lineages, which reveal that erythroid cells are particularly susceptible to oxidative stress, due to decreased NRF2 activity in hypoxia. In contrast, non-erythroid CD45+ cells exhibit increased proliferative rates in hypoxic conditions and enhanced resilience to oxidative stress. We find that even in normoxia, erythroid cells present a clear predisposition to oxidative stress, with low GSH levels and high lipid peroxidation, in contrast to CD45+ cells. Intriguingly, ROS is produced at different sites in GPA+ and CD45+ cells, revealing differences in OXPHOS and the use of canonical vs. non-canonical TCA cycle in these lineages. Our findings elucidate how hypoxia and oxidative stress distinctly affect HE-derived hematopoietic lineages, uncovering critical transcriptional and metabolic pathways that influence blood cell development.

DOI: https://doi.org/10.1016/j.jbc.2024.107815