bims-medica 2024-01-21 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–01–21
fourteen papers selected by
Brett Chrest, East Carolina University

Residual Complex I activity and amphidirectional Complex II operation support glutamate catabolism through mtSLP in anoxia.
Comparative influence of kolaviron and coenzyme Q10 on complex I activity, glutamate clearance, 3,4-dihydroxyphenethylamine metabolism, and redox stress in rotenone-induced neurotoxicity.
Cyclic fasting-mimicking diet plus bortezomib and rituximab is an effective treatment for chronic lymphocytic leukemia.
Bromine Indirubin FLIM/PLIM sensors to measure oxygen in normoxic and hypoxic PDT conditions.
The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism.
Development of a mouse model expressing a bifunctional glutathione synthesizing enzyme to study glutathione limitation in vivo.
Glucose-derived glutamate drives neuronal terminal differentiation in vitro.
Cancer mutations converge on a collection of protein assemblies to predict resistance to replication stress.
Are lipid droplets the picnic basket of brain tumours?
α-Ketoglutarate supplementation and NAD+ modulation enhance metabolic rewiring and radiosensitization in SLC25A1 inhibited cancer cells.
The effect of a ketogenic diet on inflammation-related markers: a systematic review and meta-analysis of randomized controlled trials.
New genomic classification of pediatric acute myeloid leukemia.
Using MitER for 3D analysis of mitochondrial morphology and ER contacts.
Significance of quantitative analyses of the impact of heterogeneity in mitochondrial content and shape on cell differentiation.

Sci Rep. 2024 Jan 19. 14(1): 1729

Residual Complex I activity and amphidirectional Complex II operation support glutamate catabolism through mtSLP in anoxia.

Dora Ravasz, David Bui, Sara Nazarian, Gergely Pallag, Noemi Karnok, Jennie Roberts, Bryan P Marzullo, Daniel A Tennant, Bennett Greenwood, Alex Kitayev, Collin Hill, Timea Komlódi, Carolina Doerrier, Kristyna Cunatova, Erika Fernandez-Vizarra, Erich Gnaiger, Michael A Kiebish, Alexandra Raska, Krasimir Kolev, Bence Czumbel, Niven R Narain, Thomas N Seyfried, Christos Chinopoulos.

Anoxia halts oxidative phosphorylation (OXPHOS) causing an accumulation of reduced compounds in the mitochondrial matrix which impedes dehydrogenases. By simultaneously measuring oxygen concentration, NADH autofluorescence, mitochondrial membrane potential and ubiquinone reduction extent in isolated mitochondria in real-time, we demonstrate that Complex I utilized endogenous quinones to oxidize NADH under acute anoxia. 13C metabolic tracing or untargeted analysis of metabolites extracted during anoxia in the presence or absence of site-specific inhibitors of the electron transfer system showed that NAD+ regenerated by Complex I is reduced by the 2-oxoglutarate dehydrogenase Complex yielding succinyl-CoA supporting mitochondrial substrate-level phosphorylation (mtSLP), releasing succinate. Complex II operated amphidirectionally during the anoxic event, providing quinones to Complex I and reducing fumarate to succinate. Our results highlight the importance of quinone provision to Complex I oxidizing NADH maintaining glutamate catabolism and mtSLP in the absence of OXPHOS.

DOI: https://doi.org/10.1038/s41598-024-51365-4
Niger J Physiol Sci. 2022 Dec 31. 37(2): 165-173

Comparative influence of kolaviron and coenzyme Q10 on complex I activity, glutamate clearance, 3,4-dihydroxyphenethylamine metabolism, and redox stress in rotenone-induced neurotoxicity.

A C Akinmoladun, Ibrahim Saliu, Olaoluwa Abilogun, Omotola Helen Ajibola, Zainab Abiola Amoo, Olubukola Benedicta Ojo, Ebenezer O Farombi, Mary Tolulope Olaleye.

3,4-dihydroxyphenethylamine (dopamine) depletion, inhibition of complex I activity, oxidative stress, and glutamate excitotoxicity are cardinal biochemical features of neurotoxicity induced by systemic unilateral infusion of rotenone. Kolaviron (KV), a biflavonoid from Garcinia kola seeds, has been proven to have pharmacological effects against neurotoxicity. Coenzyme Q10 plays an essential role in mitochondrial oxidative phosphorylation and as an antioxidant. This study examined the comparative influence of kolaviron and coenzyme Q10 on complex I activity, dopamine metabolism, glutamate clearance, and redox stress in rotenone-induced neurotoxicity in the cortex, hippocampus, and striatum of the brain of rats. Adult Male Wistar rats were pretreated with 200 mg/kg KV or 100 mg/kg coenzyme Q10 for 7 days followed by administration of a progressive six doses of 1.5 mg/kg rotenone within the next 48 h after which the animals were euthanized and the brain excised. On the cortical, hippocampal, and striatal regions of the brain, complex I activity, dopamine metabolism, oxidative stress markers, as well as glutamate metabolism were carried out and analyzed. In all brain regions examined, KV and coenzyme Q10 pretreatment modulated complex I activity, ameliorated redox imbalance, and enhanced dopamine metabolism via increasing the activity of tyrosine hydroxylase and decreasing monoamine oxidase activity. KV facilitated glutamate clearance through augmentation of glutamate dehydrogenase and glutamine synthetase activities. The activity of KV was comparable to that of the mitochondrial membrane antioxidant compound, coenzyme Q10, this indicates that KV is a promising therapeutic agent in the treatment of Parkinson's disease and its activity compares well with coenzyme Q10.

DOI: https://doi.org/10.54548/njps.v37i2.2
Cancer Res. 2024 Jan 19.

Cyclic fasting-mimicking diet plus bortezomib and rituximab is an effective treatment for chronic lymphocytic leukemia.

Franca Raucci, Claudio Vernieri, Maira Di Tano, Francesca Ligorio, Olga Blaževitš, Samuel Lazzeri, Anastasiya Shmahala, Giuseppe Fragale, Giulia Salvadori, Gabriele Varano, Stefano Casola, Roberta Buono, Euplio Visco, Filippo de Braud, Valter D Longo.

Cyclic fasting-mimicking diet (FMD) is an experimental nutritional intervention with potent antitumor activity in preclinical models of solid malignancies. FMD cycles are also safe and active metabolically and immunologically in cancer patients. Here, we reported on the outcome of FMD cycles in two chronic lymphocytic leukemia (CLL) patients and investigated the effects of fasting and FMD cycles in pre-clinical CLL models. Fasting mimicking conditions in murine CLL models had mild cytotoxic effects, which resulted in apoptosis activation mediated in part by lowered insulin and IGF-1 concentrations. In CLL cells, fasting conditions promoted an increase in proteasome activity that served as a starvation escape pathway. Pharmacological inhibition of this escape mechanism with the proteasome inhibitor bortezomib (BTZ) resulted in a strong enhancement of the pro-apoptotic effects of starvation conditions in vitro. In mouse CLL models, combining cyclic fasting/FMD with BTZ and rituximab (RTX), an anti-CD20 antibody, delayed CLL progression and resulted in significant prolongation of mouse survival. Overall, the effect of proteasome inhibition in combination with FMD cycles in promoting CLL death supports the targeting of starvation escape pathways as an effective treatment strategy that should be tested in clinical trials.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0295
Photodiagnosis Photodyn Ther. 2024 Jan 11. pii: S1572-1000(24)00003-6. [Epub ahead of print] 103964

Bromine Indirubin FLIM/PLIM sensors to measure oxygen in normoxic and hypoxic PDT conditions.

D N S Dos-Santos, N Naskar, E Delgado-Pinar, K Reess, J S Seixas de Melo, A Rueck.

   BACKGROUND: The induction of phototoxicity during photodynamic therapy (PDT) is dependent on oxygen availability. For this reason, the development of sensors to measure oxygen and oxygen consumption is extremely important.
APPROACH: In this project we have used Fluorescence Lifetime imaging (FLIM) and Phosphorescence Lifetime Imaging/ delayed Fluorescence Lifetime Imaging (PLIM/dFLIM) to investigate the ability of bromine indirubin derivatives as oxygen sensors.
RESULTS: The oxygen sensitivity of bromine indirubins was detected through PLIM/dFLIM. Moreover, we have observed by measuring nicotinamide adenine dinucleotide (NADH) FLIM that bromine indirubin have a significant impact on cellular metabolism by shifting the SCC-4 Cells metabolism from oxidative phosphorylation (OXPHOS) to glycolysis.
CONCLUSIONS: In conclusion, this study successfully achieves its goals and provides important insights into the use of indirubin as a potential oxygen consumption sensor with the capability to identify and differentiate between normoxic and hypoxic regions within the cells.

Keywords:  NADH-FLIM; PLIM; TCSPC; dFLIM; indirubin derivatives; oxygen consumption; ultrafast techniques

DOI:  https://doi.org/10.1016/j.pdpdt.2024.103964
PLoS Biol. 2024 Jan;22(1): e3002406

The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism.

Mona Nazemi, Bian Yanes, Montserrat Llanses Martinez, Heather J Walker, Khoa Pham, Mark O Collins, Frederic Bard, Elena Rainero.

Breast tumours are embedded in a collagen I-rich extracellular matrix (ECM) network, where nutrients are scarce due to limited blood flow and elevated tumour growth. Metabolic adaptation is required for cancer cells to endure these conditions. Here, we demonstrated that the presence of ECM supported the growth of invasive breast cancer cells, but not non-transformed mammary epithelial cells, under amino acid starvation, through a mechanism that required macropinocytosis-dependent ECM uptake. Importantly, we showed that this behaviour was acquired during carcinoma progression. ECM internalisation, followed by lysosomal degradation, contributed to the up-regulation of the intracellular levels of several amino acids, most notably tyrosine and phenylalanine. This resulted in elevated tyrosine catabolism on ECM under starvation, leading to increased fumarate levels, potentially feeding into the tricarboxylic acid (TCA) cycle. Interestingly, this pathway was required for ECM-dependent cell growth and invasive cell migration under amino acid starvation, as the knockdown of p-hydroxyphenylpyruvate hydroxylase-like protein (HPDL), the third enzyme of the pathway, opposed cell growth and motility on ECM in both 2D and 3D systems, without affecting cell proliferation on plastic. Finally, high HPDL expression correlated with poor prognosis in breast cancer patients. Collectively, our results highlight that the ECM in the tumour microenvironment (TME) represents an alternative source of nutrients to support cancer cell growth by regulating phenylalanine and tyrosine metabolism.

DOI: https://doi.org/10.1371/journal.pbio.3002406
J Biol Chem. 2024 Jan 11. pii: S0021-9258(24)00021-8. [Epub ahead of print] 105645

Development of a mouse model expressing a bifunctional glutathione synthesizing enzyme to study glutathione limitation in vivo.

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

Glutathione (GSH) is a highly abundant tripeptide thiol that performs diverse protective and biosynthetic functions in cells. While changes in GSH availability are associated with inborn errors of metabolism, cancer and neurodegenerative disorders, studying the limiting role of GSH in physiology and disease has been challenging due to its tight regulation. To address this, we generated cell and mouse models that express a bifunctional glutathione-synthesizing enzyme from Streptococcus thermophilus (GshF), which possesses both glutamate-cysteine ligase and glutathione synthase activities. GshF expression allows efficient production of GSH in the cytosol and mitochondria and prevents cell death in response to GSH depletion, but not ferroptosis induction, indicating that GSH is not a limiting factor under lipid peroxidation. CRISPR screens using engineered enzymes further revealed genes required for cell proliferation under cellular and mitochondrial GSH depletion. Among these, we identified the glutamate-cysteine ligase modifier subunit, Gclm, as a requirement for cellular sensitivity to buthionine sulfoximne, a glutathione synthesis inhibitor. Finally, GshF expression in mice is embryonically lethal but sustains postnatal viability when restricted to adulthood. Overall, our work identifies a conditional mouse model to investigate the limiting role of GSH in physiology and disease.

DOI: https://doi.org/10.1016/j.jbc.2024.105645
EMBO Rep. 2024 Jan 19.

Glucose-derived glutamate drives neuronal terminal differentiation in vitro.

Laura D'Andrea, Matteo Audano, Silvia Pedretti, Silvia Pelucchi, Ramona Stringhi, Gabriele Imperato, Giulia De Cesare, Clara Cambria, Marine H Laporte, Nicola Zamboni, Flavia Antonucci, Monica Di Luca, Nico Mitro, Elena Marcello.

  Neuronal maturation is the phase during which neurons acquire their final characteristics in terms of morphology, electrical activity, and metabolism. However, little is known about the metabolic pathways governing neuronal maturation. Here, we investigate the contribution of the main metabolic pathways, namely glucose, glutamine, and fatty acid oxidation, during the maturation of primary rat hippocampal neurons. Blunting glucose oxidation through the genetic and chemical inhibition of the mitochondrial pyruvate transporter reveals that this protein is critical for the production of glutamate, which is required for neuronal arborization, proper dendritic elongation, and spine formation. Glutamate supplementation in the early phase of differentiation restores morphological defects and synaptic function in mitochondrial pyruvate transporter-inhibited cells. Furthermore, the selective activation of metabotropic glutamate receptors restores the impairment of neuronal differentiation due to the reduced generation of glucose-derived glutamate and rescues synaptic local translation. Fatty acid oxidation does not impact neuronal maturation. Whereas glutamine metabolism is important for mitochondria, it is not for endogenous glutamate production. Our results provide insights into the role of glucose-derived glutamate as a key player in neuronal terminal differentiation.

Keywords:  Glutamate; Local Protein Translation in Neurons; Metabolism; Mitochondrial Pyruvate Carrier

DOI:  https://doi.org/10.1038/s44319-023-00048-8
Cancer Discov. 2024 Jan 18.

Cancer mutations converge on a collection of protein assemblies to predict resistance to replication stress.

Xiaoyu Zhao, Akshat Singhal, Sungjoon Park, JungHo Kong, Robin Bachelder, Trey Ideker.

Rapid proliferation is a hallmark of cancer, associated with sensitivity to therapeutics that cause DNA replication stress (RS). Many tumors exhibit drug resistance, however, via molecular pathways that are incompletely understood. Here, we develop an ensemble of predictive models that elucidate how cancer mutations impact the response to common RS-inducing (RSi) agents. The models implement recent advances in deep learning to facilitate multi-drug prediction and mechanistic interpretation. Initial studies in tumor cells identify 41 molecular assemblies that integrate alterations in hundreds of genes for accurate drug response prediction. These cover roles in transcription, repair, cell-cycle checkpoints, and growth signaling, of which 30 are shown by loss-of-function genetic screens to regulate drug sensitivity or replication restart. The model translates to cisplatin-treated cervical cancer patients, highlighting an RTK (receptor tyrosine kinase)-JAK-STAT assembly governing resistance. This study defines a compendium of mechanisms by which mutations affect therapeutic responses, with implications for precision medicine.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0641
Cell Death Discov. 2024 Jan 16. 10(1): 31

Are lipid droplets the picnic basket of brain tumours?

Tanmayi Bingi, Kian Cotton, Charley Comer, Maria Victoria Niklison-Chirou.

Are lipid droplets (LDs) necessary to maintain the viability of brain tumour cells as they move to new nutrient-poor environments? In turn, could cancers be targeted by attacking what you might think of as the cancer cells' picnic basket? Lipid metabolism reprogramming, represented by increased lipid uptake, activation of de novo lipogenesis and increased lipid storage, is a newly identified hallmark of cancers. Recently, the presence of lipid droplets has been detected in several types of cancers, such as metastatic hepatocellular carcinoma, pancreatic and breast. LDs are storage organelles that provide a source of nutrients which may drive metastasis in different tumours. Currently, several roles of LDs have been posited in various tumours. This perspective aims to review and discuss the currently understood role of LDs in brain tumours.

DOI: https://doi.org/10.1038/s41420-024-01797-8
Cell Death Discov. 2024 Jan 15. 10(1): 27

α-Ketoglutarate supplementation and NAD+ modulation enhance metabolic rewiring and radiosensitization in SLC25A1 inhibited cancer cells.

Kexu Xiang, Mikhail Kunin, Safa Larafa, Maike Busch, Nicole Dünker, Verena Jendrossek, Johann Matschke.

Metabolic rewiring is the result of the increasing demands and proliferation of cancer cells, leading to changes in the biological activities and responses to treatment of cancer cells. The mitochondrial citrate transport protein SLC25A1 is involved in metabolic reprogramming offering a strategy to induce metabolic bottlenecks relevant to radiosensitization through the accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) upon SLC25A1 inhibition (SLC25A1i). Previous studies have revealed the comparative effects of SLC25A1i or cell-permeable D-2HG (octyl-D-2HG) treatments on DNA damage induction and repair, as well as on energy metabolism and cellular function, which are crucial for the long-term survival of irradiated cells. Here, α-ketoglutarate (αKG), the precursor of D-2HG, potentiated the effects observed upon SLC25A1i on DNA damage repair, cell function and long-term survival in vitro and in vivo, rendering NCI-H460 cancer cells more vulnerable to ionizing radiation. However, αKG treatment alone had little effect on these phenotypes. In addition, supplementation with nicotinamide (NAM), a precursor of NAD (including NAD+ and NADH), counteracted the effects of SLC25A1i or the combination of SLC25A1i with αKG, highlighting a potential importance of the NAD+/NADH balance on cellular activities relevant to the survival of irradiated cancer cells upon SLC25A1i. Furthermore, inhibition of histone lysine demethylases (KDMs), as a major factor affected upon SLC25A1i, by JIB04 treatment alone or in combination with αKG supplementation phenocopied the broad effects on mitochondrial and cellular function induced by SLC25A1i. Taken together, αKG supplementation potentiated the effects on cellular processes observed upon SLC25A1i and increased the cellular demand for NAD to rebalance the cellular state and ensure survival after irradiation. Future studies will elucidate the underlying metabolic reprogramming induced by SLC25A1i and provide novel therapeutic strategies for cancer treatment.

DOI: https://doi.org/10.1038/s41420-024-01805-x
Nutr Rev. 2024 Jan 14. pii: nuad175. [Epub ahead of print]

The effect of a ketogenic diet on inflammation-related markers: a systematic review and meta-analysis of randomized controlled trials.

Jiawei Ji, Danial Fotros, Mohammad Hassan Sohouli, Periyannan Velu, Somaye Fatahi, Yinghao Liu.

   CONTEXT: Despite the important role of inflammation-related factors on the occurrence of chronic diseases, there is still conflicting evidence about the effects of the ketogenic diet (KD) on these factors.
OBJECTIVE: In order to obtain a better viewpoint, this study aimed to comprehensively investigate the effects of a KD on inflammation-related markers.
DATA SOURCES: To find pertinent randomized controlled trials up to August 2023, databases including PubMed/Medline, Web of Science, Scopus, Cochrane Library, and Embase were searched.
DATA EXTRACTION: This study included all randomized controlled trials investigating the effects of a KD on C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8, and IL-10 levels. Pooled weighted mean difference (WMD) and 95% confidence intervals (CIs) were achieved by random-effects model analysis for the best estimation of outcomes.
DATA ANALYSIS: Forty-four studies were included in this article. The pooled findings showed that a KD has an effect on lowering TNF-α (WMD: -0.32 pg/mL; 95% CI: -0.55, -0.09; P = 0.007) and IL-6 (WMD: -0.27 pg/mL; 95% CI: -0.52, -0.02; P = 0.036) compared with control groups. However, no significant effect was reported for others inflammation marker-related levels. The results of the subgroup analysis showed that, in trials following the KD for ≤8 weeks and in people aged ≤50 years, the reduction in TNF-α levels was significantly higher than in other groups. In addition, in people with a body mass index greater than 30 kg/m2 compared to a body mass index ≤30 kg/m2, IL-6 levels decreased to a greater extent after receiving the KD.
CONCLUSIONS: Consequently, adherence to a KD appears to improve some markers associated with inflammation, including TNF-α and IL-6.

Keywords:  CRP; IL-6; TNF-α; inflammation; ketogenic diet; meta-analysis

DOI:  https://doi.org/10.1093/nutrit/nuad175
Nat Genet. 2024 Jan 18.

New genomic classification of pediatric acute myeloid leukemia.

DOI: https://doi.org/10.1038/s41588-023-01639-w
Cell Rep Methods. 2024 Jan 11. pii: S2667-2375(23)00378-8. [Epub ahead of print] 100692

Using MitER for 3D analysis of mitochondrial morphology and ER contacts.

Therese Kichuk, Satyen Dhamankar, Saurabh Malani, William A Hofstadter, Scott A Wegner, Ileana M Cristea, José L Avalos.

  We have developed an open-source workflow that allows for quantitative single-cell analysis of organelle morphology, distribution, and inter-organelle contacts with an emphasis on the analysis of mitochondria and mitochondria-endoplasmic reticulum (mito-ER) contact sites. As the importance of inter-organelle contacts becomes more widely recognized, there is a concomitant increase in demand for tools to analyze subcellular architecture. Here, we describe a workflow we call MitER (pronounced "mightier"), which allows for automated calculation of organelle morphology, distribution, and inter-organelle contacts from 3D renderings by employing the animation software Blender. We then use MitER to quantify the variations in the mito-ER networks of Saccharomyces cerevisiae, revealing significantly more mito-ER contacts within respiring cells compared to fermenting cells. We then demonstrate how this workflow can be applied to mammalian systems and used to monitor mitochondrial dynamics and inter-organelle contact in time-lapse studies.

Keywords:  CP: Imaging; Saccharomyces cerevisea; image analysis; imaging; inter-organelle contact; mitochondrial-ER contact; organelle distribution; organelle morphology

DOI:  https://doi.org/10.1016/j.crmeth.2023.100692
Open Biol. 2024 Jan;14(1): 230279

Significance of quantitative analyses of the impact of heterogeneity in mitochondrial content and shape on cell differentiation.

Swati Agarwala, Sukhamoy Dhabal, Kasturi Mitra.

  Mitochondria, classically known as the powerhouse of cells, are unique double membrane-bound multifaceted organelles carrying a genome. Mitochondrial content varies between cell types and precisely doubles within cells during each proliferating cycle. Mitochondrial content also increases to a variable degree during cell differentiation triggered after exit from the proliferating cycle. The mitochondrial content is primarily maintained by the regulation of mitochondrial biogenesis, while damaged mitochondria are eliminated from the cells by mitophagy. In any cell with a given mitochondrial content, the steady-state mitochondrial number and shape are determined by a balance between mitochondrial fission and fusion processes. The increase in mitochondrial content and alteration in mitochondrial fission and fusion are causatively linked with the process of differentiation. Here, we critically review the quantitative aspects in the detection methods of mitochondrial content and shape. Thereafter, we quantitatively link these mitochondrial properties in differentiating cells and highlight the implications of such quantitative link on stem cell functionality. Finally, we discuss an example of cell size regulation predicted from quantitative analysis of mitochondrial shape and content. To highlight the significance of quantitative analyses of these mitochondrial properties, we propose three independent rationale based hypotheses and the relevant experimental designs to test them.

Keywords:  cell differentiation; cell proliferation; mitochondrial content; mitochondrial heterogeneity; mitochondrial shape; stem cells

DOI:  https://doi.org/10.1098/rsob.230279