bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2024–04–28
23 papers selected by
Marc Segarra Mondejar
  1. Warburg Effect Reshapes Tumor Immunogenicity.
  2. Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.
  3. Neuronal glycolysis: focus on developmental morphogenesis and localized subcellular functions.
  4. Raman Imaging-A Valuable Tool for Tracking Fatty Acid Metabolism-Normal and Cancer Human Colon Single-Cell Study.
  5. Regulation of mitochondrial fission by fatty acyl-coenzyme A.
  6. Optogenetically engineered calcium oscillations promote autophagy-mediated cell death via AMPK activation.
  7. Revisiting liver metabolism through acetyl-CoA carboxylase inhibition.
  8. Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.
  9. Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.
  10. BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.
  11. A glycolytic metabolite that drives BRCA2 haploinsufficiency.
  12. Machine learning enables identification of an alternative yeast galactose utilization pathway.
  13. Clear cell renal cell carcinoma with high PSMA uptake.
  14. TNF-α signals through ITK-Akt-mTOR to drive CD4+ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis.
  15. DIMet: An open-source tool for Differential analysis of targeted Isotope-labeled Metabolomics data.
  16. Mitochondrial sites of contact with the nucleus.
  17. Effect of the Mitochondrial Transaminase (GOT2) on Membrane Potential Sensitive Respiration in Mitochondria of Differentiated C2C12 Muscle Cells.
  18. Low ACADM expression predicts poor prognosis and suppressive tumor microenvironment in clear cell renal cell carcinoma.
  19. Sphingolipid biosynthesis is essential for metabolic rewiring during TH17 cell differentiation.
  20. Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases.
  21. MED15 is upregulated by HIF-2α and promotes proliferation and metastasis in clear cell renal cell carcinoma via activation of SREBP-dependent fatty acid synthesis.
  22. Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development.
  23. A multipurpose mitochondrial NIR probe for imaging ferroptosis and mitophagy.
  1. Cancer Res. 2024 Apr 24.
    Warburg Effect Reshapes Tumor Immunogenicity.
    Jose A Enríquez, María Mittelbrunn.
      Tumor cells rewire their metabolism to fulfill the demands of highly proliferative cells. This changes cellular metabolism to adapt to fuel and oxygen availability for energy production and to increase the synthesis capacity of building blocks for cell division and growth. In addition, the metabolic shift also modulates the immunogenicity of the tumor cells. Recently, Mahmood and colleagues reported a connection between mitochondrial DNA mutations in cancer cells and their response to immunotherapy in a mouse model of melanoma.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1304
  2. Nat Commun. 2024 Apr 24. 15(1): 3445
    Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.
    Jiang-Jiang Li, Tiantian Yu, Peiting Zeng, Jingyu Tian, Panpan Liu, Shuang Qiao, Shijun Wen, Yumin Hu, Qiao Liu, Wenhua Lu, Hui Zhang, Peng Huang.
      Mutations in isocitrate dehydrogenases (IDH) are oncogenic events due to the generation of oncogenic metabolite 2-hydroxyglutarate. However, the role of wild-type IDH in cancer development remains elusive. Here we show that wild-type IDH2 is highly expressed in triple negative breast cancer (TNBC) cells and promotes their proliferation in vitro and tumor growth in vivo. Genetic silencing or pharmacological inhibition of wt-IDH2 causes a significant increase in α-ketoglutarate (α-KG), indicating a suppression of reductive tricarboxylic acid (TCA) cycle. The aberrant accumulation of α-KG due to IDH2 abrogation inhibits mitochondrial ATP synthesis and promotes HIF-1α degradation, leading to suppression of glycolysis. Such metabolic double-hit results in ATP depletion and suppression of tumor growth, and renders TNBC cells more sensitive to doxorubicin treatment. Our study reveals a metabolic property of TNBC cells with active utilization of glutamine via reductive TCA metabolism, and suggests that wild-type IDH2 plays an important role in this metabolic process and could be a potential therapeutic target for TNBC.
    DOI:  https://doi.org/10.1038/s41467-024-47536-6
  3. Commun Integr Biol. 2024 ;17(1): 2343532
    Neuronal glycolysis: focus on developmental morphogenesis and localized subcellular functions.
    Gianluca Gallo.
      Glycolysis is a metabolic pathway that directly generates adenosine triphosphate (ATP), provides metabolic intermediates for anabolism, and supports mitochondrial oxidative phosphorylation. This review addresses recent advances in our understanding of the functions of neuronal glycolysis during the development of neuronal morphogenesis, focusing on the emergent concept that neuronal glycolysis serves local subcellular bioenergetic roles in maintaining neuronal function. The current evidence indicates that glycolysis is subcellularly targeted to specific organelles and molecular machinery to locally supply bioenergetic support for defined subcellular mechanisms underlying neuronal morphogenesis (i.e. axon extension, axon retraction and axonal transport). Thus, the concept of glycolysis as a "housekeeping" mechanism in neurons would benefit revision and future work aim to further define its subcellular functions at varied developmental stages.
    Keywords:  Bioenergetics; actin; axon; glycolysis; mitochondria
    DOI:  https://doi.org/10.1080/19420889.2024.2343532
  4. Int J Mol Sci. 2024 Apr 19. pii: 4508. [Epub ahead of print]25(8):
    Raman Imaging-A Valuable Tool for Tracking Fatty Acid Metabolism-Normal and Cancer Human Colon Single-Cell Study.
    Karolina Beton-Mysur, Monika Kopec, Beata Brozek-Pluska.
      Altered metabolism of lipids is a key factor in many diseases including cancer. Therefore, investigations into the impact of unsaturated and saturated fatty acids (FAs) on human body homeostasis are crucial for understanding the development of lifestyle diseases. In this paper, we focus on the impact of palmitic (PA), linoleic (LA), and eicosapentaenoic (EPA) acids on human colon normal (CCD-18 Co) and cancer (Caco-2) single cells using Raman imaging and spectroscopy. The label-free nature of Raman imaging allowed us to evaluate FAs dynamics without modifying endogenous cellular metabolism. Thanks to the ability of Raman imaging to visualize single-cell substructures, we have analyzed the changes in chemical composition of endoplasmic reticulum (ER), mitochondria, lipid droplets (LDs), and nucleus upon FA supplementation. Analysis of Raman band intensity ratios typical for lipids, proteins, and nucleic acids (I1656/I1444, I1444/I1256, I1444/I750, I1304/I1256) proved that, using Raman mapping, we can observe the metabolic pathways of FAs in ER, which is responsible for the uptake of exogenous FAs, de novo synthesis, elongation, and desaturation of FAs, in mitochondria responsible for energy production via FA oxidation, in LDs specialized in cellular fat storage, and in the nucleus, where FAs are transported via fatty-acid-binding proteins, biomarkers of human colon cancerogenesis. Analysis for membranes showed that the uptake of FAs effectively changed the chemical composition of this organelle, and the strongest effect was noticed for LA. The spectroscopy studies have been completed using XTT tests, which showed that the addition of LA or EPA for Caco-2 cells decreases their viability with a stronger effect observed for LA and the opposite effect observed for PA. For normal cells, CCD-18 Co supplementation using LA or EPA stimulated cells for growing, while PA had the opposite impact.
    Keywords:  Raman imaging; Raman spectroscopy; cancer biomarkers; colon cancer; fatty acids; metabolism
    DOI:  https://doi.org/10.3390/ijms25084508
  5. Nat Cell Biol. 2024 Apr 23.
    Regulation of mitochondrial fission by fatty acyl-coenzyme A.
      
    DOI:  https://doi.org/10.1038/s41556-024-01406-x
  6. Open Biol. 2024 Apr;14(4): 240001
    Optogenetically engineered calcium oscillations promote autophagy-mediated cell death via AMPK activation.
    Yi-Shyun Lai, Meng-Ru Hsieh, Thi My Hang Nguyen, Ying-Chi Chen, Hsueh-Chun Wang, Wen-Tai Chiu.
      Autophagy is a double-edged sword for cells; it can lead to both cell survival and death. Calcium (Ca2+) signalling plays a crucial role in regulating various cellular behaviours, including cell migration, proliferation and death. In this study, we investigated the effects of modulating cytosolic Ca2+ levels on autophagy using chemical and optogenetic methods. Our findings revealed that ionomycin and thapsigargin induce Ca2+ influx to promote autophagy, whereas the Ca2+ chelator BAPTA-AM induces Ca2+ depletion and inhibits autophagy. Furthermore, the optogenetic platform allows the manipulation of illumination parameters, including density, frequency, duty cycle and duration, to create different patterns of Ca2+ oscillations. We used the optogenetic tool Ca2+-translocating channelrhodopsin, which is activated and opened by 470 nm blue light to induce Ca2+ influx. These results demonstrated that high-frequency Ca2+ oscillations induce autophagy. In addition, autophagy induction may involve Ca2+-activated adenosine monophosphate (AMP)-activated protein kinases. In conclusion, high-frequency optogenetic Ca2+ oscillations led to cell death mediated by AMP-activated protein kinase-induced autophagy.
    Keywords:  AMPK; autophagy; calcium; cell death; optogenetics
    DOI:  https://doi.org/10.1098/rsob.240001
  7. Trends Endocrinol Metab. 2024 Apr 24. pii: S1043-2760(24)00093-6. [Epub ahead of print]
    Revisiting liver metabolism through acetyl-CoA carboxylase inhibition.
    Armando Jesús Pérez-Díaz, María Ángeles Núñez-Sánchez, Bruno Ramos-Molina.
      Liver-targeted acetyl-coenzyme A (CoA) carboxylase (ACC) inhibitors in metabolic dysfunction-associated steatotic liver disease (MASLD) trials reveal notable secondary effects: hypertriglyceridemia and altered glucose metabolism, paradoxically with reduced hepatic steatosis. In their study, Deja et al. explored how hepatic ACC influences metabolism using different pharmacological and genetic methods, coupled with targeted metabolomics and stable isotope-based tracing techniques.
    Keywords:  acetyl-CoA carboxylase; autophagy; lipogenesis; liver metabolism; malonyl-CoA
    DOI:  https://doi.org/10.1016/j.tem.2024.04.010
  8. Science. 2024 Apr 26. 384(6694): 438-446
    Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.
    Sinika Henschke, Hendrik Nolte, Judith Magoley, Tatjana Kleele, Claus Brandt, A Christine Hausen, Claudia M Wunderlich, Corinna A Bauder, Philipp Aschauer, Suliana Manley, Thomas Langer, F Thomas Wunderlich, Jens C Brüning.
      Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes in nutrient availability has remained unaddressed. Here, we found that sensory food perception rapidly induced mitochondrial fragmentation in the liver through protein kinase B/AKT (AKT)-dependent phosphorylation of serine 131 of the mitochondrial fission factor (MFFS131). This response was mediated by activation of hypothalamic pro-opiomelanocortin (POMC)-expressing neurons. A nonphosphorylatable MFFS131G knock-in mutation abrogated AKT-induced mitochondrial fragmentation in vitro. In vivo, MFFS131G knock-in mice displayed altered liver mitochondrial dynamics and impaired insulin-stimulated suppression of hepatic glucose production. Thus, rapid activation of a hypothalamus-liver axis can adapt mitochondrial function to anticipated changes of nutritional state in control of hepatic glucose metabolism.
    DOI:  https://doi.org/10.1126/science.adk1005
  9. PLoS Biol. 2024 Apr 26. 22(4): e3002602
    Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.
    Cynthia Alsayyah, Manish K Singh, Maria Angeles Morcillo-Parra, Laetitia Cavellini, Nadav Shai, Christine Schmitt, Maya Schuldiner, Einat Zalckvar, Adeline Mallet, Naïma Belgareh-Touzé, Christophe Zimmer, Mickaël M Cohen.
      Mitofusins are large GTPases that trigger fusion of mitochondrial outer membranes. Similarly to the human mitofusin Mfn2, which also tethers mitochondria to the endoplasmic reticulum (ER), the yeast mitofusin Fzo1 stimulates contacts between Peroxisomes and Mitochondria when overexpressed. Yet, the physiological significance and function of these "PerMit" contacts remain unknown. Here, we demonstrate that Fzo1 naturally localizes to peroxisomes and promotes PerMit contacts in physiological conditions. These contacts are regulated through co-modulation of Fzo1 levels by the ubiquitin-proteasome system (UPS) and by the desaturation status of fatty acids (FAs). Contacts decrease under low FA desaturation but reach a maximum during high FA desaturation. High-throughput genetic screening combined with high-resolution cellular imaging reveal that Fzo1-mediated PerMit contacts favor the transit of peroxisomal citrate into mitochondria. In turn, citrate enters the TCA cycle to stimulate the mitochondrial membrane potential and maintain efficient mitochondrial fusion upon high FA desaturation. These findings thus unravel a mechanism by which inter-organelle contacts safeguard mitochondrial fusion.
    DOI:  https://doi.org/10.1371/journal.pbio.3002602
  10. Cell. 2024 Apr 17. pii: S0092-8674(24)00346-5. [Epub ahead of print]
    BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.
    Anthony R P Verkerke, Dandan Wang, Naofumi Yoshida, Zachary H Taxin, Xu Shi, Shuning Zheng, Yuka Li, Christopher Auger, Satoshi Oikawa, Jin-Seon Yook, Melia Granath-Panelo, Wentao He, Guo-Fang Zhang, Mami Matsushita, Masayuki Saito, Robert E Gerszten, Evanna L Mills, Alexander S Banks, Yasushi Ishihama, Phillip J White, Robert W McGarrah, Takeshi Yoneshiro, Shingo Kajimura.
      Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.
    Keywords:  amino acid metabolism; bioenergetics; brown adipose tissue; diabetes; glucose homeostasis; insulin resistance; inter-organ communication; mitochondria; thermogenesis
    DOI:  https://doi.org/10.1016/j.cell.2024.03.030
  11. Cell. 2024 Apr 25. pii: S0092-8674(24)00319-2. [Epub ahead of print]187(9): 2124-2126
    A glycolytic metabolite that drives BRCA2 haploinsufficiency.
    Peng Jiang.
      Many types of tumor cells alter metabolic pathways to meet their energy and biosynthetic demands for proliferation or stress adaptation. In this issue of Cell, Kong et al. find that the glycolytic metabolite methylglyoxal causes cancer-associated mutant single-base substitution features by inducing BRCA2 proteolysis, leading to functional haploinsufficiency of BRCA2.
    DOI:  https://doi.org/10.1016/j.cell.2024.03.028
  12. Proc Natl Acad Sci U S A. 2024 Apr 30. 121(18): e2315314121
    Machine learning enables identification of an alternative yeast galactose utilization pathway.
    Marie-Claire Harrison, Emily J Ubbelohde, Abigail L LaBella, Dana A Opulente, John F Wolters, Xiaofan Zhou, Xing-Xing Shen, Marizeth Groenewald, Chris Todd Hittinger, Antonis Rokas.
      How genomic differences contribute to phenotypic differences is a major question in biology. The recently characterized genomes, isolation environments, and qualitative patterns of growth on 122 sources and conditions of 1,154 strains from 1,049 fungal species (nearly all known) in the yeast subphylum Saccharomycotina provide a powerful, yet complex, dataset for addressing this question. We used a random forest algorithm trained on these genomic, metabolic, and environmental data to predict growth on several carbon sources with high accuracy. Known structural genes involved in assimilation of these sources and presence/absence patterns of growth in other sources were important features contributing to prediction accuracy. By further examining growth on galactose, we found that it can be predicted with high accuracy from either genomic (92.2%) or growth data (82.6%) but not from isolation environment data (65.6%). Prediction accuracy was even higher (93.3%) when we combined genomic and growth data. After the GALactose utilization genes, the most important feature for predicting growth on galactose was growth on galactitol, raising the hypothesis that several species in two orders, Serinales and Pichiales (containing the emerging pathogen Candida auris and the genus Ogataea, respectively), have an alternative galactose utilization pathway because they lack the GAL genes. Growth and biochemical assays confirmed that several of these species utilize galactose through an alternative oxidoreductive D-galactose pathway, rather than the canonical GAL pathway. Machine learning approaches are powerful for investigating the evolution of the yeast genotype-phenotype map, and their application will uncover novel biology, even in well-studied traits.
    Keywords:  AI; GAL pathway; fungal evolution; galactitol; primary metabolism
    DOI:  https://doi.org/10.1073/pnas.2315314121
  13. BMJ Case Rep. 2024 Apr 24. pii: e260372. [Epub ahead of print]17(4):
    Clear cell renal cell carcinoma with high PSMA uptake.
    Maria Monica Yepes, Andrés Felipe Herrera Ortiz, Valeria Del Castillo, Julian Rojas.
      
    Keywords:  Oncology; Prostate Cancer; Radiology; Urological cancer
    DOI:  https://doi.org/10.1136/bcr-2024-260372
  14. Sci Signal. 2024 Apr 23. 17(833): eadg5678
    TNF-α signals through ITK-Akt-mTOR to drive CD4+ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis.
    Emma L Bishop, Nancy Gudgeon, Taylor Fulton-Ward, Victoria Stavrou, Jennie Roberts, Adam Boufersaoui, Daniel A Tennant, Martin Hewison, Karim Raza, Sarah Dimeloe.
      Upon activation, T cells undergo metabolic reprogramming to meet the bioenergetic demands of clonal expansion and effector function. Because dysregulated T cell cytokine production and metabolic phenotypes coexist in chronic inflammatory disease, including rheumatoid arthritis (RA), we investigated whether inflammatory cytokines released by differentiating T cells amplified their metabolic changes. We found that tumor necrosis factor-α (TNF-α) released by human naïve CD4+ T cells upon activation stimulated the expression of a metabolic transcriptome and increased glycolysis, amino acid uptake, mitochondrial oxidation of glutamine, and mitochondrial biogenesis. The effects of TNF-α were mediated by activation of Akt-mTOR signaling by the kinase ITK and did not require the NF-κB pathway. TNF-α stimulated the differentiation of naïve cells into proinflammatory T helper 1 (TH1) and TH17 cells, but not that of regulatory T cells. CD4+ T cells from patients with RA showed increased TNF-α production and consequent Akt phosphorylation upon activation. These cells also exhibited increased mitochondrial mass, particularly within proinflammatory T cell subsets implicated in disease. Together, these findings suggest that T cell-derived TNF-α drives their metabolic reprogramming by promoting signaling through ITK, Akt, and mTOR, which is dysregulated in autoinflammatory disease.
    DOI:  https://doi.org/10.1126/scisignal.adg5678
  15. Bioinformatics. 2024 Apr 24. pii: btae282. [Epub ahead of print]
    DIMet: An open-source tool for Differential analysis of targeted Isotope-labeled Metabolomics data.
    Johanna Galvis, Joris Guyon, Benjamin Dartigues, Helge Hecht, Björn Grüning, Florian Specque, Hayssam Soueidan, Slim Karkar, Thomas Daubon, Macha Nikolski.
       MOTIVATION: Many diseases, such as cancer, are characterized by an alteration of cellular metabolism allowing cells to adapt to changes in the microenvironment. Stable isotope-resolved metabolomics and downstream data analyses are widely used techniques for unraveling cells' metabolic activity to understand the altered functioning of metabolic pathways in the diseased state. While a number of bioinformatic solutions exist for the differential analysis of Stable Isotope-Resolved Metabolomics data, there is currently no available resource providing a comprehensive toolbox.
    RESULTS: In this work, we present DIMet, a one-stop comprehensive tool for differential analysis of targeted tracer data. DIMet accepts metabolite total abundances, isotopologue contributions, and isotopic mean enrichment, and supports differential comparison (pairwise and multi-group), time-series analyses, and labeling profile comparison. Moreover, it integrates transcriptomics and targeted metabolomics data through network-based metabolograms. We illustrate the use of DIMet in real SIRM datasets obtained from Glioblastoma P3 cell-line samples. DIMet is open-source, and is readily available for routine downstream analysis of isotope-labeled targeted metabolomics data, as it can be used both in the command line interface or as a complete toolkit in the public Galaxy Europe and Workfow4Metabolomics web platforms.
    AVAILABILITY: DIMet is freely available at https://github.com/cbib/DIMet, and through https://usegalaxy.eu and https://workflow4metabolomics.usegalaxy.fr. All the datasets are available at Zenodo https://zenodo.org/records/10925786.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btae282
  16. J Cell Biol. 2024 Jun 03. pii: e202305010. [Epub ahead of print]223(6):
    Mitochondrial sites of contact with the nucleus.
    Michelangelo Campanella, Brindha Kannan.
      Membrane contact sites (MCS) between mitochondria and the nucleus have been recently described. Termed nucleus associated mitochondria (NAM), they prime the expression of genes required for cellular resistance to stressors, thus offering a tethering mechanism for homeostatic communication. Here, we discuss the composition of NAM and their physiological and pathological significance.
    DOI:  https://doi.org/10.1083/jcb.202305010
  17. Am J Physiol Cell Physiol. 2024 Apr 22.
    Effect of the Mitochondrial Transaminase (GOT2) on Membrane Potential Sensitive Respiration in Mitochondria of Differentiated C2C12 Muscle Cells.
    Ritu Som, Brian D Fink, Liping Yu, William I Sivitz.
      We previously showed that the transaminase inhibitor, aminooxyacetic acid, reduced respiration energized at complex II (succinate dehydrogenase, SDH) in mitochondria isolated from mouse hindlimb muscle. The effect required a reduction in membrane potential with resultant accumulation of oxaloacetate (OAA), a potent inhibitor of SDH. To specifically assess the effect of the mitochondrial transaminase, glutamic oxaloacetic transaminase (GOT2) on complex II respiration and to determine the effect in intact cells as well as isolated mitochondria, we performed respiratory and metabolic studies in wildtype (WT) and CRISPR-generated GOT2 knockdown (KD) C2C12 myocytes. Intact cell respiration by GOT2KD cells versus WT was reduced by adding carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) to lower potential. In mitochondria of C2C12 KD cells, respiration at low potential generated by 1µM FCCP and energized at complex II by 10mM succinate + 0.5mM glutamate, (but not by complex I substrates) was reduced versus WT mitochondria. Although we could not detect OAA, metabolite data suggested that OAA inhibition of SDH may have contributed to the FCCP effect. C2C12 mitochondria differed from skeletal muscle mitochondria in that the effect of FCCP on complex II respiration was not evident with ADP addition. We also observed that C2C12 cells, unlike skeletal muscle, expressed glutamate dehydrogenase, which competes with GOT2 for glutamate metabolism. In summary, GOT2 KD reduced C2C12 respiration in intact cells at low potential. From differential substrate effects, this occurred largely at complex II. Moreover, C2C12 versus muscle mitochondria differ in complex II sensitivity to ADP and differ markedly in expression of glutamate dehydrogenase.
    Keywords:  aspartate aminotransferase; mitochondria; myocytes; oxaloacetate; succinate dehydrogenase
    DOI:  https://doi.org/10.1152/ajpcell.00576.2023
  18. Sci Rep. 2024 04 25. 14(1): 9533
    Low ACADM expression predicts poor prognosis and suppressive tumor microenvironment in clear cell renal cell carcinoma.
    Libin Zhou, Min Yin, Fei Guo, Zefeng Yu, Guobin Weng, Huimin Long.
      Clear cell renal cell carcinoma (ccRCC) represents a highly frequent renal cancer subtype. However, medium-chain acyl-CoA dehydrogenase (ACADM) encodes an important enzyme responsible for fatty acid β-oxidation (FAO) and its association with prognosis and immunity in cancers has rarely been reported. Therefore, the present work focused on exploring ACADM's expression and role among ccRCC cases. We used multiple public databases and showed the hypo levels of ACADM protein and mRNA within ccRCC. Additionally, we found that ACADM down-regulation showed a remarkable relation to the advanced stage, high histological grade, as well as dismal prognostic outcome. As suggested by Kaplan-Meier curve analysis, cases showing low ACADM levels displayed shorter overall survival (OS) as well as disease-free survival (DFS). Moreover, according to univariate/multivariate Cox regression, ACADM-mRNA independently predicted the prognosis of ccRCC. In addition, this work conducted immunohistochemistry for validating ACADM protein expression and its prognostic role in ccRCC samples. KEGG and GO analyses revealed significantly enriched genes related to ACADM expression during fatty acid metabolism. The low-ACADM group with more regulatory T-cell infiltration showed higher expression of immune negative regulation genes and higher TIDE scores, which might contribute to poor response to immunotherapies. In conclusion, our results confirmed that downregulated ACADM predicted a poor prognosis for ccRCC and a poor response to immunotherapy. Our results provide important data for developing immunotherapy for ccRCC.
    DOI:  https://doi.org/10.1038/s41598-024-59746-5
  19. Sci Adv. 2024 Apr 26. 10(17): eadk1045
    Sphingolipid biosynthesis is essential for metabolic rewiring during TH17 cell differentiation.
    Thiruvaimozhi Abimannan, Velayoudame Parthibane, Si-Hung Le, Nagampalli Vijaykrishna, Stephen D Fox, Baktiar Karim, Govind Kunduri, Daniel Blankenberg, Thorkell Andresson, Takeshi Bamba, Usha Acharya, Jairaj K Acharya.
      T helper 17 (TH17) cells are implicated in autoimmune diseases, and several metabolic processes are shown to be important for their development and function. In this study, we report an essential role for sphingolipids synthesized through the de novo pathway in TH17 cell development. Deficiency of SPTLC1, a major subunit of serine palmitoyl transferase enzyme complex that catalyzes the first and rate-limiting step of de novo sphingolipid synthesis, impaired glycolysis in differentiating TH17 cells by increasing intracellular reactive oxygen species (ROS) through enhancement of nicotinamide adenine dinucleotide phosphate oxidase 2 activity. Increased ROS leads to impaired activation of mammalian target of rapamycin C1 and reduced expression of hypoxia-inducible factor 1-alpha and c-Myc-induced glycolytic genes. SPTLCI deficiency protected mice from developing experimental autoimmune encephalomyelitis and experimental T cell transfer colitis. Our results thus show a critical role for de novo sphingolipid biosynthetic pathway in shaping adaptive immune responses with implications in autoimmune diseases.
    DOI:  https://doi.org/10.1126/sciadv.adk1045
  20. bioRxiv. 2024 Apr 21. pii: 2024.04.19.590241. [Epub ahead of print]
    Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases.
    Qiuhan Huang, Caroline Trumpff, Anna S Monzel, Shannon Rausser, Rachel Haahr, Jack Devine, Cynthia C Liu, Catherine Kelly, Elizabeth Thompson, Mangesh Kurade, Jeremy Michelson, Evan D Shaulson, Shufang Li, Kris Engelstad, Kurenai Tanji, Vincenzo Lauriola, Tian Wang, Shuang Wang, Faris M Zuraikat, Marie-Pierre St-Onge, Brett A Kaufman, Richard Sloan, Robert-Paul Juster, Anna L Marsland, Gilles Gouspillou, Michio Hirano, Martin Picard.
      GDF15 (growth differentiation factor 15) is a marker of cellular energetic stress linked to physical-mental illness, aging, and mortality. However, questions remain about its dynamic properties and measurability in human biofluids other than blood. Here, we examine the natural dynamics and psychobiological regulation of plasma and saliva GDF15 in four human studies representing 4,749 samples from 188 individuals. We show that GDF15 protein is detectable in saliva (8% of plasma concentration), likely produced by salivary glands secretory duct cells. Plasma and saliva GDF15 levels are not correlated. Using a brief laboratory socio-evaluative stressor paradigm, we find that psychological stress increases plasma (+3.4-5.3%) and saliva GDF15 (+45%) with distinct kinetics, within minutes. Moreover, saliva GDF15 exhibits a robust awakening response, declining by ∼42-92% within 30-45 minutes from its peak level at the time of waking up. Clinically, individuals with genetic mitochondrial OxPhos diseases show elevated baseline plasma and saliva GDF15, and post-stress GDF15 levels in both biofluids correlate with multi-system disease severity, exercise intolerance, and the subjective experience of fatigue. Taken together, our data establish the dynamic properties of saliva GDF15, reveal it as a stress-sensitive, and as a clinically relevant marker of mitochondrial diseases. These findings point to a shared psychobiological pathway integrating metabolic and mental stress.
    DOI:  https://doi.org/10.1101/2024.04.19.590241
  21. Cell Death Discov. 2024 Apr 22. 10(1): 188
    MED15 is upregulated by HIF-2α and promotes proliferation and metastasis in clear cell renal cell carcinoma via activation of SREBP-dependent fatty acid synthesis.
    Xiaoliang Hua, Shengdong Ge, Li Zhang, Qing Jiang, Juan Chen, Haibing Xiao, Chaozhao Liang.
      Emerging evidence has highlighted that dysregulation of lipid metabolism in clear cell renal cell carcinoma (ccRCC) is associated with tumor development and progression. HIF-2α plays an oncogenic role in ccRCC and is involved in abnormal lipid accumulation. However, the underlying mechanisms between these two phenomena remain unknown. Here, MED15 was demonstrated to be a dominant factor for HIF-2α-dependent lipid accumulation and tumor progression. HIF-2α promoted MED15 transcriptional activation by directly binding the MED15 promoter region, and MED15 overexpression significantly alleviated the lipid deposition inhibition and malignant tumor behavior phenotypes induced by HIF-2α knockdown. MED15 was upregulated in ccRCC and predicted poor prognosis. MED15 promoted lipid deposition and tumor progression in ccRCC. Mechanistic investigations demonstrated that MED15 acts as SREBP coactivator directly interacting with SREBPs to promote SREBP-dependent lipid biosynthesis enzyme expression, and promotes SREBP1 and SREBP2 activation through the PLK1/AKT axis. Overall, we describe a molecular regulatory network that links MED15 to lipid metabolism induced by the SREBP pathway and the classic HIF-2α pathway in ccRCC. Efforts to target MED15 or inhibit MED15 binding to SREBPs as a novel therapeutic strategy for ccRCC may be warranted.
    DOI:  https://doi.org/10.1038/s41420-024-01944-1
  22. Nat Commun. 2024 Apr 24. 15(1): 3468
    Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development.
    Lei Xing, Vasiliki Gkini, Anni I Nieminen, Hui-Chao Zhou, Matilde Aquilino, Ronald Naumann, Katrin Reppe, Kohichi Tanaka, Peter Carmeliet, Oskari Heikinheimo, Svante Pääbo, Wieland B Huttner, Takashi Namba.
      Metabolism has recently emerged as a major target of genes implicated in the evolutionary expansion of human neocortex. One such gene is the human-specific gene ARHGAP11B. During human neocortex development, ARHGAP11B increases the abundance of basal radial glia, key progenitors for neocortex expansion, by stimulating glutaminolysis (glutamine-to-glutamate-to-alpha-ketoglutarate) in mitochondria. Here we show that the ape-specific protein GLUD2 (glutamate dehydrogenase 2), which also operates in mitochondria and converts glutamate-to-αKG, enhances ARHGAP11B's ability to increase basal radial glia abundance. ARHGAP11B + GLUD2 double-transgenic bRG show increased production of aspartate, a metabolite essential for cell proliferation, from glutamate via alpha-ketoglutarate and the TCA cycle. Hence, during human evolution, a human-specific gene exploited the existence of another gene that emerged during ape evolution, to increase, via concerted changes in metabolism, progenitor abundance and neocortex size.
    DOI:  https://doi.org/10.1038/s41467-024-47437-8
  23. J Mater Chem B. 2024 Apr 23.
    A multipurpose mitochondrial NIR probe for imaging ferroptosis and mitophagy.
    Deeksha Rajput, Nachiket Pradhan, Shabnam Mansuri, Virupakshi Soppina, Sriram Kanvah.
      This paper explores the use of a di-cationic fluorophore for visualizing mitochondria in live cells independent of membrane potential. Through the synthesized di-cationic fluorophore, we investigate the monitoring of viscosity, ferroptosis, stress-induced mitophagy, and lysosomal uptake of damaged mitochondria. The designed fluorophore is based on DQAsomes, cationic vesicles responsible for transporting drugs and DNA to mitochondria. The symmetric fluorophores possess two charge centres separated by an alkyl chain and are distinguished by a pyridinium group for mitochondrial selectivity, the C-12 alkyl substitution for membrane affinity, and an electron donor-π-acceptor fluorescent scaffold for intramolecular charge transfer. The synthesized fluorophores, PP and NP, emit wavelengths exceeding 600 nm, with a significant Stokes shift (130-211 nm), and NP demonstrates near-infrared emission (∼690 nm). Our study underscores the potential of these fluorophores for live-cell imaging, examining physiological responses such as viscosity and ferroptosis, and highlights their utility in investigating mitophagy damage and lysosomal uptake.
    DOI:  https://doi.org/10.1039/d4tb00293h
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