bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2024‒06‒09
nineteen papers selected by
Marc Segarra Mondejar
  1. Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.
  2. Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity.
  3. The role of anaplerotic metabolism of glucose and glutamine in insulin secretion: A model approach.
  4. The picky mTORC1 in metabolic enzyme degradation.
  5. Metabolic dysregulation of tricarboxylic acid cycle and oxidative phosphorylation in glioblastoma.
  6. Heterogeneous distribution of mitochondria and succinate dehydrogenase activity in human airway smooth muscle cells.
  7. Multi-omics reveals new links between Fructosamine-3-Kinase (FN3K) and core metabolic pathways.
  8. Cysteine S -acetylation is a post-translational modification involved in metabolic regulation.
  9. Protocol for separating cancer cell subpopulations by metabolic activity using flow cytometry.
  10. Different ER-plasma membrane tethers play opposing roles in autophagy of the cortical ER.
  11. Hungry for fat: Metabolic crosstalk with lipid-rich CAFs fuels pancreatic cancer.
  12. De novo and salvage purine synthesis pathways across tissues and tumors.
  13. Metabolic reprogramming-driven homologous recombination and TCA cycle dysregulation contribute to poor prognoses in lung adenocarcinoma.
  14. Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.
  15. Structural basis for expanded substrate specificities of human long chain acyl-CoA dehydrogenase and related acyl-CoA dehydrogenases.
  16. The role of mitochondria in sex- and age-specific gene expression in a species without sex chromosomes.
  17. Depletion of cap-binding protein eIF4E dysregulates amino acid metabolic gene expression.
  18. Personalized metabolic whole-body models for newborns and infants predict growth and biomarkers of inherited metabolic diseases.
  19. Malic enzyme 1 knockout has no deleterious phenotype and is favored in the male germline under standard laboratory conditions.
  1. Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00178-5. [Epub ahead of print]36(6): 1394-1410.e12
    Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.
    Isaac Marin-Valencia, Arif Kocabas, Carlos Rodriguez-Navas, Vesselin Z Miloushev, Manuel González-Rodríguez, Hannah Lees, Kelly E Henry, Jake Vaynshteyn, Valerie Longo, Kofi Deh, Roozbeh Eskandari, Arsen Mamakhanyan, Marjan Berishaj, Kayvan R Keshari.
      A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain-it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition.
    Keywords:  brain; glucose; imaging; ketogenic diet; metabolism; propionate; pyruvate; pyruvate dehydrogenase deficiency
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.002
  2. Dev Cell. 2024 Jun 04. pii: S1534-5807(24)00325-3. [Epub ahead of print]
    Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity.
    Seungyoon B Yu, Haoming Wang, Richard G Sanchez, Natasha M Carlson, Khanh Nguyen, Andrew Zhang, Zachary D Papich, Ahmed A Abushawish, Zachary Whiddon, Weronika Matysik, Jie Zhang, Thomas C Whisenant, Majid Ghassemian, John N Koberstein, Melissa L Stewart, Samuel A Myers, Gulcin Pekkurnaz.
      Neuronal activity is an energy-intensive process that is largely sustained by instantaneous fuel utilization and ATP synthesis. However, how neurons couple ATP synthesis rate to fuel availability is largely unknown. Here, we demonstrate that the metabolic sensor enzyme O-linked N-acetyl glucosamine (O-GlcNAc) transferase regulates neuronal activity-driven mitochondrial bioenergetics in hippocampal and cortical neurons. We show that neuronal activity upregulates O-GlcNAcylation in mitochondria. Mitochondrial O-GlcNAcylation is promoted by activity-driven glucose consumption, which allows neurons to compensate for high energy expenditure based on fuel availability. To determine the proteins that are responsible for these adjustments, we mapped the mitochondrial O-GlcNAcome of neurons. Finally, we determine that neurons fail to meet activity-driven metabolic demand when O-GlcNAcylation dynamics are prevented. Our findings suggest that O-GlcNAcylation provides a fuel-dependent feedforward control mechanism in neurons to optimize mitochondrial performance based on neuronal activity. This mechanism thereby couples neuronal metabolism to mitochondrial bioenergetics and plays a key role in sustaining energy homeostasis.
    Keywords:  ATP synthesis; O-GlcNAc transferase; O-GlcNAcylation; glycosylation; mitochondria; neuronal metabolism; synaptic activity
    DOI:  https://doi.org/10.1016/j.devcel.2024.05.008
  3. Biophys Chem. 2024 May 23. pii: S0301-4622(24)00099-1. [Epub ahead of print]311 107270
    The role of anaplerotic metabolism of glucose and glutamine in insulin secretion: A model approach.
    Vladimir Grubelnik, Jan Zmazek, Marko Gosak, Marko Marhl.
      We propose a detailed computational beta cell model that emphasizes the role of anaplerotic metabolism under glucose and glucose-glutamine stimulation. This model goes beyond the traditional focus on mitochondrial oxidative phosphorylation and ATP-sensitive K+ channels, highlighting the predominant generation of ATP from phosphoenolpyruvate in the vicinity of KATP channels. It also underlines the modulatory role of H2O2 as a signaling molecule in the first phase of glucose-stimulated insulin secretion. In the second phase, the model emphasizes the critical role of anaplerotic pathways, activated by glucose stimulation via pyruvate carboxylase and by glutamine via glutamate dehydrogenase. It particularly focuses on the production of NADPH and glutamate as key enhancers of insulin secretion. The predictions of the model are consistent with empirical data, highlighting the complex interplay of metabolic pathways and emphasizing the primary role of glucose and the facilitating role of glutamine in insulin secretion. By delineating these crucial metabolic pathways, the model provides valuable insights into potential therapeutic targets for diabetes.
    Keywords:  GSH; Isocitrate/α-KG (IDH) shuttle; Mathematical model; NADPH; PEP cycle; Pancreatic beta cell; Pyruvate-malate cycle; ROS; SENP1
    DOI:  https://doi.org/10.1016/j.bpc.2024.107270
  4. Mol Cell. 2024 Jun 06. pii: S1097-2765(24)00436-2. [Epub ahead of print]84(11): 2011-2013
    The picky mTORC1 in metabolic enzyme degradation.
    Yujin Chun, David A Fruman, Gina Lee.
      In this issue of Molecular Cell, Yi et al.1 demonstrate that reduced mTORC1 activity induces the CTLH E3 ligase-dependent degradation of HMGCS1, an enzyme in the mevalonate pathway, thus revealing a unique connection between mTORC1 signaling and the degradation of a specific metabolic enzyme via the ubiquitin-proteasome system.
    DOI:  https://doi.org/10.1016/j.molcel.2024.05.013
  5. Rev Neurosci. 2024 Jun 07.
    Metabolic dysregulation of tricarboxylic acid cycle and oxidative phosphorylation in glioblastoma.
    Cristina Trejo-Solís, Norma Serrano-García, Rosa Angelica Castillo-Rodríguez, Diana Xochiquetzal Robledo-Cadena, Dolores Jimenez-Farfan, Álvaro Marín-Hernández, Daniela Silva-Adaya, Citlali Ekaterina Rodríguez-Pérez, Juan Carlos Gallardo-Pérez.
      Glioblastoma multiforme (GBM) exhibits genetic alterations that induce the deregulation of oncogenic pathways, thus promoting metabolic adaptation. The modulation of metabolic enzyme activities is necessary to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates essential for fulfilling the biosynthetic needs of glioma cells. Moreover, the TCA cycle produces intermediates that play important roles in the metabolism of glucose, fatty acids, or non-essential amino acids, and act as signaling molecules associated with the activation of oncogenic pathways, transcriptional changes, and epigenetic modifications. In this review, we aim to explore how dysregulated metabolic enzymes from the TCA cycle and oxidative phosphorylation, along with their metabolites, modulate both catabolic and anabolic metabolic pathways, as well as pro-oncogenic signaling pathways, transcriptional changes, and epigenetic modifications in GBM cells, contributing to the formation, survival, growth, and invasion of glioma cells. Additionally, we discuss promising therapeutic strategies targeting key players in metabolic regulation. Therefore, understanding metabolic reprogramming is necessary to fully comprehend the biology of malignant gliomas and significantly improve patient survival.
    Keywords:  glioma; metabolism; oncogenic signaling pathways
    DOI:  https://doi.org/10.1515/revneuro-2024-0054
  6. FASEB Bioadv. 2024 Jun;6(6): 159-176
    Heterogeneous distribution of mitochondria and succinate dehydrogenase activity in human airway smooth muscle cells.
    Sanjana Mahadev Bhat, Gary C Sieck.
      Succinate dehydrogenase (SDH) is a key mitochondrial enzyme involved in the tricarboxylic acid cycle, where it facilitates the oxidation of succinate to fumarate, and is coupled to the reduction of ubiquinone in the electron transport chain as Complex II. Previously, we developed a confocal-based quantitative histochemical technique to determine the maximum velocity of the SDH reaction (SDHmax) in single cells and observed that SDHmax corresponds with mitochondrial volume density. In addition, mitochondrial volume and motility varied within different compartments of human airway smooth muscle (hASM) cells. Therefore, we hypothesize that the SDH activity varies relative to the intracellular mitochondrial volume within hASM cells. Using 3D confocal imaging of labeled mitochondria and a concentric shell method for analysis, we quantified mitochondrial volume density, mitochondrial complexity index, and SDHmax relative to the distance from the nuclear membrane. The mitochondria within individual hASM cells were more filamentous in the immediate perinuclear region and were more fragmented in the distal parts of the cell. Within each shell, SDHmax also corresponded to mitochondrial volume density, where both peaked in the perinuclear region and decreased in more distal parts of the cell. Additionally, when normalized to mitochondrial volume, SDHmax was lower in the perinuclear region when compared to the distal parts of the cell. In summary, our results demonstrate that SDHmax measures differences in SDH activity within different cellular compartments. Importantly, our data indicate that mitochondria within individual cells are morphologically heterogeneous, and their distribution varies substantially within different cellular compartments, with distinct functional properties.
    Keywords:  airway smooth muscle; confocal microscope; intracellular distribution; mitochondria; succinate dehydrogenase
    DOI:  https://doi.org/10.1096/fba.2024-00047
  7. NPJ Syst Biol Appl. 2024 Jun 03. 10(1): 64
    Multi-omics reveals new links between Fructosamine-3-Kinase (FN3K) and core metabolic pathways.
    Safal Shrestha, Rahil Taujale, Samiksha Katiyar, Natarajan Kannan.
      Fructosamine-3-kinases (FN3Ks) are a conserved family of repair enzymes that phosphorylate reactive sugars attached to lysine residues in peptides and proteins. Although FN3Ks are present across the Tree of Life and share detectable sequence similarity to eukaryotic protein kinases, the biological processes regulated by these kinases are largely unknown. To address this knowledge gap, we leveraged the FN3K CRISPR Knock-Out (KO) HepG2 cell line alongside an integrative multi-omics study combining transcriptomics, metabolomics, and interactomics to place these enzymes in a pathway context. The integrative analyses revealed the enrichment of pathways related to oxidative stress response, lipid biosynthesis (cholesterol and fatty acids), and carbon and co-factor metabolism. Moreover, enrichment of nicotinamide adenine dinucleotide (NAD) binding proteins and localization of human FN3K (HsFN3K) to mitochondria suggests potential links between FN3K and NAD-mediated energy metabolism and redox balance. We report specific binding of HsFN3K to NAD compounds in a metal and concentration-dependent manner and provide insight into their binding mode using modeling and experimental site-directed mutagenesis. Our studies provide a framework for targeting these understudied kinases in diabetic complications and metabolic disorders where redox balance and NAD-dependent metabolic processes are altered.
    DOI:  https://doi.org/10.1038/s41540-024-00390-0
  8. bioRxiv. 2024 May 21. pii: 2024.05.21.595030. [Epub ahead of print]
    Cysteine S -acetylation is a post-translational modification involved in metabolic regulation.
    E Keith Keenan, Akshay Bareja, Yannie Lam, Paul A Grimsrud, Matthew D Hirschey.
      Cysteine is a reactive amino acid central to the catalytic activities of many enzymes. It is also a common target of post-translational modifications (PTMs), such as palmitoylation. This long-chain acyl PTM can modify cysteine residues and induce changes in protein subcellular localization. We hypothesized that cysteine could also be modified by short-chain acyl groups, such as cysteine S -acetylation. To test this, we developed sample preparation and non-targeted mass spectrometry protocols to analyze the mouse liver proteome for cysteine acetylation. Our findings revealed hundreds of sites of cysteine acetylation across multiple tissue types, revealing a previously uncharacterized cysteine acetylome. Cysteine acetylation shows a marked cytoplasmic subcellular localization signature, with tissue-specific acetylome patterns and specific changes upon metabolic stress. This study uncovers a novel aspect of cysteine biochemistry, highlighting short-chain modifications alongside known long-chain acyl PTMs. These findings enrich our understanding of the landscape of acyl modifications and suggest new research directions in enzyme activity regulation and cellular signaling in metabolism.
    DOI:  https://doi.org/10.1101/2024.05.21.595030
  9. STAR Protoc. 2024 Jun 01. pii: S2666-1667(24)00270-3. [Epub ahead of print]5(2): 103105
    Protocol for separating cancer cell subpopulations by metabolic activity using flow cytometry.
    Wiktoria Blaszczak, Bobby White, Pawel Swietach.
      Cells, even from the same line, can maintain heterogeneity in metabolic activity. Here, we present a protocol, adapted for fluorescence-activated cell sorting (FACS), that separates resuspended cells according to their metabolic rate. We describe steps for driving lactate efflux, which produces an alkaline transient proportional to fermentative rate. This pH signature, measured using pH-sensitive dyes, identifies cells with the highest metabolic rate. We then describe a fluorimetric assay of oxygen consumption and acid production to confirm the metabolic contrast between subpopulations. For complete details on the use and execution of this protocol, please refer to Blaszczak et al.1.
    Keywords:  Cancer; Flow Cytometry; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2024.103105
  10. Proc Natl Acad Sci U S A. 2024 Jun 11. 121(24): e2321991121
    Different ER-plasma membrane tethers play opposing roles in autophagy of the cortical ER.
    Dongmei Liu, Hua Yuan, Shuliang Chen, Susan Ferro-Novick, Peter Novick.
      The endoplasmic reticulum (ER) undergoes degradation by selective macroautophagy (ER-phagy) in response to starvation or the accumulation of misfolded proteins within its lumen. In yeast, actin assembly at sites of contact between the cortical ER (cER) and endocytic pits acts to displace elements of the ER from their association with the plasma membrane (PM) so they can interact with the autophagosome assembly machinery near the vacuole. A collection of proteins tether the cER to the PM. Of these, Scs2/22 and Ist2 are required for cER-phagy, most likely through their roles in lipid transport, while deletion of the tricalbins, TCB1/2/3, bypasses those requirements. An artificial ER-PM tether blocks cER-phagy in both the wild type (WT) and a strain lacking endogenous tethers, supporting the importance of cER displacement from the PM. Scs2 and Ist2 can be cross-linked to the selective cER-phagy receptor, Atg40. The COPII cargo adaptor subunit, Lst1, associates with Atg40 and is required for cER-phagy. This requirement is also bypassed by deletion of the ER-PM tethers, suggesting a role for Lst1 prior to the displacement of the cER from the PM during cER-phagy. Although pexophagy and mitophagy also require actin assembly, deletion of ER-PM tethers does not bypass those requirements. We propose that within the context of rapamycin-induced cER-phagy, Scs2/22, Ist2, and Lst1 promote the local displacement of an element of the cER from the cortex, while Tcb1/2/3 act in opposition, anchoring the cER to the plasma membrane.
    Keywords:  autophagy; endoplasmic reticulum; lipid transfer; membrane tether
    DOI:  https://doi.org/10.1073/pnas.2321991121
  11. Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00183-9. [Epub ahead of print]36(6): 1172-1174
    Hungry for fat: Metabolic crosstalk with lipid-rich CAFs fuels pancreatic cancer.
    Kostas A Papavassiliou, Athanasios G Papavassiliou.
      Some cancers prefer to metabolize lipids for their growth and metastasis. In a recent Cancer Cell study, Niu et al. revealed that SET domain containing 2, histone lysine methyltransferase (SETD2)-deficient pancreatic cancer cells induce the differentiation of lipid-laden cancer-associated fibroblasts (CAFs), which, in turn, transport lipids to promote tumor growth.
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.007
  12. Cell. 2024 May 30. pii: S0092-8674(24)00520-8. [Epub ahead of print]
    De novo and salvage purine synthesis pathways across tissues and tumors.
    Diem H Tran, Dohun Kim, Rushendhiran Kesavan, Harrison Brown, Trishna Dey, Mona Hoseini Soflaee, Hieu S Vu, Alpaslan Tasdogan, Jason Guo, Divya Bezwada, Houssam Al Saad, Feng Cai, Ashley Solmonson, Halie Rion, Rawand Chabatya, Salma Merchant, Nathan J Manales, Vanina T Tcheuyap, Megan Mulkey, Thomas P Mathews, James Brugarolas, Sean J Morrison, Hao Zhu, Ralph J DeBerardinis, Gerta Hoxhaj.
      Purine nucleotides are vital for RNA and DNA synthesis, signaling, metabolism, and energy homeostasis. To synthesize purines, cells use two principal routes: the de novo and salvage pathways. Traditionally, it is believed that proliferating cells predominantly rely on de novo synthesis, whereas differentiated tissues favor the salvage pathway. Unexpectedly, we find that adenine and inosine are the most effective circulating precursors for supplying purine nucleotides to tissues and tumors, while hypoxanthine is rapidly catabolized and poorly salvaged in vivo. Quantitative metabolic analysis demonstrates comparative contribution from de novo synthesis and salvage pathways in maintaining purine nucleotide pools in tumors. Notably, feeding mice nucleotides accelerates tumor growth, while inhibiting purine salvage slows down tumor progression, revealing a crucial role of the salvage pathway in tumor metabolism. These findings provide fundamental insights into how normal tissues and tumors maintain purine nucleotides and highlight the significance of purine salvage in cancer.
    Keywords:  cancer metabolism; de novo purine synthesis; in vivo isotope tracing; nucleotide diet; nucleotide metabolism; purine bases; purine degradation; purine salvage; tissue; tumor growth
    DOI:  https://doi.org/10.1016/j.cell.2024.05.011
  13. J Cell Mol Med. 2024 Jun;28(11): e18406
    Metabolic reprogramming-driven homologous recombination and TCA cycle dysregulation contribute to poor prognoses in lung adenocarcinoma.
    Zhanyu Xu, Dongming He, Liuliu Huang, Kun Deng, Wei Jiang, Junqi Qin, Zhiwen Zheng, Tiaozhan Zheng, Shikang Li.
      Increasing evidence has shown that homologous recombination (HR) and metabolic reprogramming are essential for cellular homeostasis. These two processes are independent as well as closely intertwined. Nevertheless, they have rarely been reported in lung adenocarcinoma (LUAD). We analysed the genomic, immune microenvironment and metabolic microenvironment features under different HR activity states. Using cell cycle, EDU and cell invasion assays, we determined the impacts of si-SHFM1 on the LUAD cell cycle, proliferation and invasion. The levels of isocitrate dehydrogenase (IDH) and α-ketoglutarate dehydrogenase (α-KGDH) were determined by ELISA in the NC and si-SHFM1 groups of A549 cells. Finally, cell samples were used to extract metabolites for HPIC-MS/MS to analyse central carbon metabolism. We found that high HR activity was associated with a poor prognosis in LUAD, and HR was an independent prognostic factor for TCGA-LUAD patients. Moreover, LUAD samples with a high HR activity presented low immune infiltration levels, a high degree of genomic instability, a good response status to immune checkpoint blockade therapy and a high degree of drug sensitivity. The si-SHFM1 group presented a significantly higher proportion of cells in the G0/G1 phase, lower levels of DNA replication, and significantly lower levels of cell migration and both TCA enzymes. Our current results indicated that there is a strong correlation between HR and the TCA cycle in LUAD. The TCA cycle can promote SHFM1-mediated HR in LUAD, raising their activities, which can finally result in a poor prognosis and impair immunotherapeutic efficacy.
    Keywords:  SHFM1; homologous recombination; lung adenocarcinoma; metabolic reprogramming; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1111/jcmm.18406
  14. Nat Commun. 2024 Jun 03. 15(1): 4700
    Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.
    Shashank Dadsena, Rodrigo Cuevas Arenas, Gonçalo Vieira, Susanne Brodesser, Manuel N Melo, Ana J García-Sáez.
      BAX and BAK are proapoptotic members of the BCL2 family that directly mediate mitochondrial outer membrane permeabilition (MOMP), a central step in apoptosis execution. However, the molecular architecture of the mitochondrial apoptotic pore remains a key open question and especially little is known about the contribution of lipids to MOMP. By performing a comparative lipidomics analysis of the proximal membrane environment of BAK isolated in lipid nanodiscs, we find a significant enrichment of unsaturated species nearby BAK and BAX in apoptotic conditions. We then demonstrate that unsaturated lipids promote BAX pore activity in model membranes, isolated mitochondria and cellular systems, which is further supported by molecular dynamics simulations. Accordingly, the fatty acid desaturase FADS2 not only enhances apoptosis sensitivity, but also the activation of the cGAS/STING pathway downstream mtDNA release. The correlation of FADS2 levels with the sensitization to apoptosis of different lung and kidney cancer cell lines by co-treatment with unsaturated fatty acids supports the relevance of our findings. Altogether, our work provides an insight on how local lipid environment affects BAX and BAK function during apoptosis.
    DOI:  https://doi.org/10.1038/s41467-024-49067-6
  15. Sci Rep. 2024 06 05. 14(1): 12976
    Structural basis for expanded substrate specificities of human long chain acyl-CoA dehydrogenase and related acyl-CoA dehydrogenases.
    Beena Narayanan, Chuanwu Xia, Ryan McAndrew, Anna L Shen, Jung-Ja P Kim.
      Crystal structures of human long-chain acyl-CoA dehydrogenase (LCAD) and the catalytically inactive Glu291Gln mutant, have been determined. These structures suggest that LCAD harbors functions beyond its historically defined role in mitochondrial β-oxidation of long and medium-chain fatty acids. LCAD is a homotetramer containing one FAD per 43 kDa subunit with Glu291 as the catalytic base. The substrate binding cavity of LCAD reveals key differences which makes it specific for longer and branched chain substrates. The presence of Pro132 near the start of the E helix leads to helix unwinding that, together with adjacent smaller residues, permits binding of bulky substrates such as 3α, 7α, l2α-trihydroxy-5β-cholestan-26-oyl-CoA. This structural element is also utilized by ACAD11, a eucaryotic ACAD of unknown function, as well as bacterial ACADs known to metabolize sterol substrates. Sequence comparison suggests that ACAD10, another ACAD of unknown function, may also share this substrate specificity. These results suggest that LCAD, ACAD10, ACAD11 constitute a distinct class of eucaryotic acyl CoA dehydrogenases.
    DOI:  https://doi.org/10.1038/s41598-024-63027-6
  16. Proc Natl Acad Sci U S A. 2024 Jun 11. 121(24): e2321267121
    The role of mitochondria in sex- and age-specific gene expression in a species without sex chromosomes.
    Ning Li, Ben A Flanagan, Suzanne Edmands.
      Mitochondria perform an array of functions, many of which involve interactions with gene products encoded by the nucleus. These mitochondrial functions, particularly those involving energy production, can be expected to differ between sexes and across ages. Here, we measured mitochondrial effects on sex- and age-specific gene expression in parental and reciprocal F1 hybrids between allopatric populations of Tigriopus californicus with over 20% mitochondrial DNA divergence. Because the species lacks sex chromosomes, sex-biased mitochondrial effects are not confounded by the effects of sex chromosomes. Results revealed pervasive sex differences in mitochondrial effects, including effects on energetics and aging involving nuclear interactions throughout the genome. Using single-individual RNA sequencing, sex differences were found to explain more than 80% of the variance in gene expression. Males had higher expression of mitochondrial genes and mitochondrially targeted proteins (MTPs) involved in oxidative phosphorylation (OXPHOS), while females had elevated expression of non-OXPHOS MTPs, indicating strongly sex-dimorphic energy metabolism at the whole organism level. Comparison of reciprocal F1 hybrids allowed insights into the nature of mito-nuclear interactions, showing both mitochondrial effects on nuclear expression, and nuclear effects on mitochondrial expression. While based on a small set of crosses, sex-specific increases in mitochondrial expression with age were associated with longer life. Network analyses identified nuclear components of strong mito-nuclear interactions and found them to be sexually dimorphic. These results highlight the profound impact of mitochondria and mito-nuclear interactions on sex- and age-specific gene expression.
    Keywords:  RNA-seq; hybrid; longevity; mitochondria; sex differences
    DOI:  https://doi.org/10.1073/pnas.2321267121
  17. Mol Cell. 2024 Jun 06. pii: S1097-2765(24)00430-1. [Epub ahead of print]84(11): 2119-2134.e5
    Depletion of cap-binding protein eIF4E dysregulates amino acid metabolic gene expression.
    Paige D Diamond, Nicholas J McGlincy, Nicholas T Ingolia.
      Protein synthesis is metabolically costly and must be tightly coordinated with changing cellular needs and nutrient availability. The cap-binding protein eIF4E makes the earliest contact between mRNAs and the translation machinery, offering a key regulatory nexus. We acutely depleted this essential protein and found surprisingly modest effects on cell growth and recovery of protein synthesis. Paradoxically, impaired protein biosynthesis upregulated genes involved in the catabolism of aromatic amino acids simultaneously with the induction of the amino acid biosynthetic regulon driven by the integrated stress response factor GCN4. We further identified the translational control of Pho85 cyclin 5 (PCL5), a negative regulator of Gcn4, that provides a consistent protein-to-mRNA ratio under varied translation environments. This regulation depended in part on a uniquely long poly(A) tract in the PCL5 5' UTR and poly(A) binding protein. Collectively, these results highlight how eIF4E connects protein synthesis to metabolic gene regulation, uncovering mechanisms controlling translation during environmental challenges.
    Keywords:  amino acid metabolism; cap-binding protein; translation
    DOI:  https://doi.org/10.1016/j.molcel.2024.05.008
  18. Cell Metab. 2024 May 25. pii: S1550-4131(24)00182-7. [Epub ahead of print]
    Personalized metabolic whole-body models for newborns and infants predict growth and biomarkers of inherited metabolic diseases.
    Elaine Zaunseder, Ulrike Mütze, Jürgen G Okun, Georg F Hoffmann, Stefan Kölker, Vincent Heuveline, Ines Thiele.
      Comprehensive whole-body models (WBMs) accounting for organ-specific dynamics have been developed to simulate adult metabolism, but such models do not exist for infants. Here, we present a resource of 360 organ-resolved, sex-specific models of newborn and infant metabolism (infant-WBMs) spanning the first 180 days of life. These infant-WBMs were parameterized to represent the distinct metabolic characteristics of newborns and infants, including nutrition, energy requirements, and thermoregulation. We demonstrate that the predicted infant growth was consistent with the recommendation by the World Health Organization. We assessed the infant-WBMs' reliability and capabilities for personalization by simulating 10,000 newborns based on their blood metabolome and birth weight. Furthermore, the infant-WBMs accurately predicted changes in known biomarkers over time and metabolic responses to treatment strategies for inherited metabolic diseases. The infant-WBM resource holds promise for personalized medicine, as the infant-WBMs could be a first step to digital metabolic twins for newborn and infant metabolism.
    Keywords:  constraint-based metabolic modeling; digital metabolic twins; infant metabolism; inherited metabolic diseases; metabolism; metabolomics; newborn screening
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.006
  19. PLoS One. 2024 ;19(6): e0303577
    Malic enzyme 1 knockout has no deleterious phenotype and is favored in the male germline under standard laboratory conditions.
    Jonathan M Alektiar, Mengrou Shan, Megan D Radyk, Li Zhang, Christopher J Halbrook, Lin Lin, Carlos Espinoza, Ivan F Mier, Brooke L Lavoie, Lucie Salvatore, Marina Pasca di Magliano, Lewis C Cantley, Jacob L Mueller, Costas A Lyssiotis.
      Malic Enzyme 1 (ME1) plays an integral role in fatty acid synthesis and cellular energetics through its production of NADPH and pyruvate. As such, it has been identified as a gene of interest in obesity, type 2 diabetes, and an array of epithelial cancers, with most work being performed in vitro. The current standard model for ME1 loss in vivo is the spontaneous Mod-1 null allele, which produces a canonically inactive form of ME1. Herein, we describe two new genetically engineered mouse models exhibiting ME1 loss at dynamic timepoints. Using murine embryonic stem cells and Flp/FRT and Cre/loxP class switch recombination, we established a germline Me1 knockout model (Me1 KO) and an inducible conditional knockout model (Me1 cKO), activated upon tamoxifen treatment in adulthood. Collectively, neither the Me1 KO nor Me1 cKO models exhibited deleterious phenotype under standard laboratory conditions. Knockout of ME1 was validated by immunohistochemistry and genotype confirmed by PCR. Transmission patterns favor Me1 loss in Me1 KO mice when maternally transmitted to male progeny. Hematological examination of these models through complete blood count and serum chemistry panels revealed no discrepancy with their wild-type counterparts. Orthotopic pancreatic tumors in Me1 cKO mice grow similarly to Me1 expressing mice. Similarly, no behavioral phenotype was observed in Me1 cKO mice when aged for 52 weeks. Histological analysis of several tissues revealed no pathological phenotype. These models provide a more modern approach to ME1 knockout in vivo while opening the door for further study into the role of ME1 loss under more biologically relevant, stressful conditions.
    DOI:  https://doi.org/10.1371/journal.pone.0303577
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