bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2022‒09‒11
seven papers selected by
Lakesh Kumar
BITS Pilani
  1. The role of Toxoplasma TFIIS-like protein in the early stages of mRNA transcription.
  2. Blocking AMPK signalling to acetyl-CoA carboxylase increases cisplatin-induced acute kidney injury and suppresses the benefit of metformin.
  3. The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin.
  4. Lycopene ameliorates hyperlipidemia via potentiation of AMP-activated protein kinase and inhibition of ATP-citrate lyase in diabetic hyperlipidemic rat model.
  5. Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain.
  6. Tangeretin Protects Mice from Alcohol-Induced Fatty Liver by Activating Mitophagy through the AMPK-ULK1 Pathway.
  7. Roles of the Apicoplast Across the Life Cycles of Rodent and Human Malaria Parasites.
  1. Biochim Biophys Acta Gen Subj. 2022 Sep 01. pii: S0304-4165(22)00158-1. [Epub ahead of print] 130240
    The role of Toxoplasma TFIIS-like protein in the early stages of mRNA transcription.
    Pallabi Mitra, Sneha Banerjee, Chittiraju Khandavalli, Abhijit S Deshmukh.
      BACKGROUND: The mRNA transcription is a multistep process involving distinct sets of proteins associated with RNA polymerase II (RNAPII) through various stages. Recent studies have highlighted the role of RNAPII-associated proteins in facilitating the assembly of functional complexes in a crowded nuclear milieu. RNAPII dynamics and gene expression regulation have been primarily studied in model eukaryotes like yeasts and mammals and remain largely unchartered in protozoan parasites like Toxoplasma gondii, where considerable gene expression changes accompany stage differentiations. Here we report a key modulator of RNAPII activity, TFIIS in Toxoplasma gondii (TgTFIIS).METHODS: A Pull-down assay demonstrated that TgTFIIS binds to RNAPII subunit TgRPB1. Truncation mutants of TFIIS help us define the regions critical for its binding to TgRPB1. Co-immunoprecipitation analysis confirmed the interaction between the native TgTFIIS and TgRPB1. Confocal microscopy revealed a predominantly nuclear localization. Native TgTFIIS was able to bind promoter DNA which was consistent with the CHIP results.
    RESULTS: TgTFIIS complements initiation defects in yeast mutants, and the regions implicated in RNAPII binding appeared essential for this function. Interestingly, the C-terminal zinc finger domain necessary for its potential elongation function is dispensable for TgRPB1 binding. TgTFIIS was found to be associated with the promoter region along with its association with the ORF on an RNAPII transcribed gene.
    CONCLUSION: The observations were in line with the potential role of TgTFIIS in early events of RNAPII transcription in addition to elongation.
    GENERAL SIGNIFICANCE: The study elucidates the potential role of RNAPII-associated proteins in multiple steps of transcription.
    Keywords:  RNAPII transcription; TFIIS; Toxoplasma; Transcription elongation; Transcription initiation
    DOI:  https://doi.org/10.1016/j.bbagen.2022.130240
  2. Biomed Pharmacother. 2022 Sep;pii: S0753-3322(22)00766-1. [Epub ahead of print]153 113377
    Blocking AMPK signalling to acetyl-CoA carboxylase increases cisplatin-induced acute kidney injury and suppresses the benefit of metformin.
    Geoff Harley, Marina Katerelos, Kurt Gleich, David P de Souza, Vinod K Narayana, Bruce E Kemp, David A Power, Peter F Mount.
      BACKGROUND: Acute kidney injury (AKI) is accompanied by dysregulation of cellular energy metabolism and accumulation of intracellular lipid. Phosphorylation of acetyl-CoA carboxylase (ACC) by AMP-activated protein kinase (AMPK) inhibits fatty acid synthesis and promotes fatty acid oxidation (FAO), vital for kidney tubular epithelial cells (TECs). The diabetes drug metformin is protective in models of AKI; however, it is not known whether ACC phosphorylation plays a role.METHODS: Cisplatin-induced AKI (CI-AKI) was established in ACC1/2 double knock-in (ACC1/2DKI) mice, harbouring mutations that disrupt fatty acid metabolism, and the role of metformin was studied in this model. Outcomes measured included serum biochemistry, expression of kidney injury markers such as neutrophil gelatinase-associated lipocalin (NGAL), and metabolomic analysis.
    FINDINGS: ACC1/2DKI mice demonstrated more severe CI-AKI than wild type (WT), as assessed by serum urea and creatinine, histological injury, and expression of NGAL and interleukin-6. Metformin protected against AKI in WT mice, shown by reduced NGAL, but this effect was absent in ACC1/2DKI mice. In cultured TECs exposed to cisplatin, metformin reduced expression of cleaved caspase-3, however, this effect was diminished in ACC1/2DKI TECs. Analysis of kidney polar metabolites found numerous differences between metformin-treated CI-AKI in ACC1/2DKI and WT mice, involving multiple pathways of amino acid, nucleoside, and energy metabolism.
    INTERPRETATION: Severity of CI-AKI is exacerbated by the inability to regulate metabolism via phosphorylation of ACC. ACC phosphorylation contributes to the protective effect of metformin against AKI, influencing multiple mechanisms involved in the pathogenesis of kidney injury.
    Keywords:  AMP-activated protein kinase; Acetyl-CoA carboxylase; Cisplatin-induced acute kidney injury; Fatty acid oxidation; Metabolomics; Metformin; Phosphorylation
    DOI:  https://doi.org/10.1016/j.biopha.2022.113377
  3. Int J Mol Sci. 2022 Sep 02. pii: 10064. [Epub ahead of print]23(17):
    The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin.
    Tatsuya Shimada, Yohsuke Yabuki, Takuya Noguchi, Mei Tsuchida, Ryuto Komatsu, Shuhei Hamano, Mayuka Yamada, Yusuke Ezaki, Yusuke Hirata, Atsushi Matsuzawa.
      Liver kinase B1 (LKB1) is a serine/threonine protein kinase that acts as a key tumor suppressor protein by activating its downstream kinases, such as AMP-activated protein kinase (AMPK). However, the regulatory actions of LKB1 and AMPK on DNA damage response (DDR) remain to be explored. In this study, we investigated the function of LKB1 in DDR induced by cisplatin, a representative DNA-damaging agent, and found that LKB1 stabilizes and activates p53 through the c-Jun N-terminal kinase (JNK) pathway, which promotes cisplatin-induced apoptosis in human fibrosarcoma cell line HT1080. On the other hand, we found that AMPKα1 and α2 double knockout (DKO) cells showed enhanced stabilization of p53 and increased susceptibility to apoptosis induced by cisplatin, suggesting that AMPK negatively regulates cisplatin-induced apoptosis. Moreover, the additional stabilization of p53 and subsequent apoptosis in AMPK DKO cells were clearly canceled by the treatment with the antioxidants, raising the possibility that AMPK suppresses the p53 activation mediated by oxidative stress. Thus, our findings unexpectedly demonstrate the reciprocal regulation of p53 by LKB1 and AMPK in DDR, which provides insights into the molecular mechanisms of DDR.
    Keywords:  AMPKα; DNA damage; DNA damage response; LKB1; apoptosis; cisplatin
    DOI:  https://doi.org/10.3390/ijms231710064
  4. Life Sci. 2022 Sep 05. pii: S0024-3205(22)00634-8. [Epub ahead of print] 120934
    Lycopene ameliorates hyperlipidemia via potentiation of AMP-activated protein kinase and inhibition of ATP-citrate lyase in diabetic hyperlipidemic rat model.
    Mohamed M Elseweidy, Alaa S Elawady, Mohammed S Sobh, Gehad M Elnagar.
      AIM: The present study aimed mainly to demonstrate the metabolic effects of lycopene (LYC) or atorvastatin (ATOR) in diabetic hyperlipidemic rat model.MAIN METHODS: Rats were randomly classified into four groups; the first was fed normal chow diet (NC) while the other three groups received streptozotocin (STZ) along with CCT-diet. The second group received no treatment (diabetic hyperlipidemic control, DHC), the third one received ATOR (50 mg/kg/day) while the fourth one received LYC (20 mg/kg/day). Serum and tissue samples were collected for biochemical and histological evaluations.
    KEY FINDINGS: DHC rats demonstrated significant hyperglycemia, dyslipidemia, increased hepatic fatty acids synthetase (FAS), malondialdehyde (MDA), tumor necrosis factor- alpha (TNF-α), 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase and ATP Citrate lyase (ACLY). However, hepatic reduced glutathione (GSH) and phosphorylated form of AMP-activated protein kinase (AMPK-P) activities showed significant decrease. ATOR or LYC administration induced hypoglycemic and hypolipidemic effects; decreased hepatic levels of MDA, TNF-α, HMG-CoA reductase, ACLY and FAS along with GSH and AMPK-P increases. Histopathological findings showed clear correlation with the biomarkers results.
    SIGNIFICANCE: LYC demonstrated favorable significant effects regarding the biomarkers studied as compared to ATOR and may be expressed as a potent therapeutic agent of natural origin for hyperlipidemia complications either alone or in combination with other hypolipidemic drugs.
    Keywords:  AMPK-P; ATP citrate lyase; Atorvastatin; Hyperlipidemia; Lycopene
    DOI:  https://doi.org/10.1016/j.lfs.2022.120934
  5. Int J Mol Sci. 2022 Sep 03. pii: 10073. [Epub ahead of print]23(17):
    Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain.
    Agnieszka Jankowska-Kulawy, Joanna Klimaszewska-Łata, Sylwia Gul-Hinc, Anna Ronowska, Andrzej Szutowicz.
      The human brain is characterised by the most diverse morphological, metabolic and functional structure among all body tissues. This is due to the existence of diverse neurons secreting various neurotransmitters and mutually modulating their own activity through thousands of pre- and postsynaptic interconnections in each neuron. Astroglial, microglial and oligodendroglial cells and neurons reciprocally regulate the metabolism of key energy substrates, thereby exerting several neuroprotective, neurotoxic and regulatory effects on neuronal viability and neurotransmitter functions. Maintenance of the pool of mitochondrial acetyl-CoA derived from glycolytic glucose metabolism is a key factor for neuronal survival. Thus, acetyl-CoA is regarded as a direct energy precursor through the TCA cycle and respiratory chain, thereby affecting brain cell viability. It is also used for hundreds of acetylation reactions, including N-acetyl aspartate synthesis in neuronal mitochondria, acetylcholine synthesis in cholinergic neurons, as well as divergent acetylations of several proteins, peptides, histones and low-molecular-weight species in all cellular compartments. Therefore, acetyl-CoA should be considered as the central point of metabolism maintaining equilibrium between anabolic and catabolic pathways in the brain. This review presents data supporting this thesis.
    Keywords:  acetyl-CoA metabolism; aging; neurodegenerative diseases; thiamine deficiency; zinc dyshomeostasis
    DOI:  https://doi.org/10.3390/ijms231710073
  6. J Agric Food Chem. 2022 Sep 05.
    Tangeretin Protects Mice from Alcohol-Induced Fatty Liver by Activating Mitophagy through the AMPK-ULK1 Pathway.
    Jianjin Guo, Yuan Chen, Fang Yuan, Li Peng, Chen Qiu.
      Alcoholic beverages are widely consumed all over the world, but continuous ethanol exposure leads to hepatic steatosis that, without proper treatment, will later develop into severe liver disorders. In this study, we investigated the potential protective effect of tangeretin, a flavonoid derived from citrus peel, against alcoholic fatty liver. The in vivo effects of tangeretin were analyzed by oral intake in a chronic-binge alcohol feeding C57BL/6j mouse model, while the underlying mechanism was explored by in vitro studies performed on ethanol-treated hepatic AML-12 cells. Ethanol feeding increased the serum alanine aminotransferase and aspartate aminotransferase levels, the liver weight, and the serum and liver triacylglycerol contents, whereas 20 and 40 mg/kg tangeretin treatment promoted a dose-dependent suppression of these effects. Interestingly, tangeretin prevented increases in the liver oxidative stress level and protected the hepatocyte mitochondria from ethanol-induced morphologic abnormalities. A mechanistic study showed that 20 μM tangeretin treatment activated mitophagy through an AMP-activated protein kinase (AMPK)-uncoordinated 51-like kinase 1 (Ulk1) pathway, thereby restoring mitochondria respiratory function and suppressing steatosis. By contrast, blocking the AMPK-Ulk1 pathway with compound C reversed the hepatoprotective effect of tangeretin. Overall, tangeretin activated mitophagy and protected against ethanol-induced hepatic steatosis through an AMPK-Ulk1-dependent mechanism.
    Keywords:  AMPK; alcoholic fatty liver; chronic-binge ethanol model; mitophagy; tangeretin
    DOI:  https://doi.org/10.1021/acs.jafc.2c02927
  7. J Eukaryot Microbiol. 2022 Sep 07. e12947
    Roles of the Apicoplast Across the Life Cycles of Rodent and Human Malaria Parasites.
    Hayley D Buchanan, Christopher D Goodman, Geoffrey I McFadden.
      Malaria parasites are diheteroxenous, requiring two hosts-a vertebrate and a mosquito-to complete their life cycle. Mosquitoes are the definitive host where malaria parasite sex occurs, and vertebrates are the intermediate host, supporting asexual amplification and more significant geographic spread. In this review, we examine the roles of a single malaria parasite compartment, the relict plastid known as the apicoplast, at each life cycle stage. We focus mainly on two malaria parasite species-Plasmodium falciparum and P. berghei-comparing the changing, yet ever crucial, roles of their apicoplasts.
    Keywords:  Metabolism; Plasmodium; apicoplast; malaria; plastid
    DOI:  https://doi.org/10.1111/jeu.12947
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