bims-toxgon 2022-11-13 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2022–11–13
eight papers selected by
Lakesh Kumar, BITS Pilani

SIRT1 Promotes Host Protective Immunity against Toxoplasma gondii by Controlling the FoxO-Autophagy Axis via the AMPK and PI3K/AKT Signalling Pathways.
AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.
Histone lactylation: a new epigenetic axis for host-parasite signalling in malaria?
Regulation of insulin secretion in mouse islets: metabolic amplification by alpha-ketoisocaproate coincides with rapid and sustained increase in acetyl-CoA content.
Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules.
Role of AMPK in Regulation of Oxaliplatin-Resistant Human Colorectal Cancer.
Protein acylation links metabolism and the control of signal transduction, transcription regulation, growth and pathogenicity in Actinobacteria.
HDAC11, an emerging therapeutic target for metabolic disorders.

Int J Mol Sci. 2022 Nov 05. pii: 13578. [Epub ahead of print]23(21):

SIRT1 Promotes Host Protective Immunity against Toxoplasma gondii by Controlling the FoxO-Autophagy Axis via the AMPK and PI3K/AKT Signalling Pathways.

Jina Lee, Jinju Kim, Jae-Hyung Lee, Yong Min Choi, Hyeonil Choi, Hwan-Doo Cho, Guang-Ho Cha, Young-Ha Lee, Eun-Kyeong Jo, Byung-Hyun Park, Jae-Min Yuk.

  Sirtuin 1 (SIRT1) regulates cellular processes by deacetylating non-histone targets, including transcription factors and intracellular signalling mediators; thus, its abnormal activation is closely linked to the pathophysiology of several diseases. However, its function in Toxoplasma gondii infection is unclear. We found that SIRT1 contributes to autophagy activation via the AMP-activated protein kinase (AMPK) and PI3K/AKT signalling pathways, promoting anti-Toxoplasma responses. Myeloid-specific Sirt1-/- mice exhibited an increased cyst burden in brain tissue compared to wild-type mice following infection with the avirulent ME49 strain. Consistently, the intracellular survival of T. gondii was markedly increased in Sirt1-deficient bone-marrow-derived macrophages (BMDMs). In contrast, the activation of SIRT1 by resveratrol resulted in not only the induction of autophagy but also a significantly increased anti-Toxoplasma effect. Notably, SIRT1 regulates the FoxO-autophagy axis in several human diseases. Importantly, the T. gondii-induced phosphorylation, acetylation, and cytosolic translocation of FoxO1 was enhanced in Sirt1-deficient BMDMs and the pharmacological inhibition of PI3K/AKT signalling reduced the cytosolic translocation of FoxO1 in BMDMs infected with T. gondii. Further, the CaMKK2-dependent AMPK signalling pathway is responsible for the effect of SIRT1 on the FoxO3a-autophagy axis and for its anti-Toxoplasma activity. Collectively, our findings reveal a previously unappreciated role for SIRT1 in Toxoplasma infection.

Keywords:  AMP-activated protein kinase; Class O of forkhead box transcription factors; PI3K/AKT signalling pathway; Sirtuin 1; Toxoplasma gondii; autophagy; bone-marrow-derived macrophages

DOI:  https://doi.org/10.3390/ijms232113578
Sci Adv. 2022 Nov 11. 8(45): eabo7956

AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.

Lisa Tilokani, Fiona M Russell, Stevie Hamilton, Daniel M Virga, Mayuko Segawa, Vincent Paupe, Anja V Gruszczyk, Margherita Protasoni, Luis-Carlos Tabara, Mark Johnson, Hanish Anand, Michael P Murphy, D Grahame Hardie, Franck Polleux, Julien Prudent.

Mitochondria are dynamic organelles that undergo membrane remodeling events in response to metabolic alterations to generate an adequate mitochondrial network. Here, we investigated the function of mitochondrial fission regulator 1-like protein (MTFR1L), an uncharacterized protein that has been identified in phosphoproteomic screens as a potential AMP-activated protein kinase (AMPK) substrate. We showed that MTFR1L is an outer mitochondrial membrane-localized protein modulating mitochondrial morphology. Loss of MTFR1L led to mitochondrial elongation associated with increased mitochondrial fusion events and levels of the mitochondrial fusion protein, optic atrophy 1. Mechanistically, we show that MTFR1L is phosphorylated by AMPK, which thereby controls the function of MTFR1L in regulating mitochondrial morphology both in mammalian cell lines and in murine cortical neurons in vivo. Furthermore, we demonstrate that MTFR1L is required for stress-induced AMPK-dependent mitochondrial fragmentation. Together, these findings identify MTFR1L as a critical mitochondrial protein transducing AMPK-dependent metabolic changes through regulation of mitochondrial dynamics.

DOI: https://doi.org/10.1126/sciadv.abo7956
Trends Parasitol. 2022 Nov 07. pii: S1471-4922(22)00257-4. [Epub ahead of print]

Histone lactylation: a new epigenetic axis for host-parasite signalling in malaria?

Catherine J Merrick.

  Epigenetic modifications play important roles in the biology of malaria parasites. The new epigenetic mark histone lactylation, discovered only recently in humans, is also present in malaria parasites. It may have important functions as a key player in the epigenetic repertoire of Plasmodium.

Keywords:  Plasmodium; epigenetics; hyperlactataemia; lactate; lactylation; malaria

DOI:  https://doi.org/10.1016/j.pt.2022.10.004
Naunyn Schmiedebergs Arch Pharmacol. 2022 Nov 10.

Regulation of insulin secretion in mouse islets: metabolic amplification by alpha-ketoisocaproate coincides with rapid and sustained increase in acetyl-CoA content.

Uwe Panten, Dennis Brüning, Ingo Rustenbeck.

  Glucose and alpha-ketoisocaproate, the keto acid analogue of leucine, stimulate insulin secretion in the absence of other exogenous fuels. Their mitochondrial metabolism in the beta-cell raises the cytosolic ATP/ADP ratio, thereby providing the triggering signal for the exocytosis of the insulin granules. However, additional amplifying signals are required for the full extent of insulin secretion stimulated by these fuels. While it is generally recognized that the amplifying signals are also derived from the mitochondrial metabolism, their exact nature is still unclear. The current study tests the hypothesis that the supply of cytosolic acetyl-CoA is a signal in the amplifying pathway. The contents of acetyl-CoA and acetyl-CoA plus CoA-SH were measured in isolated mouse islets. Insulin secretion was recorded in isolated perifused islets. In islets, the ATP-sensitive K+ channels of which were pharmacologically closed and which were preincubated without exogenous fuel, 10 mmol/L alpha-ketoisocaproate enhanced the acetyl-CoA content after 5 and 20 min incubations and decreased the acetyl-CoA plus CoA-SH within 5 min, but not after 20 min. In islets not exposed to drugs, the preincubation with 3 mmol/L glucose, a non-triggering concentration, elevated the acetyl-CoA content. This content was further increased after 5 min and 20 min incubations with 30 mmol/L glucose, concurrent with a strong increase in insulin secretion. Alpha-ketoisocaproate and glucose increase the supply of acetyl-CoA in the beta-cell cytosol during both phases of insulin secretion. Most likely, this increase provides a signal for the metabolic amplification.

Keywords:  Acetyl-CoA; Alpha-ketoisocaproate; Beta-cell; Glucose; Insulin secretion; Metabolic amplification

DOI:  https://doi.org/10.1007/s00210-022-02290-8
Pharmaceuticals (Basel). 2022 Oct 29. pii: 1341. [Epub ahead of print]15(11):

Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules.

Giusy Tassone, Marco Mazzorana, Cecilia Pozzi.

  Protozoan parasites are responsible for several harmful and widespread human diseases that cause high morbidity and mortality. Currently available treatments have serious limitations due to poor efficiency, strong adverse effects, and high cost. Hence, the identification of new targets and the development of specific drug therapies against parasitic diseases are urgent needs. Heat shock protein 90 (HSP90) is an ATP-dependent molecular chaperone that plays a key role in parasite survival during the various differentiation stages, spread over the vector insect and the human host, which they undergo during their life cycle. The N-terminal domain (NTD) of HSP90, containing the main determinants for ATPase activity, represents the most druggable domain for inhibitor targeting. The molecules investigated on parasite HSP90 are mainly developed from known inhibitors of the human counterpart, and they have strong limitations due to selectivity issues, accounting for the high conservation of the ATP-binding site between the parasite and human proteins. The current review highlights the recent structural progress made to support the rational design of new molecules able to effectively block the chaperone activity of parasite HSP90.

Keywords:  HSP90; chaperone function; heat shock proteins; inhibitors; neglected tropical diseases; protozoan parasites; selectivity

DOI:  https://doi.org/10.3390/ph15111341
Biomedicines. 2022 Oct 25. pii: 2690. [Epub ahead of print]10(11):

Role of AMPK in Regulation of Oxaliplatin-Resistant Human Colorectal Cancer.

Sun Young Park, Ye Seo Chung, So Yeon Park, So Hee Kim.

  Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In this study, oxaliplatin-resistant (OR) colorectal cancer (CRC) cells of HCT116, HT29, SW480 and SW620 were established by gradually increasing the drug concentration to 2.5 μM. The inhibitory concentrations of cell growth by 50% (IC50) of oxaliplatin were 4.40-12.7-fold significantly higher in OR CRC cells as compared to their respective parental (PT) CRC cells. Phospho-Akt and phospho-mammalian target of rapamycin (mTOR) decreased in PT CRC cells but was overexpressed in OR CRC cells in response to oxaliplatin. In addition, an oxaliplatin-mediated decrease in phospho-AMP-activated protein kinase (AMPK) in PT CRC cells induced autophagy. Contrastingly, an increased phospho-AMPK in OR CRC cells was accompanied by a decrease in LC3B, further inducing the activity of glycolytic enzymes, such as glucose transporter 1 (GLUT1), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK1), to mediate cell survival. Inhibition of AMPK in OR CRC cells induced autophagy through inactivation of Akt/mTOR pathway and a decrease in GLUT1, PFKFB3, and PFK1. Collectively, targeting AMPK may provide solutions to overcome chemoresistance in OR CRC cells and restore chemosensitivity to anticancer drugs.

Keywords:  AMPK; Akt-mTOR; autophagy; chemoresistance; colorectal cancer; glycolysis; oxaliplatin

DOI:  https://doi.org/10.3390/biomedicines10112690
Mol Microbiol. 2022 Nov 08.

Protein acylation links metabolism and the control of signal transduction, transcription regulation, growth and pathogenicity in Actinobacteria.

Zhi-Yao Peng, Yu Fu, Liu-Chang Zhao, Yu-Qi Dong, Zong-Qin Chen, Di You, Bang-Ce Ye.

  Actinobacteria have a complex life cycle, including morphological and physiological differentiation which are often associated with the biosynthesis of secondary metabolites. Recently, increased interest in posttranslational modifications (PTMs) in these Gram-positive bacteria has highlighted the importance of PTMs as signals that provide functional diversity and regulation by modifying proteins to respond to diverse stimuli. Here, we review the developments in research on acylation, a typical PTM that uses acyl-CoA or related metabolites as donors, as well as the understanding of the direct link provided by acylation between cell metabolism and signal transduction, transcriptional regulation, cell growth and pathogenicity in Actinobacteria.

Keywords:  Actinobacteria; PTM-metabolic engineering; acyl-CoA; acylation; secondary metabolism

DOI:  https://doi.org/10.1111/mmi.14998
Front Endocrinol (Lausanne). 2022 ;13 989305

HDAC11, an emerging therapeutic target for metabolic disorders.

Huizhen Chen, Chunguang Xie, Qiu Chen, Shougang Zhuang.

  Histone deacetylase 11 (HDAC11) is the only member of the class IV HDAC, and the latest member identified. It is highly expressed in brain, heart, kidney and some other organs, and located in mitochondria, cytoplasm and nuclei, depending on the tissue and cell types. Although studies in HDAC11 total knockout mice suggest its dispensable features for tissue development and life, it participates in diverse pathophysiological processes, such as DNA replication, tumor growth, immune regulation, oxidant stress injury and neurological function of cocaine. Recent studies have shown that HDAC11 is also critically involved in the pathogenesis of some metabolic diseases, including obesity, diabetes and complications of diabetes. In this review, we summarize the recent progress on the role and mechanism of HDAC11 in the regulation of metabolic disorders, with the focus on its regulation on adipogenesis, lipid metabolism, metabolic inflammation, glucose tolerance, immune responses and energy consumption. We also discuss the property and selectivity of HDAC11 inhibitors and their applications in a variety of in vitro and in vivo models of metabolic disorders. Given that pharmacological and genetic inhibition of HDAC11 exerts a beneficial effect on various metabolic disorders, HDAC11 may be a potential therapeutic target to treat chronic metabolic diseases.

Keywords:  HDAC11; diabetes; diabetic complications; metabolic disorders; obesity

DOI:  https://doi.org/10.3389/fendo.2022.989305