bims-meprid 2024-04-21 papers

bims-meprid

Biomed News

on Metabolic-dependent epigenetic reprogramming in differentiation and disease

Issue of 2024–04–21
seven papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

Activation of hepatic acetyl-CoA carboxylase by S-nitrosylation in response to diet.
The emerging importance of the α-keto acid dehydrogenase complexes in serving as intracellular and intercellular signaling platforms for the regulation of metabolism.
Protein acylations induced by a ketogenic diet demonstrate diverse patterns depending on organs and differ between histones and global proteins.
SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19.
Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence.
Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism.
De novo purine metabolism is a metabolic vulnerability of cancers with low p16 expression.

J Lipid Res. 2024 Apr 17. pii: S0022-2275(24)00047-6. [Epub ahead of print] 100542

Activation of hepatic acetyl-CoA carboxylase by S-nitrosylation in response to diet.

Nicholas M Venetos, Colin T Stomberski, Zhaoxia Qian, Richard T Premont, Jonathan S Stamler.

  Nitric oxide (NO), produced primarily by nitric oxide synthase (NOS) enzymes, is known to influence energy metabolism by stimulating fat uptake and oxidation. The effects of NO on de novo lipogenesis, however, are less clear. Here we demonstrate that hepatic expression of eNOS is reduced following prolonged administration of a hypercaloric high-fat diet. This results in marked reduction in the amount of S-nitrosylation of liver proteins including notably Acetyl-CoA Carboxylase (ACC), the rate-limiting enzyme in de novo lipogenesis. We further show that ACC S-nitrosylation markedly increases enzymatic activity. Diminished eNOS expression and ACC S-nitrosylation may thus represent a physiological adaptation to caloric excess by constraining lipogenesis. Our findings demonstrate that S-nitrosylation of liver proteins is subject to dietary control and suggest that de novo lipogenesis is coupled to dietary and metabolic conditions through ACC S-nitrosylation.

Keywords:  Acetyl-CoA Carboxylase; Cell signaling; Dietary fat; Lipogenesis; Liver; S-nitrosylation; Triglycerides

DOI:  https://doi.org/10.1016/j.jlr.2024.100542
Redox Biol. 2024 Apr 10. pii: S2213-2317(24)00131-9. [Epub ahead of print]72 103155

The emerging importance of the α-keto acid dehydrogenase complexes in serving as intracellular and intercellular signaling platforms for the regulation of metabolism.

Ryan J Mailloux.

The α-keto acid dehydrogenase complex (KDHc) class of mitochondrial enzymes is composed of four members: pyruvate dehydrogenase (PDHc), α-ketoglutarate dehydrogenase (KGDHc), branched-chain keto acid dehydrogenase (BCKDHc), and 2-oxoadipate dehydrogenase (OADHc). These enzyme complexes occupy critical metabolic intersections that connect monosaccharide, amino acid, and fatty acid metabolism to Krebs cycle flux and oxidative phosphorylation (OxPhos). This feature also imbues KDHc enzymes with the heightened capacity to serve as platforms for propagation of intracellular and intercellular signaling. KDHc enzymes serve as a source and sink for mitochondrial hydrogen peroxide (mtH2O2), a vital second messenger used to trigger oxidative eustress pathways. Notably, deactivation of KDHc enzymes through reversible oxidation by mtH2O2 and other electrophiles modulates the availability of several Krebs cycle intermediates and related metabolites which serve as powerful intracellular and intercellular messengers. The KDHc enzymes also play important roles in the modulation of mitochondrial metabolism and epigenetic programming in the nucleus through the provision of various acyl-CoAs, which are used to acylate proteinaceous lysine residues. Intriguingly, nucleosomal control by acylation is also achieved through PDHc and KGDHc localization to the nuclear lumen. In this review, I discuss emerging concepts in the signaling roles fulfilled by the KDHc complexes. I highlight their vital function in serving as mitochondrial redox sensors and how this function can be used by cells to regulate the availability of critical metabolites required in cell signaling. Coupled with this, I describe in detail how defects in KDHc function can cause disease states through the disruption of cell redox homeodynamics and the deregulation of metabolic signaling. Finally, I propose that the intracellular and intercellular signaling functions of the KDHc enzymes are controlled through the reversible redox modification of the vicinal lipoic acid thiols in the E2 subunit of the complexes.

DOI: https://doi.org/10.1016/j.redox.2024.103155
Biochem Biophys Res Commun. 2024 Apr 16. pii: S0006-291X(24)00496-0. [Epub ahead of print]712-713 149960

Protein acylations induced by a ketogenic diet demonstrate diverse patterns depending on organs and differ between histones and global proteins.

Minami Ito, Yuya Nishida, Tatsuya Iwamoto, Akiko Kanai, Shuhei Aoyama, Kyosei Ueki, Hirotsugu Uzawa, Hitoshi Iida, Hirotaka Watada.

  An essential ketone body, β-hydroxybutyrate (BOHB), plays various roles in physiological regulations via protein acylations such as lysine acetylation and β-hydroxybutyrylation. Here, to understand how BOHB systemically regulates acylations from an overarching perspective, we administered a ketogenic diet to mice to increase BOHB concentration and examined acylations. We found that global acetylation and β-hydroxybutyrylation dramatically increase in various organs except for the brains, where the increase was much smaller than in the other organs. Interestingly, we observe no increase in histone acetylation in the organs where significant global protein acetylation occurs despite a substantial rise in histone β-hydroxybutyrylation. Finally, we compared the transcriptome data of the mice's liver after the ketogenic diet to the public databases, showing that upregulated genes are enriched in those related to histone β-hydroxybutyrylation in starvation. Our data indicate that a ketogenic diet induces diverse patterns of acylations depending on organs and protein localizations, suggesting that different mechanisms regulate acylations and that the ketogenic diet is associated with starvation in terms of protein modifications.

Keywords:  Acetylation; Histone modifications; Ketogenic diet; β-hydroxybutyrate; β-hydroxybutyrylation

DOI:  https://doi.org/10.1016/j.bbrc.2024.149960
Pharmacol Res. 2024 Apr 11. pii: S1043-6618(24)00114-2. [Epub ahead of print] 107170

SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19.

Joseph W Guarnieri, Jeffrey A Haltom, Yentli E Soto Albrecht, Timothy Lie, Arnold Z Olali, Gabrielle A Widjaja, Sujata S Ranshing, Alessia Angelin, Deborah Murdock, Douglas C Wallace.

  To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey of the cellular metabolic pathways modulated by SARS-CoV-2 infection and confirmed their importance for SARS-CoV-2 propagation by cataloging the effects of specific pathway inhibitors. This revealed that SARS-CoV-2 strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased mitochondrial reactive oxygen species (mROS) production. The elevated mROS stabilizes HIF-1α which redirects carbon molecules from mitochondrial oxidation through glycolysis and the pentose phosphate pathway (PPP) to provide substrates for viral biogenesis. mROS also induces the release of mitochondrial DNA (mtDNA) which activates innate immunity. The restructuring of cellular energy metabolism is mediated in part by SARS-CoV-2 Orf8 and Orf10 whose expression restructures nuclear DNA (nDNA) and mtDNA OXPHOS gene expression. These viral proteins likely alter the epigenome, either by directly altering histone modifications or by modulating mitochondrial metabolite substrates of epigenome modification enzymes, potentially silencing OXPHOS gene expression and contributing to long-COVID.

Keywords:  Mitochondria; OXPHOS; SARS-CoV-2; epigenome; gene regulation; inhibitors; metabolism

DOI:  https://doi.org/10.1016/j.phrs.2024.107170
Nat Commun. 2024 Apr 13. 15(1): 3200

Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence.

Lingzhi Li, Ting Xiang, Jingjing Guo, Fan Guo, Yiting Wu, Han Feng, Jing Liu, Sibei Tao, Ping Fu, Liang Ma.

Histone lysine crotonylation (Kcr), as a posttranslational modification, is widespread as acetylation (Kac); however, its roles are largely unknown in kidney fibrosis. In this study, we report that histone Kcr of tubular epithelial cells is abnormally elevated in fibrotic kidneys. By screening these crotonylated/acetylated factors, a crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) is found to remarkably increase histone 3 lysine 9 crotonylation (H3K9cr) level without influencing H3K9ac in kidneys and tubular epithelial cells. The integrated analysis of ChIP-seq and RNA-seq of fibrotic kidneys reveal that the hub proinflammatory cytokine IL-1β, which is regulated by H3K9cr, play crucial roles in fibrogenesis. Furthermore, genetic and pharmacologic inhibition of ACSS2 both suppress H3K9cr-mediated IL-1β expression, which thereby alleviate IL-1β-dependent macrophage activation and tubular cell senescence to delay renal fibrosis. Collectively, our findings uncover that H3K9cr exerts a critical, previously unrecognized role in kidney fibrosis, where ACSS2 represents an attractive drug target to slow fibrotic kidney disease progression.

DOI: https://doi.org/10.1038/s41467-024-47315-3
Proc Natl Acad Sci U S A. 2024 Apr 23. 121(17): e2318420121

Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism.

Ajay Kumar, Chenxian Ye, Afia Nkansah, Thomas Decoville, Garrett M Fogo, Peter Sajjakulnukit, Mack B Reynolds, Li Zhang, Osbourne Quaye, Young-Ah Seo, Thomas H Sanderson, Costas A Lyssiotis, Cheong-Hee Chang.

  In response to an immune challenge, naive T cells undergo a transition from a quiescent to an activated state acquiring the effector function. Concurrently, these T cells reprogram cellular metabolism, which is regulated by iron. We and others have shown that iron homeostasis controls proliferation and mitochondrial function, but the underlying mechanisms are poorly understood. Given that iron derived from heme makes up a large portion of the cellular iron pool, we investigated iron homeostasis in T cells using mice with a T cell-specific deletion of the heme exporter, FLVCR1 [referred to as knockout (KO)]. Our finding revealed that maintaining heme and iron homeostasis is essential to keep naive T cells in a quiescent state. KO naive CD4 T cells exhibited an iron-overloaded phenotype, with increased spontaneous proliferation and hyperactive mitochondria. This was evidenced by reduced IL-7R and IL-15R levels but increased CD5 and Nur77 expression. Upon activation, however, KO CD4 T cells have defects in proliferation, IL-2 production, and mitochondrial functions. Iron-overloaded CD4 T cells failed to induce mitochondrial iron and exhibited more fragmented mitochondria after activation, making them susceptible to ferroptosis. Iron overload also led to inefficient glycolysis and glutaminolysis but heightened activity in the hexosamine biosynthetic pathway. Overall, these findings highlight the essential role of iron in controlling mitochondrial function and cellular metabolism in naive CD4 T cells, critical for maintaining their quiescent state.

Keywords:  heme; iron; mitochondria; tonic signaling

DOI:  https://doi.org/10.1073/pnas.2318420121
Cancer Res Commun. 2024 Apr 16.

De novo purine metabolism is a metabolic vulnerability of cancers with low p16 expression.

Naveen Kumar Tangudu, Raquel Buj, Hui Wang, Jiefei Wang, Aidan R Cole, Apoorva Uboveja, Richard Fang, Amandine Amalric, Baixue Yang, Adam Chatoff, Claudia V Crispim, Peter Sajjakulnukit, Maureen A Lyons, Kristine Cooper, Nadine Hempel, Costas A Lyssiotis, Uma R Chandran, Nathaniel W Snyder, Katherine M Aird.

p16 is a tumor suppressor encoded by the CDKN2A gene whose expression is lost in ~50% of all human cancers. In its canonical role, p16 inhibits the G1-S phase cell cycle progression through suppression of cyclin dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway. However, the broader impact of p16/CDKN2A loss on other nucleotide metabolic pathways and potential therapeutic targets remains unexplored. Using CRISPR KO libraries in isogenic human and mouse melanoma cell lines, we determined several nucleotide metabolism genes essential for the survival of cells with loss of p16/CDKN2A. Consistently, many of these genes are upregulated in melanoma cells with p16 knockdown or endogenously low CDKN2A expression. We determined that cells with low p16/CDKN2A expression are sensitive to multiple inhibitors of de novo purine synthesis, including anti-folates. Finally, tumors with p16 knockdown were more sensitive to the anti-folate methotrexate in vivo than control tumors. Together, our data provide evidence to reevaluate the utility of these drugs in patients with p16/CDKN2Alow tumors as loss of p16/CDKN2A may provide a therapeutic window for these agents.

DOI: https://doi.org/10.1158/2767-9764.CRC-23-0450