bims-meprid 2021-05-02 papers

Antioxidants (Basel). 2021 Apr 08. pii: 572. [Epub ahead of print]10(4):

Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan.

Acetyl-CoA is a metabolite at the crossroads of central metabolism and the substrate of histone acetyltransferases regulating gene expression. In many tissues fasting or lifespan extending calorie restriction (CR) decreases glucose-derived metabolic flux through ATP-citrate lyase (ACLY) to reduce cytoplasmic acetyl-CoA levels to decrease activity of the p300 histone acetyltransferase (HAT) stimulating pro-longevity autophagy. Because of this, compounds that decrease cytoplasmic acetyl-CoA have been described as CR mimetics. But few authors have highlighted the potential longevity promoting roles of nuclear acetyl-CoA. For example, increasing nuclear acetyl-CoA levels increases histone acetylation and administration of class I histone deacetylase (HDAC) inhibitors increases longevity through increased histone acetylation. Therefore, increased nuclear acetyl-CoA likely plays an important role in promoting longevity. Although cytoplasmic acetyl-CoA synthetase 2 (ACSS2) promotes aging by decreasing autophagy in some peripheral tissues, increased glial AMPK activity or neuronal differentiation can stimulate ACSS2 nuclear translocation and chromatin association. ACSS2 nuclear translocation can result in increased activity of CREB binding protein (CBP), p300/CBP-associated factor (PCAF), and other HATs to increase histone acetylation on the promoter of neuroprotective genes including transcription factor EB (TFEB) target genes resulting in increased lysosomal biogenesis and autophagy. Much of what is known regarding acetyl-CoA metabolism and aging has come from pioneering studies with yeast, fruit flies, and nematodes. These studies have identified evolutionary conserved roles for histone acetylation in promoting longevity. Future studies should focus on the role of nuclear acetyl-CoA and histone acetylation in the control of hypothalamic inflammation, an important driver of organismal aging.

Keywords: acetyl-CoA; acetylation; aging; autophagy; calorie restriction; histone deacetylase

DOI: https://doi.org/10.3390/antiox10040572

Front Immunol. 2021 ;12 641883

Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications.

Yijia Li, Yangzhe Wu, Yi Hu.

Cellular metabolism of both cancer and immune cells in the acidic, hypoxic, and nutrient-depleted tumor microenvironment (TME) has attracted increasing attention in recent years. Accumulating evidence has shown that cancer cells in TME could outcompete immune cells for nutrients and at the same time, producing inhibitory products that suppress immune effector cell functions. Recent progress revealed that metabolites in the TME could dysregulate gene expression patterns in the differentiation, proliferation, and activation of immune effector cells by interfering with the epigenetic programs and signal transduction networks. Nevertheless, encouraging studies indicated that metabolic plasticity and heterogeneity between cancer and immune effector cells could provide us the opportunity to discover and target the metabolic vulnerabilities of cancer cells while potentiating the anti-tumor functions of immune effector cells. In this review, we will discuss the metabolic impacts on the immune effector cells in TME and explore the therapeutic opportunities for metabolically enhanced immunotherapy.

Keywords: anti-tumor immunity; epigenetic modifications; immune cell reprogramming; metabolites; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2021.641883

Sci Adv. 2021 Apr;pii: eabe7359. [Epub ahead of print]7(18):

Mitochondrial respiration controls the Prox1-Vegfr3 feedback loop during lymphatic endothelial cell fate specification and maintenance.

Wanshu Ma, Hyea Jin Gil, Xiaolei Liu, Lauren P Diebold, Marc A Morgan, Michael J Oxendine-Burns, Peng Gao, Navdeep S Chandel, Guillermo Oliver.

Recent findings indicate that mitochondrial respiration regulates blood endothelial cell proliferation; however, its role in differentiating lymphatic endothelial cells (LECs) is unknown. We hypothesized that mitochondria could work as a sensor of LECs' metabolic specific needs by determining their functional requirements according to their differentiation status and local tissue microenvironment. Accordingly, we conditionally deleted the QPC subunit of mitochondrial complex III in differentiating LECs of mouse embryos. Unexpectedly, mutant mice were devoid of a lymphatic vasculature by mid-gestation, a consequence of the specific down-regulation of main LEC fate regulators, particularly Vegfr3, leading to the loss of LEC fate. Mechanistically, this is a result of reduced H3K4me3 and H3K27ac in the genomic locus of key LEC fate controllers (e.g., Vegfr3 and Prox1). Our findings indicate that by sensing the LEC differentiation status and microenvironmental metabolic conditions, mitochondrial complex III regulates the critical Prox1-Vegfr3 feedback loop and, therefore, LEC fate specification and maintenance.

DOI: https://doi.org/10.1126/sciadv.abe7359

Annu Rev Immunol. 2021 Apr 26. 39 395-416

Mitochondrial Metabolism Regulation of T Cell-Mediated Immunity.

Elizabeth M Steinert, Karthik Vasan, Navdeep S Chandel.

Recent evidence supports the notion that mitochondrial metabolism is necessary for T cell activation, proliferation, and function. Mitochondrial metabolism supports T cell anabolism by providing key metabolites for macromolecule synthesis and generating metabolites for T cell function. In this review, we focus on how mitochondrial metabolism controls conventional and regulatory T cell fates and function.

Keywords: ROS; TCA cycle; acetyl-CoA; epigenetics; inflammation; l-2-hydroxyglutarate; l-2HG

DOI: https://doi.org/10.1146/annurev-immunol-101819-082015

Cancers (Basel). 2021 Apr 01. pii: 1666. [Epub ahead of print]13(7):

O-GlcNAcylation and O-GlcNAc Cycling Regulate Gene Transcription: Emerging Roles in Cancer.

Matthew P Parker, Kenneth R Peterson, Chad Slawson.

O-linked β-N-acetylglucosamine (O-GlcNAc) is a single sugar post-translational modification (PTM) of intracellular proteins linking nutrient flux through the Hexosamine Biosynthetic Pathway (HBP) to the control of cis-regulatory elements in the genome. Aberrant O-GlcNAcylation is associated with the development, progression, and alterations in gene expression in cancer. O-GlcNAc cycling is defined as the addition and subsequent removal of the modification by O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA) provides a novel method for cells to regulate various aspects of gene expression, including RNA polymerase function, epigenetic dynamics, and transcription factor activity. We will focus on the complex relationship between phosphorylation and O-GlcNAcylation in the regulation of the RNA Polymerase II (RNAP II) pre-initiation complex and the regulation of the carboxyl-terminal domain of RNAP II via the synchronous actions of OGT, OGA, and kinases. Additionally, we discuss how O-GlcNAcylation of TATA-box binding protein (TBP) alters cellular metabolism. Next, in a non-exhaustive manner, we will discuss the current literature on how O-GlcNAcylation drives gene transcription in cancer through changes in transcription factor or chromatin remodeling complex functions. We conclude with a discussion of the challenges associated with studying O-GlcNAcylation and present several new approaches for studying O-GlcNAc regulated transcription that will advance our understanding of the role of O-GlcNAc in cancer.

Keywords: O-GlcNAc; O-GlcNAc transferase; O-GlcNAcase; transcription

DOI: https://doi.org/10.3390/cancers13071666

J Mol Cell Cardiol. 2021 Apr 26. pii: S0022-2828(21)00085-7. [Epub ahead of print]

Protein acetylation in cardiac aging.

Ashley Francois, Alessandro Canella, Lynn Marcho, Matthew S Stratton.

Biological aging is attributed to progressive dysfunction in systems governing genetic and metabolic integrity. At the cellular level, aging is evident by accumulated DNA damage and mutation, reactive oxygen species, alternate lipid and protein modifications, alternate gene expression programs, and mitochondrial dysfunction (Sun et al., 2016; Nekhaeva et al., 2002; Kong et al., 2014). These effects sum to drive altered tissue morphology and organ dysfunction (Ballard and Edelberg, 2008; Han and Ren, 2010; Pina and Fitzpatrick, 1996). Protein-acylation has emerged as a critical mediator of age-dependent changes in these processes (Sun et al., 2016; Nekhaeva et al., 2002; Kong et al., 2014). Despite decades of research focus from academia and industry, heart failure remains a leading cause of death in the United States while the 5 year mortality rate for heart failure remains over 40% Benjamin et al. (2019). Over 90% of heart failure deaths occur in patients over the age of 65 and heart failure is the leading cause of hospitalization in Medicare beneficiaries (Strait and Lakatta, 2012). In 1931, Cole and Koch discovered age-dependent accumulation of phosphates in skeletal muscle (Cole and Koch, 1931). These and similar findings provided supporting evidence for, now well accepted, theories linking metabolism and aging. Nearly two decades later, age-associated alterations in biochemical molecules were described in the heart (Kaufman and Poliakoff, 1950). From these small beginnings, the field has grown substantially in recent years. This growing research focus on cardiac aging has, in part, been driven by advances on multiple public health fronts that allow population level clinical presentation of aging related disorders. It is estimated that by 2030, 25% of the worldwide population will be over the age of 65 (Lakatta, 2002). This review provides an overview of acetylation-dependent regulation of biological processes related to cardiac aging and introduces emerging non-acetyl, acyl-lysine modifications in cardiac function and aging.

Keywords: Acetylation; Cardiac aging; Epigenetic; Histone deacetylase

DOI: https://doi.org/10.1016/j.yjmcc.2021.04.007