Krebs cycle intermediates regulate DNA and histone methylation: epigenetic impact on the aging process. Salminen Antero,Kauppinen Anu,Hiltunen Mikko,Kaarniranta Kai Ageing research reviews Many aging theories have proposed that mitochondria and energy metabolism have a major role in the aging process. There are recent studies indicating that Krebs cycle intermediates can shape the epigenetic landscape of chromatin by regulating DNA and histone methylation. A growing evidence indicates that epigenetics plays an important role in the regulation of healthspan but also is involved in the aging process. 2-Oxoglutarate (α-ketoglutarate) is a key metabolite in the Krebs cycle but it is also an obligatory substrate for 2-oxoglutarate-dependent dioxygenases (2-OGDO). The 2-OGDO enzyme family includes the major enzymes of DNA and histone demethylation, i.e. Ten-Eleven Translocation (TETs) and Jumonji C domain containing (JmjC) demethylases. In addition, 2-OGDO members can regulate collagen synthesis and hypoxic responses in a non-epigenetical manner. Interestingly, succinate and fumarate, also Krebs cycle intermediates, are potent inhibitors of 2-OGDO enzymes, i.e. the balance of Krebs cycle reactions can affect the level of DNA and histone methylation and thus control gene expression. We will review the epigenetic mechanisms through which Krebs cycle intermediates control the DNA and histone methylation. We propose that age-related disturbances in the Krebs cycle function induce stochastic epigenetic changes in chromatin structures which in turn promote the aging process. 10.1016/j.arr.2014.05.004

Mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation links the tricarboxylic acid (TCA) cycle with methionine metabolism and nuclear DNA methylation. Lozoya Oswaldo A,Martinez-Reyes Inmaculada,Wang Tianyuan,Grenet Dagoberto,Bushel Pierre,Li Jianying,Chandel Navdeep,Woychik Richard P,Santos Janine H PLoS biology Mitochondrial function affects many aspects of cellular physiology, and, most recently, its role in epigenetics has been reported. Mechanistically, how mitochondrial function alters DNA methylation patterns in the nucleus remains ill defined. Using a cell culture model of induced mitochondrial DNA (mtDNA) depletion, in this study we show that progressive mitochondrial dysfunction leads to an early transcriptional and metabolic program centered on the metabolism of various amino acids, including those involved in the methionine cycle. We find that this program also increases DNA methylation, which occurs primarily in the genes that are differentially expressed. Maintenance of mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation in the context of mtDNA loss rescues methionine salvage and polyamine synthesis and prevents changes in DNA methylation and gene expression but does not affect serine/folate metabolism or transsulfuration. This work provides a novel mechanistic link between mitochondrial function and epigenetic regulation of gene expression that involves polyamine and methionine metabolism responding to changes in the tricarboxylic acid (TCA) cycle. Given the implications of these findings, future studies across different physiological contexts and in vivo are warranted. 10.1371/journal.pbio.2005707

Tricarboxylic Acid Cycle Metabolites as Mediators of DNA Methylation Reprogramming in Bovine Preimplantation Embryos. Ispada Jessica,da Fonseca Junior Aldcejam Martins,de Lima Camila Bruna,Dos Santos Erika Cristina,Fontes Patricia Kubo,Nogueira Marcelo Fábio Gouveia,da Silva Vinicius Lourenço,Almeida Fernanda Nascimento,Leite Saul de Castro,Chitwood James Lee,Ross Pablo Juan,Milazzotto Marcella Pecora International journal of molecular sciences In many cell types, epigenetic changes are partially regulated by the availability of metabolites involved in the activity of chromatin-modifying enzymes. Even so, the association between metabolism and the typical epigenetic reprogramming that occurs during preimplantation embryo development remains poorly understood. In this work, we explore the link between energy metabolism, more specifically the tricarboxylic acid cycle (TCA), and epigenetic regulation in bovine preimplantation embryos. Using a morphokinetics model of embryonic development (fast- and slow-developing embryos), we show that DNA methylation (5mC) and hydroxymethylation (5hmC) are dynamically regulated and altered by the speed of the first cleavages. More specifically, slow-developing embryos fail to perform the typical reprogramming that is necessary to ensure the generation of blastocysts with higher ability to establish specific cell lineages. Transcriptome analysis revealed that such differences were mainly associated with enzymes involved in the TCA cycle rather than specific writers/erasers of DNA methylation marks. This relationship was later confirmed by disturbing the embryonic metabolism through changes in α-ketoglutarate or succinate availability in culture media. This was sufficient to interfere with the DNA methylation dynamics despite the fact that blastocyst rates and total cell number were not quite affected. These results provide the first evidence of a relationship between epigenetic reprogramming and energy metabolism in bovine embryos. Likewise, levels of metabolites in culture media may be crucial for precise epigenetic reprogramming, with possible further consequences in the molecular control and differentiation of cells. 10.3390/ijms21186868

Lysine Succinylation and Acetylation in Pseudomonas aeruginosa. Gaviard Charlotte,Broutin Isabelle,Cosette Pascal,Dé Emmanuelle,Jouenne Thierry,Hardouin Julie Journal of proteome research Pseudomonas aeruginosa is a multi-drug-resistant human opportunistic pathogen largely involved in nosocomial infections. Unfortunately, effective antibacterial agents are lacking. Exploring its physiology at the post-translational modifications (PTMs) level may contribute to the renewal of combat tactics. Recently, lysine succinylation was discovered in bacteria and seems to be an interesting PTM. We present the first succinylome and acetylome of P. aeruginosa PA14 cultured in the presence of four different carbon sources using a 2D immunoaffinity approach coupled to nanoliquid chromatography tandem mass spectrometry. A total of 1520 succinylated (612 proteins) and 1102 acetylated (522 proteins) lysine residues were characterized. Citrate was the carbon source in which we identified the higher number of modified proteins. Interestingly, 622 lysine residues (312 proteins) were observed either acetylated or succinylated. Some of these proteins, were involved in virulence, adaptation, resistance, and so on. A label-free quantification points out the existence of different protein forms for a same protein (unmodified, succinylated or acetylated) and suggests different abundance as a function of the carbon sources. This work is a promising starting point for further investigations on the biological role of lysine succinylation in P. aeruginosa. 10.1021/acs.jproteome.8b00210