Search Results (7)

The progressive decline in functional β-cell mass in Type 2 Diabetes (T2D) is increasingly recognized not as a simple apoptotic loss, but as a complex erosion of cellular identity termed “dedifferentiation.” Central to this phenotypic shift is the metabolo-epigenetic axis, where mitochondria act as the primary sensing hub, transducing nutrient flux into biochemical signals that govern the chromatin landscape. This review synthesizes current evidence on how mitochondrial metabolites—including Acetyl-CoA, α-ketoglutarate, and NAD+—serve as obligatory co-factors for the epigenetic machinery. We explore how chronic metabolic stress triggers a “Systemic epigenetic destabilization,” leading to the loss of lineage-specific markers and the formation of persistent “metabolic scars.” Furthermore, we discuss the clinical implications of these changes, specifically regarding the phenomenon of metabolic memory and the molecular limits of β-cell reversibility. By integrating foundational transcriptional studies with emerging epigenomic data, we propose that targeting the mitochondrial–epigenetic axis offers a strategic window for re-differentiating failing β-cells and restoring glycemic homeostasis. Full article

Endothelial dysfunction is the main initiating factor in atherosclerosis. Through mechanotransduction, shear stress regulates endothelial cell function in both homeostatic and diseased states. Accumulating evidence reveals that epigenetic changes play critical roles in the etiology of cardiovascular diseases, including atherosclerosis. The metabolic regulation of epigenetics has emerged as an important factor in the control of gene expression in diseased states, but to the best of our knowledge, this connection remains largely unexplored in endothelial dysfunction and atherosclerosis. In this review, we (1) summarize how shear stress (or flow) regulates endothelial (dys)function; (2) explore the epigenetic alterations that occur in the endothelium in response to disturbed flow; (3) review endothelial cell metabolism under different shear stress conditions; and (4) suggest mechanisms which may link this altered metabolism to the regulation of the endothelial epigenome by modulations in metabolite availability. We believe that metabolic regulation plays an important role in endothelial epigenetic reprogramming and could pave the way for novel metabolism-based therapeutic strategies. Full article

The blastocyst develops a unique metabolism that facilitates the creation of a specialized microenvironment at the site of implantation characterized by high levels of lactate and reduced pH. While historically perceived as a metabolic waste product, lactate serves as a signaling molecule which facilitates the invasion of surrounding tissues by cancers and promotes blood vessel formation during wound healing. However, the role of lactate in reproduction, particularly at the implantation site, is still being considered. Here, we detail the biological significance of the microenvironment created by the blastocyst at implantation, exploring the origin and significance of blastocyst-derived lactate, its functional role at the implantation site and how understanding this mediator of the maternal–fetal dialogue may help to improve implantation in assisted reproduction. Full article

We present a novel thermodynamic approach to the epigenomics of cancer metabolism. Here, any change in a cancer cell’s membrane electric potential is completely irreversible, and as such, cells must consume metabolites to reverse the potential whenever required to maintain cell activity, a process driven by ion fluxes. Moreover, the link between cell proliferation and the membrane’s electric potential is for the first time analytically proven using a thermodynamic approach, highlighting how its control is related to inflow and outflow of ions; consequently, a close interaction between environment and cell activity emerges. Lastly, we illustrate the concept by evaluating the Fe${}^{2+}$-flux in the presence of carcinogenesis-promoting mutations of the TET1/2/3 gene family. Full article

In the past, reactive nitrogen species (RNS) were supposed to be stress-induced by-products of disturbed metabolism that cause oxidative damage to biomolecules. However, emerging evidence demonstrates a substantial role of RNS as endogenous signals in eukaryotes. In plants, S-nitrosoglutathione (GSNO) is the dominant RNS and serves as the ^•NO donor for S-nitrosation of diverse effector proteins. Remarkably, the endogenous GSNO level is tightly controlled by S-nitrosoglutathione reductase (GSNOR) that irreversibly inactivates the glutathione-bound NO to ammonium. Exogenous feeding of diverse RNS, including GSNO, affected chromatin accessibility and transcription of stress-related genes, but the triggering function of RNS on these regulatory processes remained elusive. Here, we show that GSNO reductase-deficient plants (gsnor1-3) accumulate S-adenosylmethionine (SAM), the principal methyl donor for methylation of DNA and histones. This SAM accumulation triggered a substantial increase in the methylation index (MI = [SAM]/[S-adenosylhomocysteine]), indicating the transmethylation activity and histone methylation status in higher eukaryotes. Indeed, a mass spectrometry-based global histone profiling approach demonstrated a significant global increase in H3K9me2, which was independently verified by immunological detection using a selective antibody. Since H3K9me2-modified regions tightly correlate with methylated DNA regions, we also determined the DNA methylation status of gsnor1-3 plants by whole-genome bisulfite sequencing. DNA methylation in the CG, CHG, and CHH contexts in gsnor1-3 was significantly enhanced compared to the wild type. We propose that GSNOR1 activity affects chromatin accessibility by controlling the transmethylation activity (MI) required for maintaining DNA methylation and the level of the repressive chromatin mark H3K9me2. Full article

Type 1 diabetes (T1D) is an autoimmune condition where the body’s immune cells destroy their insulin-producing pancreatic beta cells leading to dysregulated glycaemia. Individuals with T1D control their blood glucose through exogenous insulin replacement therapy, often using multiple daily injections or pumps. However, failure to accurately mimic intrinsic glucose regulation results in glucose fluctuations and long-term complications impacting key organs such as the heart, kidneys, and/or the eyes. It is well established that genetic and environmental factors contribute to the initiation and progression of T1D, but recent studies show that epigenetic modifications are also important. Here, we discuss key epigenetic modifications associated with T1D pathogenesis and discuss how recent research is finding ways to harness epigenetic mechanisms to prevent, reverse, or manage T1D. Full article

The biguanide metformin is the first drug to be tested as a gerotherapeutic in the clinical trial TAME (Targeting Aging with Metformin). The current consensus is that metformin exerts indirect pleiotropy on core metabolic hallmarks of aging, such as the insulin/insulin-like growth factor 1 and AMP-activated protein kinase/mammalian Target Of Rapamycin signaling pathways, downstream of its primary inhibitory effect on mitochondrial respiratory complex I. Alternatively, but not mutually exclusive, metformin can exert regulatory effects on components of the biologic machinery of aging itself such as chromatin-modifying enzymes. An integrative metabolo-epigenetic outlook supports a new model whereby metformin operates as a guardian of cell identity, capable of retarding cellular aging by preventing the loss of the information-theoretic nature of the epigenome. The ultimate anti-aging mechanism of metformin might involve the global preservation of the epigenome architecture, thereby ensuring cell fate commitment and phenotypic outcomes despite the challenging effects of aging noise. Metformin might therefore inspire the development of new gerotherapeutics capable of preserving the epigenome architecture for cell identity. Such gerotherapeutics should replicate the ability of metformin to halt the erosion of the epigenetic landscape, mitigate the loss of cell fate commitment, delay stochastic/environmental DNA methylation drifts, and alleviate cellular senescence. Yet, it remains a challenge to confirm if regulatory changes in higher-order genomic organizers can connect the capacity of metformin to dynamically regulate the three-dimensional nature of epigenetic landscapes with the 4th dimension, the aging time. Full article