Epigenetic Control of Mitochondrial Function in the Vasculature

Abstract

The molecular signatures of epigenetic regulation and chromatin architecture are emerging as pivotal regulators of mitochondrial function. Recent studies unveiled a complex intersection among environmental factors, epigenetic signals, and mitochondrial metabolism, ultimately leading to alterations of vascular phenotype and increased cardiovascular risk. Changing environmental conditions over the lifetime induce covalent and post-translational chemical modification of the chromatin template which sensitize the genome to establish new transcriptional programs and, hence, diverse functional states. On the other hand, metabolic alterations occurring in mitochondria affect the availability of substrates for chromatin-modifying enzymes, thus leading to maladaptive epigenetic signatures altering chromatin accessibility and gene transcription. Indeed, several components of the epigenetic machinery require intermediates of cellular metabolism (ATP, AcCoA, NADH, α-ketoglutarate) for enzymatic function. In the present review, we describe the emerging role of epigenetic modifications as fine tuners of gene transcription in mitochondrial dysfunction and vascular disease. Specifically, the following aspects are described in detail: (i) mitochondria and vascular function, (ii) mitochondrial ROS, (iii) epigenetic regulation of mitochondrial function; (iv) the role of mitochondrial metabolites as key effectors for chromatin-modifying enzymes; (v) epigenetic therapies. Understanding epigenetic routes may pave the way for new approaches to develop personalized therapies to prevent mitochondrial insufficiency and its complications.

Metabolic Regulation of Stem Cells and Differentiation: A Forkhead Box O Transcription Factor Perspective

“…Metabolic pathways, cell signaling, and epigenetics reciprocally interact, ensuring a tight regulation of stem cell differentiation (reviewed in Refs. 3,117,180). The complex nature of these regulatory cross talks challenges disclosing the causal/ temporal nature of the changes in metabolism and stem cell states.…”

The vascular epigenome in patients with obesity and type 2 diabetes: opportunities for personalized therapies

“…Noteworthy, such gene-related methylation patterns persisted in patient-derived fibroblasts after prolonged passage in normoglycemic conditions, thus demonstrating the existence of a transcriptional memory driven by hyperglycemia (38). Along the same line, experiments in primary human endothelial cells showed that hyperglycemia reduces DNA methylation at the promoter of the mitochondrial adaptor p66 Shc , a key protein involved in cytochrome c oxidation and accumulation of free radicals (39). Reduced methylation of p66 Shc promoter and increased H3 acetylation -known activating epigenetic marks -were associated with gene upregulation, mitochondrial oxidative stress and impaired availability of nitric oxide, eventually leading to vascular dysfunction.…”

Importance of the Use of Oxidative Stress Biomarkers and Inflammatory Profile in Aqueous and Vitreous Humor in Diabetic Retinopathy

“…ROS generated from mitochondrial oxidative phosphorylation is the most representative source of OS in endothelial cells, which cause peroxidation of PUFAs, protein damage and consequently mitochondrial DNA (mtDNA) damage [239,242,243]. Methylation of mtDNA has recently been associated with the development of diseases and as a potential biomarker.…”

“…As a general methylation biomarker, 5hmc can be seen at rac family small GTPase 1, which leads to increased binding of NF-kB linking this epigenetic modification with inflammation in DR [245]. In the retina, there is a more specific area where methylation is occurring called D-loop where transcription and replication of mtDNA is controlled [243,246] which has been used as a biomarker in a clinical study that showed significantly higher methylation rates in the serum of patients with PDR than patients without DR, these had higher methylation rates than non-diabetic patients [247] functioning as a novel diagnostic tool. Another potential biomarker related with DNA methylation in DR is homocysteine, of which high levels have been associated with increased risk of developing DR in diabetic patients, and with higher global DNA methylation probably linking it to altered metabolic memory phenomenon [248,249].…”