AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1

Abstract

Adenosine monophosphate (AMP)–activated protein kinase (AMPK) acts as a master regulator of cellular energy homeostasis by directly phosphorylating metabolic enzymes and nutrient transporters and by indirectly promoting the transactivation of nuclear genes involved in mitochondrial biogenesis and function. We explored the mechanism of AMPK-mediated induction of gene expression. We identified AMPK consensus phosphorylation sequences in three proteins involved in nucleosome remodeling: DNA methyltransferase 1 (DNMT1), retinoblastoma binding protein 7 (RBBP7), and histone acetyltransferase 1 (HAT1). DNMT1 mediates DNA methylation that limits transcription factor access to promoters and is inhibited by RBBP7. Acetylation of histones by HAT1 creates a more relaxed chromatin-DNA structure that favors transcription. AMPK-mediated phosphorylation resulted in the activation of HAT1 and inhibition of DNMT1. For DNMT1, this inhibition was both a direct effect of phosphorylation and the result of increased interaction with RBBP7. In human umbilical vein cells, pharmacological AMPK activation or pulsatile shear stress triggered nucleosome remodeling and decreased cytosine methylation, leading to increased expression of nuclear genes encoding factors involved in mitochondrial biogenesis and function, such as peroxisome proliferator–activated receptor gamma coactivator–1α (PGC-1α), transcription factor A (Tfam), and uncoupling proteins 2 and 3 (UCP2 and UCP3). Similar effects were seen in the aortas of mice given pharmacological AMPK activators, and these effects required AMPK2α. These results enhance our understanding of AMPK-mediated mitochondrial gene expression through nucleosome remodeling.

Aerobic training induces differential expression of genes involved in lipid metabolism in skeletal muscle and white adipose tissues

“…Indeed, mice lacking IL-6 present lower activity of AMPK, 28 which regulates cellular energy homeostasis and is involved in mitochondrial biogenesis and function. 29 TNF-α seems to induce the lipolytic process by acting through several intracellular pathways for example, by inhibiting insulin receptor signaling, by counteracting the antilipolytic effect of adenosine on protein G, by reducing Gi-protein content or even by directly inducing the phosphorylation of the protein perilipin and reducing of its expression. 26 As reviewed above, metabolic adaptations promoted by aerobic training involve very complex and integrated mechanisms, which are likely tissue-specific.…”

Dietary Supplementation of Methyl Donor l‐Methionine Alters Epigenetic Modification in Type 2 Diabetes

“…Also, inhibited transmethylation and trans‐sulfuration pathway may also contribute to imbalance the pool of l ‐Met. Our study shows that l ‐Met‐S reversed these by AMPK activation, which inhibits the DNMT1 through phosphorylation of Ser 730 residue of DNMT1 …”

Epigenetic effects of metformin: From molecular mechanisms to clinical implications

“…The effect of AMPK activation on HATs varies, increasing the activity of some HATs and decreasing that of others; thus, metformin may likewise have varying effects. For example, Marin et al reported, using a mouse embryonic fibroblast model, that via AMPK activation, metformin induced HAT1 phosphorylation, increasing its activity. Conversely, in multiple other studies, the phosphorylation of the HATs p300 and the CREB‐binding protein (CBP) by AMPK reduced their activity …”

“…Interestingly, these changes were not apparent in patients receiving metformin plus insulin. These changes in methylation may be a result of reduced DNMT activity; activation of AMPK by metformin has been reported to phosphorylate DNMT1 at Ser730 and, consequently, to inhibit its methyltransferase activity . This was associated with a decrease in promoter methylation of 6 target genes in wild type mouse embryonic fibroblasts, but not in AMPK knockout cells or in cells with a DNMT1 Ser730 > Ala730 substitution.…”

“…The effect of AMPK activation on HATs varies, increasing the activity of some HATs and decreasing that of others; thus, metformin may likewise have varying effects. For example, Marin et al 39 phosphoenolpyruvate carboxykinase 1 (Pck1). Metformin significantly decreased blood glucose levels in wild-type mice but did not in mice with mutant CBP (S436A), suggesting that this mechanism may play a key role in the antidiabetic activity of metformin.…”