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

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Science Signaling  31 Jan 2017:
Vol. 10, Issue 464, eaaf7478
DOI: 10.1126/scisignal.aaf7478

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Epigenetic control of mitochondria

When cellular energy is low, cells activate the kinase AMPK, which promotes mitochondrial biogenesis and function. Marin et al. found that AMPK phosphorylated three proteins involved in nucleosome remodeling: the DNA methyltransferase DNMT1, the histone acetyltransferase HAT1, and RBBP7, which inhibits DNMT1 and is a HAT1 coactivator. AMPK-mediated phosphorylation of these proteins triggered nucleosome remodeling that favored the transcription of nuclear-encoded genes involved in mitochondrial biogenesis and function in human cultured endothelial cells and mouse aortas. These results show that AMPK coordinates mitochondrial function with energy status through epigenetic regulation of nuclear gene expression.


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.

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