https://www.medicinalgenomics.com/wp-content/uploads/2013/01/Resveratrol-rescues-mito-function-through-sirtuin-and-PGC-1.pdf

Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha.

Metabolic control through the PGC-1 family of transcription coactivators.

Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability. Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMP-activated protein kinase (AMPK) complex. Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to reprogramme cellular metabolism from anabolism to catabolism. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targets of AMPK are involved in various aspects of mitochondrial homeostasis, including mitophagy. This Review discusses how AMPK functions as a central mediator of the cellular response to energetic stress and mitochondrial insults and coordinates multiple features of autophagy and mitochondrial biology.

/pdf/ampk-guardian-of-metabolism-and-mitochondrial-homeostasis-2xckib51mn.pdf

AMPK: guardian of metabolism and mitochondrial homeostasis.

Mitochondria contain their own genetic system and undergo a unique mode of cytoplasmic inheritance. Each organelle has multiple copies of a covalently closed circular DNA genome (mtDNA). The entire...

http://www.biomol.it/unictbiolmol-lab/figure_didattica/R09.PhysRev88.611.pdf

Transcriptional Paradigms in Mammalian Mitochondrial Biogenesis and Function

Transcriptional complexes that contain peroxisome-proliferator-activated receptor coactivator (PGC)-1alpha control mitochondrial oxidative function to maintain energy homeostasis in response to nutrient and hormonal signals. An important component in the energy and nutrient pathways is mammalian target of rapamycin (mTOR), a kinase that regulates cell growth, size and survival. However, it is unknown whether and how mTOR controls mitochondrial oxidative activities. Here we show that mTOR is necessary for the maintenance of mitochondrial oxidative function. In skeletal muscle tissues and cells, the mTOR inhibitor rapamycin decreased the gene expression of the mitochondrial transcriptional regulators PGC-1alpha, oestrogen-related receptor alpha and nuclear respiratory factors, resulting in a decrease in mitochondrial gene expression and oxygen consumption. Using computational genomics, we identified the transcription factor yin-yang 1 (YY1) as a common target of mTOR and PGC-1alpha. Knockdown of YY1 caused a significant decrease in mitochondrial gene expression and in respiration, and YY1 was required for rapamycin-dependent repression of those genes. Moreover, mTOR and raptor interacted with YY1, and inhibition of mTOR resulted in a failure of YY1 to interact with and be coactivated by PGC-1alpha. We have therefore identified a mechanism by which a nutrient sensor (mTOR) balances energy metabolism by means of the transcriptional control of mitochondrial oxidative function. These results have important implications for our understanding of how these pathways might be altered in metabolic diseases and cancer.

mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex

Estrogen-related receptor α (ERRα) is one of the first orphan nuclear receptors to be identified, yet its physiological functions are still unclear. We show here that ERRα is an effector of the transcriptional coactivator PGC-1α [peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α], and that it regulates the expression of genes involved in oxidative phosphorylation and mitochondrial biogenesis. Inhibition of ERRα compromises the ability of PGC-1α to induce the expression of genes encoding mitochondrial proteins and to increase mitochondrial DNA content. A constitutively active form of ERRα is sufficient to elicit both responses. ERRα binding sites are present in the transcriptional control regions of ERRα/PGC-1α-induced genes and contribute to the transcriptional response to PGC-1α. The ERRα-regulated genes described here have been reported to be expressed at reduced levels in humans that are insulin-resistant. Thus, changes in ERRα activity could be linked to pathological changes in metabolic disease, such as diabetes.

https://www.pnas.org/content/pnas/101/17/6472.full.pdf

The estrogen-related receptor α (ERRα) functions in PPARγ coactivator 1α (PGC-1α)-induced mitochondrial biogenesis

Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), a tissue-specific and inducible transcriptional coactivator for several nuclear receptors, plays a key role in energy metabolism. We report here that PGC-1alpha coactivator activity is potentiated by arginine methylation by protein arginine methyltransferase 1 (PRMT1), another nuclear receptor coactivator. Mutation of three substrate arginines in the C-terminal region of PGC-1alpha abolished the cooperative coactivator function of PGC-1alpha and PRMT1, and compromised the ability of PGC-1alpha to induce endogenous target genes. Finally, endogenous PRMT1 contributes to PGC-1alpha coactivator activity, and to the induction of genes important for mitochondrial biogenesis.

/pdf/activation-of-nuclear-receptor-coactivator-pgc-1a-by-4fso116gvf.pdf

Roger Emter

Papers

The estrogen-related receptor α (ERRα) functions in PPARγ coactivator 1α (PGC-1α)-induced mitochondrial biogenesis

Activation of nuclear receptor coactivator PGC-1α by arginine methylation