Reduced Histone Expression or a Defect in Chromatin Assembly Induces Respiration

Galdieri, Luciano; Zhang, Tiantian; Rogerson, Daniella; Vančura, Aleš

doi:10.1128/mcb.00770-15

Cited by 27 publications

(35 citation statements)

References 84 publications

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“…Denatured proteins were separated on 10 or 12% denaturing polyacrylamide gels. Western blotting was performed as described previously (82). Western blots were quantified using NIH ImageJ software (W. siRNA Transfections-Human AMPK␣1/2 (sc-45312), ACCA (sc-40312), LKB1 (sc-35816), and non-silencing (sc-37007) siRNAs were obtained from Santa Cruz Biotechnology.…”

Section: Methodsmentioning

confidence: 99%

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells

Galdieri¹,

Gatla

Vancurova

et al. 2016

Journal of Biological Chemistry

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Edited by Alex TokerAMP-activated protein kinase (AMPK) is an energy sensor and master regulator of metabolism. AMPK functions as a fuel gauge monitoring systemic and cellular energy status. Activation of AMPK occurs when the intracellular AMP/ATP ratio increases and leads to a metabolic switch from anabolism to catabolism. AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC), which catalyzes carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting reaction in de novo synthesis of fatty acids. AMPK thus regulates homeostasis of acetylCoA, a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription. Nucleocytosolic concentration of acetyl-CoA affects histone acetylation and links metabolism and chromatin structure. Here we show that activation of AMPK with the widely used antidiabetic drug metformin or with the AMP mimetic 5-aminoimidazole-4-carboxamide ribonucleotide increases the inhibitory phosphorylation of ACC and decreases the conversion of acetyl-CoA to malonyl-CoA, leading to increased protein acetylation and altered gene expression in prostate and ovarian cancer cells. Direct inhibition of ACC with allosteric inhibitor 5-(tetradecyloxy)-2-furoic acid also increases acetylation of histones and non-histone proteins. Because AMPK activation requires liver kinase B1, metformin does not induce protein acetylation in liver kinase B1-deficient cells. Together, our data indicate that AMPK regulates the availability of nucleocytosolic acetyl-CoA for protein acetylation and that AMPK activators, such as metformin, have the capacity to increase protein acetylation and alter patterns of gene expression, further expanding the plethora of metformin's physiological effects.Acetylation is one of the epigenetic post-translational modifications of histones; it affects chromatin structure and regulates diverse cellular functions, such as gene expression, DNA replication and repair, and cellular proliferation (1, 2). Acetylation and deacetylation of chromatin histones, mediated by histone acetyltransferases (HATs) 3 and histone deacetylases (HDACs), respectively, represent the major mechanisms for epigenetic gene regulation. The dynamic balance between histone acetylation and deacetylation, mediated by the activities of HATs and HDACs, is stringently regulated in healthy cells but is often dysregulated in cancer (3, 4).Histone acetylation depends on intermediary metabolism for supplying acetyl-CoA in the nucleocytosolic compartment (5). In mammalian cells, the nucleocytosolic enzyme ATP-citrate lyase is the major source of acetyl-CoA for histone acetylation (6). Another mechanism for generation of acetyl-CoA in the nucleus involves translocation of pyruvate dehydrogenase from mitochondria to the nucleus (7). In yeast, global histone acetylation depends on nucleocytosolic acetyl-CoA produced by acetyl-CoA synthetase (5). In both yeast and mammalian cells, the nucleocytosolic acetyl-CoA is the link among cellular energy, carbon metabolism, histone acetylation, ...

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Section: Methodsmentioning

confidence: 99%

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells

Galdieri¹,

Gatla

Vancurova

et al. 2016

Journal of Biological Chemistry

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“…Our previous work has shown that altered chromatin structure in S. cerevisiae induces transcription of HAP4 and respiration (36). On the basis of nucleosomal chromatin architecture, yeast genes can be classified into two broad groups: growth genes and stress genes (37).…”

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confidence: 99%

“…The respiratory genes in S. cerevisiae belong to the stress gene category unlike respiratory genes in higher eukaryotes (38,39). Altered chromatin structure in S. cerevisiae makes promotors of respiratory genes more accessible to transcription factors and allows increased expression of respiratory genes and transition from fermentation to respiration (36). The increased transcription of respiratory genes and induction of respiration require a product of mitochondrial carbon metabolism (36).…”

mentioning

confidence: 99%

Increased heme synthesis in yeast induces a metabolic switch from fermentation to respiration even under conditions of glucose repression

Zhang

Zeng

et al. 2017

Journal of Biological Chemistry

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Regulation of mitochondrial biogenesis and respiration is a complex process that involves several signaling pathways and transcription factors as well as communication between the nuclear and mitochondrial genomes. Under aerobic conditions, the budding yeast metabolizes glucose predominantly by glycolysis and fermentation. We have recently shown that altered chromatin structure in yeast induces respiration by a mechanism that requires transport and metabolism of pyruvate in mitochondria. However, how pyruvate controls the transcriptional responses underlying the metabolic switch from fermentation to respiration is unknown. Here, we report that this pyruvate effect involves heme. We found that heme induces transcription of, the transcriptional activation subunit of the Hap2/3/4/5p complex, required for growth on nonfermentable carbon sources, in a Hap1p- and Hap2/3/4/5p-dependent manner. Increasing cellular heme levels by inactivating , which encodes a repressor of many hypoxic genes, or by overexpressing or induced respiration and elevated ATP levels. Increased heme synthesis, even under conditions of glucose repression, activated Hap1p and the Hap2/3/4/5p complex and induced transcription of and genes required for the tricarboxylic acid (TCA) cycle, electron transport chain, and oxidative phosphorylation, leading to a switch from fermentation to respiration. Conversely, inhibiting metabolic flux into the TCA cycle reduced cellular heme levels and transcription. Together, our results indicate that the glucose-mediated repression of respiration in budding yeast is at least partly due to the low cellular heme level.

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“…Mitochondrial biosynthesis up-regulates both mitochondrial respiratory chain enzymes and mitochondrial antioxidant factors (such as Mn-SOD and GSH-Px) (30,31). Mitochondrial biosynthesis depends on the expression of mitochondrial genome (mtDNA) and nuclear genome (nDNA), and mtDNA is the main target of ROS-mediated damage (32). PGC-1α plays a central role in the regulation of mitochondrial production.…”

Section: Discussionmentioning

confidence: 99%

Tongmai Yangxin Pills Improves Cardiac Function by Enhancing the Expression of SIRT3 and PGC-1α in a Rat Model of Isoproterenol-Induced Cardiomyopathy

Zhu

Chen

et al. 2020

Preprint

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Background: Mitochondrial biosynthesis regulated by the PGC-1α-NRF1-TFAM pathway is closely related to mitochondrial function and mitochondrial reactive oxygen generation, and is considered to be a new possible therapeutic target for the treatment of heart failure.Methods: Tongmai Yangxin Pills (TMYXP) is a Chinese patent medicine for the treatment of ischemic heart disease. It has the ability to scavenge oxygen free radicals and improve the antioxidant capacity of the heart muscle, thereby protecting cardiomyocytes, however, its mechanism is not well established. In this study, to investigate the mechanisms of TMYXP in cardiac protection, a rat model of cardiomyopathy was established by continuous isoproterenol (ISO) stimulation. Changes in the rat body weight, heart weight index (HWI), echocardiography, histological staining and biochemical indicators were examined.Results: Our results suggested that TMYXP reduced myocardial remodeling, inhibited deterioration of cardiac function, and delayed HF onset in rats with ISO-induced cardiomyopathy. Meanwhile, TMYXP markedly reduced ROS production, increased the levels of antioxidant enzymes, improved function of the mitochondrial respiratory chain, and promoted ATP production in myocardial tissues. In addition, TMYXP inhibited cytochrome C (Cyt C) release in mitochondria and caspase-3 activation in cytosol, thereby reducing the apoptosis of myocardial cells. Finally, TMYXP remarkably up-regulated the mRNA and protein expression levels of SIRT3, PGC-1α, NRF1 and TFAM in myocardial cells.Conclusions: Taken together, our results suggest that TMYXP regulates mitochondrial biosynthesis mediated enhancing the expression of SIRT3 and PGC-1α, thereby improving the cardiac function in rats with ISO-induced cardiomyopathy.

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Reduced Histone Expression or a Defect in Chromatin Assembly Induces Respiration

Cited by 27 publications

References 84 publications

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells

Increased heme synthesis in yeast induces a metabolic switch from fermentation to respiration even under conditions of glucose repression

Tongmai Yangxin Pills Improves Cardiac Function by Enhancing the Expression of SIRT3 and PGC-1α in a Rat Model of Isoproterenol-Induced Cardiomyopathy

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