Adenylate Kinase and AMP Signaling Networks: Metabolic Monitoring, Signal Communication and Body Energy Sensing

Dzeja, Petras P.; Terzic, André

doi:10.3390/ijms10041729

Cited by 366 publications

(329 citation statements)

References 269 publications

(631 reference statements)

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“…Under these conditions, mitochondrial ATP extruded in the cytosol allows AK to transform AMP into ADP that can be readily converted into extra ATP in the mitochondria. In keeping with this interpretation, silencing of the main cellular AK isoforms AK1 and AK2 (27,30) prevents the increase of ATP content above basal levels in Glu Ϫ cells undergoing PARP-1 activation (Fig. 3G).…”

Section: Discussionsupporting

confidence: 70%

“…Key enzymes converting AMP back to ADP are AKs (27) that catalyze the AMPϩATP7ADPϩADP reaction in a forward or reverse direction based on the relative concentrations of the nucleotides. AKs are key enzymes involved in intracellular AMP signaling and metabolic regulation (27). We speculated, therefore, that AK activity prevents AMP increase in Glu Ϫ cells given their maintained ATP content during PARP-1 hyperactivation.…”

Section: Effect Of Glucose On Adp and Amp Content During Parp-1mentioning

confidence: 99%

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Glucose Deprivation Converts Poly(ADP-ribose) Polymerase-1 Hyperactivation into a Transient Energy-producing Process

Buonvicino

Formentini

Cipriani

et al. 2013

Journal of Biological Chemistry

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Background: Excessive activation of enzyme poly(ADP-ribose) polymerase-1 (PARP-1) causes ATP depletion and kills cells. Results: We found that in the absence of glucose PARP-1 triggers an adenylate kinase-dependent increase of ATP. Conclusion: PARP-1 hyperactivation is not invariantly related to ATP loss. Significance: This study adds to the complexity of PARP-1 hyperactivity and energy derangement.Massive poly(ADP-ribose) formation by poly(ADP-ribose) polymerase-1 (PARP-1) triggers NAD depletion and cell death. These events have been invariantly related to cellular energy failure due to ATP shortage. The latter occurs because of both ATP consumption for NAD resynthesis and impairment of mitochondrial ATP formation caused by an increase of the AMP/ADP ratio. ATP depletion is therefore thought to be an inevitable consequence of NAD loss and a hallmark of PARP-1 activation. Here, we challenge this scenario by showing that PARP-1 hyperactivation in cells cultured in the absence of glucose (Glu ؊ cells) is followed by NAD depletion and an unexpected PARP-1 activity-dependent ATP increase. We found increased ADP content in resting Glu ؊ cells, a condition that counteracts the increase of the AMP/ADP ratio during hyperpoly(ADP-ribosyl)ation and preserves mitochondrial coupling. We also show that the increase of ATP in Glu ؊ cells is due to adenylate kinase activity, transforming AMP into ADP which, in turn, is converted into ATP by coupled mitochondria. Interestingly, PARP-1-dependent mitochondrial release of apoptosisinducing factor (AIF) and cytochrome complex (Cyt c) is reduced in Glu ؊ cells, even though cell death eventually occurs.Overall, the present study identifies basal ADP content and adenylate kinase as key determinants of bioenergetics during PARP-1 hyperactivation and unequivocally demonstrates that ATP loss is not metabolically related to NAD depletion.Poly(ADP-ribosyl)ation is a post-translational modification of proteins operated by poly(ADP-ribose) polymerases (PARPs) 2 (1). PARP-1, the oldest and best characterized member of the PARP family, is a nuclear enzyme converting NAD into polymers of poly(ADP-ribose) (PAR) that regulate chromatin-interacting proteins through steric hindrance and electrostatic repulsion (2). By so doing, the enzyme plays a key role in various nuclear process involved in maintenance of nuclear homeostasis such as DNA repair and epigenetic regulation of gene expression (3-5). Somehow paradoxically, besides this pleiotypic physiological role, PARP-1 is a powerful trigger of cell death (6, 7). This occurs when the enzymes undergo hyperactivation because of extensive DNA damage. PARP-1-dependent cell death was originally described as a necrotic process (8, 9), but an involvement of PARP-1 in apoptosis (10) and autophagy (11) has also been reported. In keeping with the central role of the enzyme in cell demise, chemical inhibitors of PARP-1 exert widespread cytoprotection in disparate in vitro and in vivo disease models (12). It has been proposed that intracellular NAD depletion a...

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Section: Discussionsupporting

confidence: 70%

Section: Effect Of Glucose On Adp and Amp Content During Parp-1mentioning

confidence: 99%

Glucose Deprivation Converts Poly(ADP-ribose) Polymerase-1 Hyperactivation into a Transient Energy-producing Process

Buonvicino

Formentini

Cipriani

et al. 2013

Journal of Biological Chemistry

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“…In intact cells AMP is a strong metabolic signal that regulates cellular energy production through several signaling pathways including AMP kinase (reviewed in Ref. 31). Therefore, intracellular dialysis of large concentrations of AMP likely causes drastic changes in cellular metabolism that are expected to be cell type-specific.…”

Section: Discussionmentioning

confidence: 99%

Identification of Direct and Indirect Effectors of the Transient Receptor Potential Melastatin 2 (TRPM2) Cation Channel

Tóth

Csanády

2010

Journal of Biological Chemistry

109

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Transient receptor potential melastatin 2 (TRPM2) is a Ca2؉ -permeable cation channel involved in physiological and pathophysiological processes linked to oxidative stress. TRPM2 channels are co-activated by intracellular Ca 2؉ and ADP-ribose (ADPR) but also modulated in intact cells by several additional factors. Superfusion of TRPM2-expressing cells with H 2 O 2 or intracellular dialysis of cyclic ADPR (cADPR) or nicotinic acid adenine dinucleotide phosphate (NAADP) activates, whereas dialysis of AMP inhibits, TRPM2 whole-cell currents. Additionally, H 2 O 2 , cADPR, and NAADP enhance ADPR sensitivity of TRPM2 currents in intact cells. Because in whole-cell recordings the entire cellular machinery for nucleotide and Ca 2؉homeostasis is intact, modulators might affect TRPM2 activity either directly, by binding to TRPM2, or indirectly, by altering the local concentrations of the primary ligands ADPR and Ca 2؉ . To identify direct modulators of TRPM2, we have studied the effects of H 2 O 2 , AMP, cADPR, NAADP, and nicotinic acid adenine dinucleotide in inside-out patches from Xenopus oocytes expressing human TRPM2, by directly exposing the cytosolic faces of the patches to these compounds. H 2 O 2 (1 mM) and enzymatically purified cADPR (10 M) failed to activate, whereas AMP (200 M) failed to inhibit TRPM2 currents. NAADP was a partial agonist (maximal efficacy, ϳ50%), and nicotinic acid adenine dinucleotide was a full agonist, but both had very low affinities (K 0.5 ‫؍‬ 104 and 35 M). H 2 O 2 , cADPR, and NAADP did not enhance activation by ADPR. Considering intracellular concentrations of these compounds, none of them are likely to directly affect the TRPM2 channel protein in a physiological context. TRPM22 is a member of the transient receptor potential family of proteins and forms a nonselective cation channel that is permeable to Ca 2ϩ (1). TRPM2 channels are abundantly expressed in the brain, in hematopoietic tissues, and in leukocytes (1-4) and activate under conditions of oxidative stress to cause elevations in intracellular [Ca 2ϩ ] ([Ca 2ϩ ] i ) that contribute to chemotactic responses (5) and chemokine production (6) of immune cells, as well as to neuronal cell death following ischemia (4,7,8).The primary activators of TRPM2 are ADP-ribose (ADPR) and Ca 2ϩ (2-4); simultaneous binding of both agonists is required for channel opening (9). TRPM2 channels are homotetramers (10), and ADPR binds to the NUDT9-H domains located at the cytosolic C termini of the subunits, named based on sequence homology to the mitochondrial enzyme NUDT9 (2). Both NUDT9 and isolated NUDT9-H bind ADPR and convert it to AMP and ribose-5-phosphate (2, 11), but the role in TRPM2 channel gating of the very slow ADPR hydrolase (ADPRase) activity of NUDT9-H is unknown. In intact cells ADPR activates TRPM2 only in the presence of either intra-or extracellular Ca 2ϩ (4, 12, 13); biophysical studies in inside-out patches have shown that the activatory Ca 2ϩ -binding sites are located intracellularly of the gate, such that extracellular...

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“…6B). In addition, we studied the expression level of transcripts of Ak1 (Adenylate kinase 1) that is involved in the inter-conversion of adenine nucleotides and plays an important role in cellular energy homeostasis [27]. We found that Ak1 mRNA was reduced by approximately 50% in HD hearts (Fig.…”

Section: Transcriptional Remodeling Of Genes Involved In the Synthesimentioning

confidence: 97%

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Toczek

Zielonka

Zukowska

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Huntington's disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed an increased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentially involve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be caused locally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation. Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plus an inhibition of resynthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscle dysfunction in both pre-clinical and clinical HD settings.Keywords: Huntington's disease, cardiomyopathy, arrhythmia, energy imbalance, catabolism of nucleotides, heart failure 3 SUMMARY Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related cardiomyopathy has been widely described in different mouse models, however there is little known about the source of the pathological remodelling in HD hearts. We found that contractile dysfunction in HD settings might be caused by components of cellular energy imbalance, changes in catabolism of adenine nucleotides, steady-state internal redox derangements and an activation of AMPK, leading to a shift in the cardiac substrate preference. These changes were accompanied by increased concentrations of adenine nucleotide catabolites (inosine, hypoxanthine, xanthine and uric acid) and uridine in both HD mouse models and HD patients' plasma. These metabolites represent the first identified biomarkers related to striated muscle dysfunction in HD. Our study explores a mechanism that might lead to HD-related cardiomyopathy and opens new avenues for therapeutic treatments in HD. HIGHLIGHTS• Heart dysfunction in HD is caused by the altered metabolism of nucleotides in vivo • Altered energy imbalances may lead to heart malfunction in HD in vivo• Increased lev...

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Adenylate Kinase and AMP Signaling Networks: Metabolic Monitoring, Signal Communication and Body Energy Sensing

Cited by 366 publications

References 269 publications

Glucose Deprivation Converts Poly(ADP-ribose) Polymerase-1 Hyperactivation into a Transient Energy-producing Process

Glucose Deprivation Converts Poly(ADP-ribose) Polymerase-1 Hyperactivation into a Transient Energy-producing Process

Identification of Direct and Indirect Effectors of the Transient Receptor Potential Melastatin 2 (TRPM2) Cation Channel

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

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