Adenylate kinase(AK)-catalyzed energetic and AMP metabolic signaling (AK->AMP->AMP-sensors) is increasingly recognized among major stress-response elements in cardiac cells, critical in regulating diverse cellular processes. At present, however, molecular and cellular mechanisms regulating AK-catalyzed phosphotransfer, the main AMP signal generator, AK interactions with AMP-metabolic sensors and intracellular AMP signal dynamics, are largely unknown. We have obtained evidence that AK phosphotransfer communicates energetic signals from mitochondria to myofibrils, the nucleus and the plasma membrane, securing efficient energy supply and metabolic sensing. The central hypothesis of this proposal is that dynamics of AK phosphotransfer and AMP signal generation, regulated by functional, hormonal and metabolic state, promotes efficient cellular energetics and, by association with AMP-sensing modules, integrates AMP signal transduction into adaptive response to metabolic stress. This hypothesis is supported by preliminary data that indicate: 1) AK phosphotransfer flux and AMP metabolic pool size are regulated by the cell's functional and hormonal states and respond rapidly to metabolic stress; 2) AK1 associates/co-localizes with metabolic sensor AMP-activated protein kinase (AMPK); 3) AK1 deficiency is associated with defective AMP signaling and stress response. Based on this in Aim #1 we propose to define the cellular regulatory mechanisms coupling AK-catalyzed phosphotransfer, AMP signal dynamics and metabolic sensors response;
In Aim #2, we will determine mechanisms and the significance of AK co- localization and molecular/functional interactions with AMPK in metabolic signaling. Finally, in Aim #3, we will determine the significance of the AK->AMP->AMP-sensors system in transducting metabolic signals triggering cardioprotective response. The proposed aims will be addressed using wilde type and transgenic AK1-deficient animals. AK phosphotransfer flux and AMP turnover will be quantified using 180-assisted 31P NMR and mass spectrometric techniques. Molecular, proteomic and imaging techniques will be employed to define AK intracellular interactions and new AMP signaling targets. As a long-term objective, this proposal will establish cellular and molecular mechanisms that regulate AK phosphotransfer and associated AMP signaling circuits sustaining efficient and stress tolerant myocardial energetics. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085744-02
Application #
7502607
Study Section
Special Emphasis Panel (ZRG1-CVS-P (02))
Program Officer
Adhikari, Bishow B
Project Start
2007-09-30
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$377,500
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Wang, Feilong; Zhang, Song; Vuckovic, Ivan et al. (2018) Glycolytic Stimulation Is Not a Requirement for M2 Macrophage Differentiation. Cell Metab 28:463-475.e4
Wang, Feilong; Zhang, Song; Jeon, Ryounghoon et al. (2018) Interferon Gamma Induces Reversible Metabolic Reprogramming of M1 Macrophages to Sustain Cell Viability and Pro-Inflammatory Activity. EBioMedicine 30:303-316
Luthra, Gauri; Vuckovic, Ivan; Bangdiwala, A et al. (2018) First and second trimester urinary metabolic profiles and fetal growth restriction: an exploratory nested case-control study within the infant development and environment study. BMC Pregnancy Childbirth 18:48
Kazak, Lawrence; Chouchani, Edward T; Lu, Gina Z et al. (2017) Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity. Cell Metab 26:660-671.e3
Kazak, Lawrence; Chouchani, Edward T; Lu, Gina Z et al. (2017) Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity. Cell Metab 26:693
Xu, Yi-Zhou; Chen, Chao-Feng; Chen, Bin et al. (2016) The Modulating Effects of Cardiac Resynchronization Therapy on Myocardial Metabolism in Heart Failure. Pacing Clin Electrophysiol 39:1404-1409
Guzun, R; Kaambre, T; Bagur, R et al. (2015) Modular organization of cardiac energy metabolism: energy conversion, transfer and feedback regulation. Acta Physiol (Oxf) 213:84-106
Nemutlu, Emirhan; Gupta, Anu; Zhang, Song et al. (2015) Decline of Phosphotransfer and Substrate Supply Metabolic Circuits Hinders ATP Cycling in Aging Myocardium. PLoS One 10:e0136556
Zhang, Liang; Zhang, Song; Maezawa, Izumi et al. (2015) Modulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer's Disease. EBioMedicine 2:294-305
Nemutlu, Emirhan; Zhang, Song; Xu, Yi-Zhou et al. (2015) Cardiac resynchronization therapy induces adaptive metabolic transitions in the metabolomic profile of heart failure. J Card Fail 21:460-9

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