Metabolic signaling and energetic environment in the nucleus is critical for cell division and initiation of tissue regeneration after injury. However energy supply routes to nuclear ATP-dependent processes and metabolic signaling circuits that govern cardiomyocyte cell cycle are unknown. Our studies demonstrate that adenylate kinase (AK)-phosphotransfer (2ADP<->ATP+AMP) plays a major role in metabolic signaling and transmission of high-energy phosphoryls from mitochondria to the nucleus to support nuclear transport. Preliminary studies using genetic and siRNA approaches indicate that the AK isoform network is critical for metabolic reprogram- ming facilitating stem cell cardiac differentiation. W have discovered that during cell cycle cytosolic AK1 trans- locates to the nucleus and associates with mitotic spindles to provide energy for cell division. However, AK1 translocation to the nucleus doesn't occur in mitotically arrested adult cardiomyocytes. Furthermore, we have discovered that deficiency of the AK2 isoform, which is localized in mitochondria, arrests stem cell develop- mental programming and is embryonically lethal. Using 18O-labeling technology we demonstrate that heart re-generative capacity depends on AK2 expression and dynamics of AMP-signaling through AK-AMP-AMPK axis which is a part of p53/p21/cyclin metabolic checkpoint regulating G1/S cell cycle transition. This highlights the significance of AK isoform and AMP-signaling network in regulating nuclear energetics and cell cycle. However molecular mechanisms of AK translocation to the nucleus and association with mitotic spindle and cytokinesis apparatus and the significance of AK and AMP-signaling in energy support of cell cycle, cardiomyocyte renewal and heart regeneration are unknown. Objective/Hypothesis: Based on new discoveries we will test hypothesis that nuclear translocation of AK isoforms and AMP-signaling is critical for the energetics of the cardiomyocyte cell cycle, and that AK-AMP-AMPK signaling axis is a key part of G1/S metabolic checkpoint licensing cardiomyocyte renewal and heart regeneration.
The Specific Aims will determine:
Aim #1 The significance of the AK isoforms in cardiomyocyte nuclear energetics and energy support of cell cycle machinery and AMP-signaling dependent metabolic checkpoint regulating heart regenerative potential.
Aim #2 Molecular mechanisms of cell cycle dependent translocation of AK isoforms to the cell nucleus and association with mitotic spindles and cytokinesis machinery and the role in integration of mitochondrial and nuclear energetic processes.
Aim #3 Mechanisms regulating AK isoform expression, cytosolic-nuclear distribution and AMP signaling by metabolic and growth factors in order to promote nuclear energetics and metabolic checkpoint facilitating stem cell cardiac differentiation and adult cardiomyocyte cell cycle required for heart regeneration. The expected outcome and the novelty of this application will be in defining for the first time molecular mechanisms governing nuclear energetics and AMP-signaling circuits during cell cycle and cell differentiation critical for cardiogenesis, heart renewal and regeneration.

Public Health Relevance

Heart regeneration after injury is an emerging critical area in cardiovascular biology and medicine. Successful repair of injured heart requires stimulation of cardiomyocyte regeneration which is one of the most urgent problems in cardiovascular biology and medicine. This innovative study will discover molecular mechanisms and establish rationale and foundation for the development methods for targeted regulation of nuclear energetic and AMP-metabolic signaling circuits to facilitate cardiac differentiation and heart regeneration which would have critical impact for regenerative medicine. Specifically, we will develop approaches for targeting AK isoforms to the nucleus and for regulation of AK expression and AMP-signaling by metabolic and growth factors to promote energetics and re-entry of adult cardiomyocytes into cell cycle. PUBLIC HEALTH RELEVANCE: Heart regeneration after injury is an emerging critical area in cardiovascular biology and medicine. This application will define for the first time molecular mechanisms governing energetics and metabolic signaling circuits in cell nucleus during cell division cycle critical in stem cell cardiogenesis, heart renewal and regeneration. This innovative study will discover molecular mechanisms and establish approaches for targeting adenylate kinase(AK) isoforms to the cell nucleus and for regulation of AK expression and AMP-signaling by metabolic and growth factors to promote energetics and re-entry of adult cardiomyocytes into cell cycle. This project is a part of Mayo Clinic Regenerative Medicine program where we apply our developed system bioenergetics approach and advance imaging and stable isotope based phosphometabolomic technologies to determine the significance of phosphotransfer and metabolic signaling circuits and energy transfer pathways to the cell nucleus to activate cardiomyocyte cell cycle and facilitate heart regeneration.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Adhikari, Bishow B
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Mayo Clinic, Rochester
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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
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
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
Mangalam, Ak; Poisson, Lm; Nemutlu, E et al. (2013) Profile of Circulatory Metabolites in a Relapsing-remitting Animal Model of Multiple Sclerosis using Global Metabolomics. J Clin Cell Immunol 4:
Nemutlu, Emirhan; Zhang, Song; Juranic, Nenad O et al. (2012) 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases. Croat Med J 53:529-34
Trushina, Eugenia; Nemutlu, Emirhan; Zhang, Song et al. (2012) Defects in mitochondrial dynamics and metabolomic signatures of evolving energetic stress in mouse models of familial Alzheimer's disease. PLoS One 7:e32737
Folmes, Clifford D L; Nelson, Timothy J; Dzeja, Petras P et al. (2012) Energy metabolism plasticity enables stemness programs. Ann N Y Acad Sci 1254:82-9
Alekseev, Alexey E; Reyes, Santiago; Selivanov, Vitaly A et al. (2012) Compartmentation of membrane processes and nucleotide dynamics in diffusion-restricted cardiac cell microenvironment. J Mol Cell Cardiol 52:401-9
Nemutlu, Emirhan; Juranic, Nenad; Zhang, Song et al. (2012) Electron spray ionization mass spectrometry and 2D 31P NMR for monitoring 18O/16O isotope exchange and turnover rates of metabolic oligophosphates. Anal Bioanal Chem 403:697-706

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