Adenylate Kinase Isoform Network: A Major Hub in Cell Energetics and Metabolic Signaling - Systems Biology of Metabolic and Signaling Networks - page 147

and AMP metabolic signaling is associated with Alzheimer's and Huntington
neurodegenerative disorders (Park et al. 2012 ; Seong et al. 2005 ) and the patho-
physiological process of temporal lobe epilepsy (Peng et al. 2012 ). The level of
AK4 is decreased in Parkinson's disease models in response to Parkin expression
(Narendra et al. 2012 ). Moreover, AK4 was discovered to be a progression-
associated gene in human lung cancer that promotes metastasis (Jan et al. 2012 ).
In this regard, new findings indicate that development of feto-placental unit and
reproductive efficiency of women as well as blood glucose and glycated hemoglo-
bin levels depends on the genetic variability of Ak(1)1 and Ak(1)2 phenotypes
(Fulvia et al. 2011 ; Gloria-Bottini et al. 2011 , 2012 , 2013 ). The therapeutic poten-
tial of modulating adenylate kinase activity is demonstrated by the finding that
decreased expression of AK1 in myocardial infarction is restored by resveratrol
treatment, contributing to increase myocardial energetic efficiency (Lin et al. 2011 ).
Taken together, these new data suggest very fundamental roles of adenylate kinase
isoforms in various human organs to support vital physiological functions, while
dysregulation of adenylate kinase-mediated energetic and metabolic signaling
precipitates disease phenotypes.
6.2 Adenylate Kinase Isoforms in Nuclear and Cell Cycle
Energetics
Many nuclear processes, including DNA replication and cell cycle events such as
mitotic spindle movement, chromosome disjunction, and karyokinesis, also
ATP-dependent chromatin remodeling and gene transcription, as well as initiation
of developmental and regenerative programming, require robust energy supply
(Dzeja and Terzic 2003 , 2007 , 2009 ; Folmes et al. 2011a , b , 2012a ; Morettini
et al. 2008 ; Rosenfeld et al. 2009 ). However, the nucleus is separated from the
cytosolic energetic system, and energy supply routes to nuclear processes, includ-
ing cell cycle and cytokinesis machinery, are largely unknown (Dzeja et al. 2002 ;
Dzeja and Terzic 2007 ). In this regard, cells and nuclei of dividing and regenerating
cells in tissues are enriched in energetic and phosphotransfer enzymes to support
high energy needs of genetic reprogramming and cell division cycle (Dzeja and
Terzic 2009 ; Hand et al. 2009 ; Noda 1973 ; Ottaway and Mowbray 1977 ; Rosenfeld
et al. 2009 ). Cell life and renewal rate of a cell population depend on balance
between cell division, cell cycle arrest, differentiation, and apoptosis (Mandal
et al. 2010 ; Walsh et al. 2010 ). During evolution, cells have developed a conserved
metabolic signaling mechanism controlling cell division, proliferation, and regen-
eration depending on nutrient and energy resources (Collavin et al. 1999 ; Folmes
et al. 2012a , b ; Nakada et al. 2010 ; Romito et al. 2010 ). When energy resources are
plenty, cells can grow, proliferate, and regenerate. When energy is low, metabolic
signaling turns on a cascade which activates cell cycle metabolic checkpoints
preventing cell division (Dzeja and Terzic 2009 ; Gan et al. 2010 ; Mandal