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by both leptin and fructose, convey to the brain false “low energy” signals forcing it
to increase food consumption (Dzeja and Terzic 2009 ). The uncovered AMP
metabolic flux-sensing mechanism opens new avenues for targeted regulation of
the heart regenerative potential, which is critical for repair of injured hearts. We are
developing approaches to regulate AMP signaling and increase AK1 entry into the
nucleus of adult cardiomyocytes to facilitate nuclear energetics, reentry into cell
cycle, proliferative potential, and regeneration (Dzeja et al. 2011a ; Rubart and Field
2006 ; Walsh et al. 2010 ).
Accordingly, nuclear translocation of AK1, and in some cases AK2, upon
association with mitotic spindle and cytokinesis apparatus provides local ATP
regenerating capacity (~P) necessary for energy-dependent mitosis and cytokinesis.
AMPK plays a critical role in phosphorylating (
P) and orchestrating cell cycle
components (Dzeja et al. 2011a ). At the same time, AK-AMP-AMPK signaling
axis controls the p53/p21/cyclin metabolic cell cycle checkpoint (Mandal
et al. 2010 ). In adult heart, high energy metabolism, AMP signaling dynamics,
and relatively high AMPK activity might be interpreted as conditions unfavorable
for undergoing mitosis. p53 also regulates membrane-associated AK1
expression
which can provide local signals to membrane-associated AMPK and exert addi-
tional control on the G1/S transition (Collavin et al. 1999 ). LKB1 is an important
regulator of AMPK and downstream metabolic checkpoint events associated with
cell proliferation (Gurumurthy et al. 2010 ; Nakada et al. 2010 ). Moreover, the
AK-AMP-AMPK axis controls GSK3
β
β
which inhibits cell cycle progression;
conversely inhibition of GSK3
restarts cardiomyocyte cell cycle (Campa
et al. 2008 ; Woulfe et al. 2010 ). Defects in AK1 nuclear translocation and
AMP/LKB1/AMPK signaling could result in polyploidy and insufficient energy,
and signaling to cytokinesis machinery could lead to multinucleation (Jansen
et al. 2009 ; Liu et al. 2010 ; Nakada et al. 2010 ; Walsh et al. 2010 ). Another
phosphotransfer enzyme thymidine kinase, the activity of which is critical for
dTTP production and DNA replication, is downregulated in adult cardiomyocytes
limiting regenerative potential (Gillette and Claycomb 1974 ). Thus, energy supply
to nuclear processes is an emerging field in cellular physiology with the potential to
advance our understanding of metabolic requirements and energetic costs of
executing cell division cycle and developmental and regenerative programming.
In summary, accumulating evidence suggests a fundamental role for adenylate
kinase and phosphotransfer enzymes in general in cellular energetics and metabolic
signaling processes. Their importance is highlighted by the wide range of metabolic
rearrangements and compensations in energy and metabolic networks induced by
genetic deficiencies (Dzeja et al. 2011b ; Janssen et al. 2000 ), while uncompensated
deficiency (AK2) is embryonically lethal (Fujisawa et al. 2009 ; Zhang et al. 2010b ).
β
Acknowledgments This work was supported by National Institutes of Health, Marriott Heart
Disease Research Program, Marriott Foundation, and Mayo Clinic. We thank Mayo Graduate
School student Jennifer Shing for reading and editing the manuscript.
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