Abstract 392: Metabolic Signaling Mechanisms Governing Heart Regenerative Capacity
Energy metabolism and metabolic signaling circuits orchestrate cell commitment to self-renewal, lineage specification, differentiation and regeneration. When energy resources are plenty, cell can grow, proliferate and regenerate, however when energy is low - augmented adenylate kinase (AK)-mediated AMP signaling turns on AMPK which silences p53/p21/cyclin cell cycle metabolic checkpoint and halts cell division. Using mouse neonatal hearts, with high and low regenerative capacity, we have determined metabolomic profiles and dynamics of phosphotransfer circuits using 18O-phosphoryl labeling mass-spectrometric and 18O-assisted 31P NMR techniques. We demonstrate that loss of heart regenerative capacity after birth is associated with marked changes in heart AK-catalyzed phosphotransfer flux and AMP signaling along with changes in expression levels of p21, cyclin A and E and thymidine kinase. It appears, that in adult heart increased expression of AK isoforms (AK1, AK2 and AK1β) and augmented high energy phosphoryl and AMP signal dynamics is misread by AMPK-sensor as "low energy" state inducing blockade of cell cycle metabolic checkpoint and cardiomyocyte proliferation and renewal. Using AK-GFP constructs and immunocytochemistry we further demonstrate the distribution of AK1, AK1β, AK2 and AMPK between cytosol and nucleus and association with mitotic spindle and cytokinetic apparatus during cell division cycle. AK1 translocation to the nucleus, however, doesn’t occur in adult cardiomyocytes deficient in cytokinesis. Protein knockdown using siRNA indicates that AK2 is critical for cardiomyocyte mitochondrial biogenesis and network formation. Furthermore, we have discovered that deficiency of the AK2 isoform, which is localized in mitochondria intermembrane-intra-cristae space, arrests developmental programming and is embryonically lethal in mice. The uncovered shift in metabolic signaling mechanisms opens new avenues for targeted regulation of heart regenerative potential critical for repair of injured hearts.
Author Disclosures: S. Zhang: None. P. Dzeja: None.
- © 2015 by American Heart Association, Inc.