Abstract
Metabolic signaling mechanisms of tissue regeneration is still an enigma. Energy state and metabolite signals regulate cell commitment to self-renewal, lineage specification, differentiation and regeneration. In a favorable metabolic environment, cells can grow and proliferate, however when energy is low - metabolic monitoring system sends signals to cell cycle checkpoint to halt cell division and preserve fuel resources. We demonstrate that loss of heart regenerative capacity after birth in mice is associated with marked changes in metabolome, AK-catalyzed phosphotransfer flux (β-ATP[ 18 O]), ATP turnover (γ-ATP[ 18 O]) and AMP-AMPK signaling along with changes in expression levels of p21, cyclins A and E, pGSK3β and thymidine kinase. Marked reduction of thymidine phosphorylation capacity prevents DNA synthesis and cell proliferation. It emerges, that in adult heart augmented ATP turnover and AMP signal dynamics is misread by AMPK-sensor as "low energy" state inducing blockade of cell cycle metabolic checkpoint and cardiomyocyte proliferation and regeneration after injury. This occurs through augmented adenylate kinase (AK)-mediated AMP signaling which turns on AMPK consequently silencing p53/p21/cyclin cell cycle checkpoint. Changes in expression levels AK1, AK1β, AK2 and AK5 isoforms occur with arrest of heart regeneration. Protein knockdown using siRNA and CRISPR/Cas9 approach 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.
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