Abstract 280: The Effect of YAP/TAZ on Glycolysis and Mitochondrial Oxidative Phosphorylation in Cardiomyocytes

Abstract

The heart requires a high rate of adenosine triphosphate (ATP) production to maintain healthy cardiac function and viability. Anaerobic glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) are the main metabolic pathways by which ATP is generated in mammalian cells, including cardiomyocytes. Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which are major downstream effectors of the Hippo signaling pathway, play an important role in the regulation of heart size and cellular homeostasis of cardiomyocytes. However, interplay between YAP/TAZ and cardiac energy metabolism has been poorly understood. Here we examined the effect of YAP/TAZ on glycolysis and OXPHOS in isolated neonatal rat ventricular cardiomyocytes (NRVMs). Extracellular acidification rate (ECAR; an index of glycolysis) and oxygen consumption rate (OCR; an index of OXPHOS) of NRVMs transduced with adenoviruses harboring YAP, TAZ, or LacZ (control) for 6 days were assessed by Seahorse XFe96 analyzer. Both YAP and TAZ significantly increased not only the ECAR of basal glycolysis (1.5-fold and 1.3-fold, respectively, p<0.05), glycolytic maximal capacity (1.4-fold and 1.3-fold, respectively, p<0.05), and glycolytic reserve capacity (1.3-fold and 1.2-fold, respectively, P<0.05) (n=12-15) but also basal OCR (1.3-fold and 1.3-fold, respectively, p<0.05) (n=6-10) compared to control LacZ. Quantitative PCR analysis showed that mRNA levels of Pfkm, a key glycolytic enzyme, and subunits of protein complexes I though V in the electron transport chain are significantly increased (1.3-1.9-fold, n=5-6, p<0.05) by both YAP and TAZ compared with control. These results suggest that YAP/TAZ increase ATP production by accelerating glycolysis and OXPHOS in cardiomyocytes.