YAP regulates the hypertrophy and apoptosis of antler chondrocytes through maintaining calcium homeostasis and mitochondrial function

Abstract

YAP is required for chondrogenesis and endochondral bone formation, but its effect on the hypertrophy and apoptosis of antler chondrocytes remains unclear. The present study revealed that YAP was abundantly expressed in antler chondrocytes. Inactivation of YAP restrained the hypertrophy of antler chondrocytes and facilitated chondrocyte apoptosis. Further analysis indicated that blockage of YAP induced the accumulation of cytosolic Ca²⁺ by enhancing the stability of IP3R1/2 mRNA dependent on YTHDF2, that had been identified as a direct downstream target of YAP/TEAD. Meanwhile, attenuation of YAP activated the cytosolic Ca²⁺-mediated PPP3R1/NFATC pathway and then brought about the elevation of mitochondrial Ca²⁺ via NFATC-targeted MCU. In antler chondrocytes, inactivation of YAP disrupted the mitochondrial morphology, diminished the ATP content and lowered the mitochondrial membrane potential, but these effects were neutralized by the blockage of MCU. Moreover, inhibition of YAP promoted the leakage of mtROS from dysfunctional mitochondria into the cytosol through opening the mitochondrial permeability transition pore, resulting in intracellular ROS accumulation and lipid peroxidation. Addition of ROS scavenger rescued the defective differentiation of antler chondrocytes and protected chondrocytes against apoptosis under the context of YAP inactivation. Collectively, YAP regulated the hypertrophy and apoptosis of antler chondrocytes through maintaining Ca²⁺ homeostasis and mitochondrial function.