MCU regulating bone remodeling and osteogenic function through mitochondrial calcium homeostasis and oxidative stress alteration.

Mitochondria regulate cellular metabolism, signaling, immunity, and differentiation, affecting various diseases including diabetes, cancer, and osteoporosis. Mitochondrial calcium uniporter (MCU) unidirectionally transports Ca2+ across the inner mitochondrial membrane to the mitochondrial matrix. Ca2+ shuttles continuously through mitochondria and plays an essential role in the regulation of several cellular processes. However, the effects of MCU on bone metabolism-related diseases and the underlying pathophysiologic mechanisms have not been fully elucidated. Here, we found that MCU overexpression led to reduced bone volume fraction, bone trabecular thickness and number in mice in vivo. That was associated with MCU-mediated oxidative stress, overload of mitochondrial calcium, and decrease in mitochondrial membrane potential in osteoblasts. In vitro, MCU activation inhibited osteogenic differentiation capacity of osteoblasts in both early and late stages of osteogenesis. Additionally, MCU opening negatively regulated BMP/Smad signaling through ROS accumulation, thereby inhibiting osteogenic differentiation. Our results provide promising new targets for the future development of osteogenic function regulation and tissue engineering applications.