Rescuing mitochondrial dysfunction in macrophages prevents osteonecrosis of the jaw in anti-resorptive therapy

Here, we demonstrate that zoledronic acid (ZA) impairs mitochondrial bioenergetic function in macrophages, resulting in elevated mitochondrial membrane potential, accumulated mitochondrial reactive oxygen species, and increased expression of HIF-1α, which subsequently promotes a pro-inflammatory transition in macrophages.

Importantly, ZA inhibits autophagy-initiating complex via activation of the TLR4-MyD88/PI3K-AKT-mTOR pathway, thereby impeding clearance of dysfunctional mitochondria to sustain superoxide production.