ATF5-mediated mitochondrial UPR inhibited RANKL in Porphyromonas gingivalis LPS-treated osteoblasts

The purpose of this study was to investigate whether mitochondrial unfolded protein response (UPR^mt) was induced in Porphyromonas gingivalis-lipopolysaccharide (P. gingivalis-LPS)-treated osteoblasts and to study the relationship among UPR^mt, mitochondrial function and bone resorption in periodontitis.

Osteoblasts were treated with P.gingivalis-LPS. Nicotinamide riboside (NR) and doxycycline (DOX) were used to enhance UPR^mt, while small interference RNA was transfected to knock down activating transcription factor 5 (ATF5). Protein and mRNA levels of genes involved in UPR^mt and bone metabolism were measured. Intracellular reactive oxygen species (ROS), mitochondrial ROS and mitochondrial membrane potential were detected by flow cytometry and confocal imaging.

UPR^mt and receptor activator of NF-κB ligand (RANKL) expression were induced in P. gingivalis-LPS-treated osteoblasts. Enhancement of UPR^mt by NR or DOX decreased RANKL and RANKL/osteoprotegerin (OPG) ratio in osteoblasts. UPR^mt inhibition by ATF5 knockdown aggravated mitochondrial dysfunction and promoted RANKL expression in P.gingivalis-LPS-treated osteoblasts.

ATF5-mediated UPR^mt regulates RANKL expression through mtROS and mitochondrial membrane potential. UPR^mt could be a potential target involved in the regulation of bone resorption in periodontitis.