Abnormal MtROS Production Exacerbates Fat Accumulation and Bone Loss by Suppressing Protein Synthesis

Objectives: Osteoporosis affects nearly 3.5 million individuals each year, and it can complicate implant surgery and restorative procedures in dentistry. Bone-fat imbalance is a critical mechanism underlying osteoporosis (OP), yet the specific causes remain unclear. This study aims to elucidate the relationship between mitochondrial reactive oxygen species (mtROS) and adipose accumulation in osteoporosis.
Methods: Mitochondrial function in osteoporotic conditions was characterized using a combination of Seahorse, transmission electron microscopy (TEM), ELISA, MitoTracker, and MitoSOX probes. Four in vitro cell models were established to enhance mtROS, including Antimycin, the mitochondrial redox cycler MitoPQ, as well as Lonp1-siRNA and Lars2-siRNA treatments. Additionally, two mtROS scavenger models utilizing MitoTEMPO and glutathione (GSH) were developed. SunSET, RT-qPCR, Western blotting, and immunofluorescence were employed to investigate the relationship between mtROS and adipose accumulation in bone marrow mesenchymal stem cells (BMSCs), along with the associated underlying mechanisms. Furthermore, ovariectomized (OVX) mice were treated with the mtROS scavenger MitoTEMPO via intraperitoneal injection to evaluate the rescue effect of mtROS scavenger.
Results: Mitochondrial dysfunction was observed in BMSCs derived from osteoporotic mice. Notably, mtROS, as a significant byproduct of this dysfunction, accumulated alongside lipid buildup in these BMSCs. In vitro cell models demonstrated that increased mtROS levels promoted lipid accumulation, while scavenging mtROS effectively reversed this effect. The primary mechanism identified was that elevated mtROS inhibited cellular protein synthesis, decreased the expression of ribosomal S6 protein, and activated SREBP1 through increased ammonia levels, which in turn promoted cellular lipid accumulation. In vivo experiments indicated that mtROS scavenging therapy significantly improved osteoporosis and reduced lipid accumulation in the bone marrow.
Conclusions: mtROS serves as a driving force in the accumulation of adipose tissue associated with OP. Scavenging mtROS can effectively reverse the progression of OP, representing a promising novel therapeutic approach and target for the treatment of OP.