FTMT-mediated suppression of mitophagy links iron accumulation to osteoporosis.

Primary osteoporosis is a major age-related disease with a significant global health burden. While iron accumulation is a known risk factor, the mechanisms linking it to bone loss remain unclear. Here, we report that impaired mitophagy in bone marrow mesenchymal stem cells (BMSCs) is a hallmark of osteoporosis and is critically exacerbated by iron accumulation. We found that iron accumulation in BMSCs inhibits mitophagy, leading to mitochondrial dysfunction, increased oxidative stress, and cellular senescence, ultimately impairing osteogenic differentiation. Importantly, targeted activation of mitophagy, either pharmacologically or genetically, restored mitochondrial health, reduced senescence, and rescued bone formation. Conversely, Pink1 deficiency in BMSCs was sufficient to induce osteoporosis. Mechanistically, we identified that the mitochondrial ferritin FTMT is upregulated under iron-loading conditions and binds to PINK1, suppressing its phosphorylation and thereby preventing mitophagy initiation. This pathway is clinically relevant, as BMSCs from osteoporotic patients with high ferritin levels showed elevated FTMT and reduced PINK1 phosphorylation. Therefore, we identify a novel pathway in which FTMT-mediated disruption of mitophagy drives iron-induced osteoporosis. Our findings highlight mitophagy activation as a therapeutic strategy to prevent and treat bone loss under iron accumulation.