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. Zhang et al report that iron accumulation disrupts bone formation by upregulating FTMT, which inhibits PINK1-mediated mitophagy in bone marrow mesenchymal stem cells. This study identifies mitophagy activation as a promising therapeutic strategy for iron-related osteoporosis. 1. Clinical Correlation: BMSCs from iron accumulation-induced osteoporosis patients exhibit impaired osteogenic differentiation. 2. Mechanistic Insight: Iron accumulation accelerates BMSCs senescence and suppresses osteogenesis by inhibiting mitophagy in murine models. 3. PINK1 Dependency: Pink1 deletion in BMSCs alone induced bone loss, confirming mitophagy’s pivotal role. 4. Molecular Pathway: Iron upregulates mitochondrial ferritin (FTMT), which binds PINK1 and inhibits its phosphorylation, disrupting mitophagy. This dual mechanism (downregulated expression and impaired function) was partially validated in human samples. 5. Therapeutic Rescue: Pharmacological activation of mitophagy or Pink1 overexpression restored BMSCs osteogenic capacity and mitigated senescence.
Zhang et al. (Wed,) studied this question.