Periosteal mitochondria DNA structures drive aging-associated poor skeletal repair

Insufficient skeletal repair is the primary threat of health span and lifespan in elders with increasingly vast global burden; yet, to date, the knowledge of resolving this crisis remains limited. In this study, we addressed the specific mechanisms underlying aging-associated poor bone repair, which are driven by the mitochondrial DNA structures mitochondrial G-quadruplex (mtG4). We found that mtG4 is spatiotemporal-wisely accumulated within Pdgfra⁺ periosteal mesenchymal stromal/stem cells (PPM) both in healthy and premature aging, which substantially increases cellular senescence and the degenerative alterations of PPM. By utilizing transgenic lineage tracking, PPM organoids formation, mitochondrial transgenic mutation, organoids transplantation, and serial cellular molecular investigations, we reveal that mtG4 in PPM restricts vital mitochondrial genes' transcription to cause mitochondrial dysfunction, which utterly leads to severe mitophagy and cell senescence. These senescent PPM demonstrates impaired stemness and disrupted fate determination, finally phenocopying aging-associated poor bone repair. This study decodes the mitochondrial genomic reasons for insufficient bone repair during aging, which offers insights for developing cell-type- and disease-specific senolytic therapies in the future.