Periosteal mitochondria DNA structures drive aging-associated poor skeletal repair
Yanlin Wu1,2, Chuyi Han1, Xue Yang1,2
1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Abstract:
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.
Insights
Aging bone repair is hindered by mitochondrial G-quadruplexes (mtG4) accumulating in stem cells, causing senescence and dysfunction. This discovery offers new targets for senolytic therapies to improve skeletal repair in elders.
Area of Science:
- Gerontology
- Molecular Biology
- Regenerative Medicine
Background:
- Aging is associated with impaired skeletal repair, posing a significant global health challenge.
- Current understanding of the mechanisms behind age-related bone repair deficits remains limited.
Purpose of the Study:
- To investigate the role of mitochondrial DNA structures, specifically mitochondrial G-quadruplexes (mtG4), in aging-associated poor bone repair.
- To elucidate the cellular and molecular mechanisms by which mtG4 impacts periosteal mesenchymal stromal/stem cells (PPM).
Main Methods:
- Utilized transgenic lineage tracking, PPM organoid formation, and mitochondrial transgenic mutation models.
- Conducted organoid transplantation and serial cellular molecular investigations.
- Analyzed the spatiotemporal accumulation of mtG4 in PPM during aging.
Main Results:
- mtG4 accumulates in PPM during both healthy and premature aging, increasing cellular senescence and degenerative alterations.
- mtG4 restricts vital mitochondrial gene transcription, leading to mitochondrial dysfunction, mitophagy, and cell senescence in PPM.
- Senescent PPM exhibit impaired stemness and disrupted fate determination, mimicking age-related bone repair failure.
Conclusions:
- mtG4 in PPM is a key driver of aging-associated poor bone repair by inducing mitochondrial dysfunction and senescence.
- This study decodes the mitochondrial genomic basis for impaired bone healing in aging.
- Findings provide insights for developing targeted senolytic therapies for age-related skeletal conditions.
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