Periosteal mitochondria DNA structures drive aging-associated poor skeletal repair

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.