Mitochondria replenishment enhances senescent periodontal ligament stem cell osteogenesis and facilitates bone repair
image: Schematic diagram illustrating how transplanted young mitochondria activate the AKAP1/cAMP/PKA pathway in aged PDLSCs, restoring mitochondrial membrane potential (ΔΨm), reducing ROS, and enhancing bone formation.
Credit: Nano Research, Tsinghua University Press
With global population aging, repairing bone defects has become increasingly challenging. Periodontal ligament stem cells (PDLSCs) are ideal seed cells for bone regeneration due to their multipotent differentiation capacity. However, their functionality declines with age. Mitochondria, the cellular energy hubs, regulate metabolic pathways, redox balance, and cell fate. Age-related mitochondrial dysfunction—marked by damaged mtDNA, reduced membrane potential (ΔΨm), and elevated reactive oxygen species (ROS)—compromises ATP production and antioxidant defenses, impairing tissue repair. Inspired by natural mitochondrial transfer between cells during injury, mitochondrial replenishment therapy has emerged as a novel strategy to restore cellular function by delivering healthy mitochondria to aged or damaged cells.
The research team systematically revealed that mitochondrial dysfunction is the core cause of osteogenic decline in aged PDLSCs. Micro-CT and immunohistochemical analyses showed significant bone loss and reduced osteogenic markers (OCN, RUNX2) in aged mice. Transmission electron microscopy (TEM) revealed swollen mitochondria with disorganized cristae in aged PDLSCs, accompanied by elevated ROS and diminished ΔΨm.
By transplanting mitochondria from young PDLSCs into aged cells, the team successfully restored mitochondrial function, reduced ROS levels, and upregulated osteogenic gene/protein expression. Mechanistic studies identified that mitochondrial replenishment activates the AKAP1/cAMP/PKA pathway, stabilizing mitochondrial homeostasis. In rat cranial defect models, aged PDLSCs with transplanted functional mitochondria nearly doubled new bone volume (BV/TV) compared to controls, achieving regeneration levels close to young cells.
“Our study is the first to demonstrate that mitochondrial replenishment can reverse age-related osteogenic decline in PDLSCs by restoring mitochondrial dynamics and signaling,” said Prof. Shiqiang Gong, co-corresponding author and associated professor at Huazhong University of Science and Technology. “This approach not only addresses bone regeneration but also opens avenues for treating other aging-associated diseases.”
This breakthrough highlights mitochondrial replenishment as a viable strategy to rejuvenate aged stem cells, offering clinical potential for bone defect repair in elderly patients. The discovery of the AKAP1/cAMP/PKA pathway’s role provides a mechanistic foundation for future therapies targeting mitochondrial dysfunction.
Other contributors include Xiangyao Wang, Yuxiao Zhang, Yuanyuan Li, Kehan Zhang, Lin Pan, Ahsawle Ozathaley, Yaxin Wu, Qilin Li from the Huazhong University of Science and Technology and Min Yu, Yan Liu from the Peking University.
This work was financially supported by the Hubei Natural Science Foundation JCZRYB202500274 (S.Q.G.), the National Natural Science Foundations of China 82230030 (Y.L.), National Key Research and Development Program of China 2024YFA1210400 (Y.L.), Beijing Natural Science Foundation L234017 (Y.L.), Key R & D Plan of Ningxia Hui Autonomous Region 2020BCG01001 (Y.L.), First-Class Discipline Team of Kunming Medical University 2024XKTDTS08 (Y.L.), Innovative Research Team of High-level Local Universities in Shanghai SHSMU-ZLCX20212402(Y.L.).
About the Authors
Dr. Jing Mao is currently a professor at the Center of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Her research is centered on dental materials and the application of oral-derived stem cells in tissue regeneration. She has published over 80 academic papers in prestigious journals such as Journal of Dental Research, Acta Biomaterialia, and Stem Cells Translational Medicine, including 2 highly cited papers and 1 paper recognized as the most influential international academic paper in China.
Dr. Shiqiang Gong is an associate professor at the Center of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. His research interests include dental materials and mitochondrial-targeting strategies for tissue remodeling and regeneration. As the first or corresponding author, he has published over 20 SCI-indexed papers in high-impact journals such as Journal of Controlled Release, Nano Research, Acta Biomaterialia, and Chinese Chemical Letters.
Dr. Yan Liu is Boya Distinguished Professor at Peking University and Distinguished Professor of Changjiang Scholars Program, Ministry of Education of China. Her research focuses on basic and translational research on treatment of maxillofacial deformities and regeneration of defective tissues. As the first or corresponding author, she has published over 90 SCI-indexed papers in high-impact journals including Nature Commun, Adv Mater, JACS, Adv Funct Mater.
Dr. Gaoshaer Nuerlan received her D.D.S. degree from Huazhong University of Science and Technology (2022). Currently, she is a postgraduate student at Center of Stomatology, Tongji Medical College, Huazhong University of Science and Technology. Her research focuses on the mechanism and application of mitochondrial transfer in age-relate bone diseases.
About Nano Research
Nano Research is a peer-reviewed, open access, international and interdisciplinary research journal, sponsored by Tsinghua University and the Chinese Chemical Society, published by Tsinghua University Press on the platform SciOpen. It publishes original high-quality research and significant review articles on all aspects of nanoscience and nanotechnology, ranging from basic aspects of the science of nanoscale materials to practical applications of such materials. After 18 years of development, it has become one of the most influential academic journals in the nano field. Nano Research has published more than 1,000 papers every year from 2022, with its cumulative count surpassing 7,000 articles. In 2024 InCites Journal Citation Reports, its 2024 IF is 9.0 (8.7, 5 years), and it continues to be the Q1 area among the four subject classifications. Nano Research Award, established by Nano Research together with TUP and Springer Nature in 2013, and Nano Research Young Innovators (NR45) Awards, established by Nano Research in 2018, have become international academic awards with global influence.