The Mitochondrial Permeability Transition Pore Regulates Bioenergetics and Adipogenic Differentiation of Mesenchymal Stem Cells
Year: 2026
Type: preprint
Abstract: During aging, bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSC) shift their lineage commitment away from osteogenesis and towards adipogenesis, resulting in bone loss and marrow fat accumulation. We previously reported that during osteogenesis, BMSCs activate mitochondrial oxidative phosphorylation (OXPHOS) by downregulating cyclophilin D (CypD) expression and, consequently, mitochondrial permeability transition pore (MPTP) activity. We also reported that in contrast, during adipogenesis, BMSCs upregulate CypD/MPTP, activate glycolysis, and inhibit OXPHOS. To further study the role of CypD/MPTP in BMSC bioenergetics and adipogenesis and bone marrow fat accumulation, we used CypD/MPTP loss-of-function (LOF) or gain-of-function (GOF) models in osteoadipoprogenitors in vitro and in vivo. We found that CypD/MPTP LOF impairs while GOF enhances adipogenesis in vitro and in ectopic bone grafts in vivo. In addition, bioenergetic profiling and metabolomics analyses show evidence of corresponding metabolic reprogramming in CypD/MPTP LOF and GOF cells. In summary, our study demonstrated the role of CypD/MPTP activity during BMSC adipogenesis, facilitating the understanding of stem cell fate determination and molecular mechanism of age-related bone loss as well as bone marrow fat accumulation.
Source: Preprints.org
Authors: Chen Yu, Sarah Catheline, ROMAN ELISEEV
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7125142986
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