Cyclophilin D, Regulator of Mitochondrial Permeability Transition and Bioenergetics, Promotes Adipogenic Differentiation of Mesenchymal Stem Cells

TL;DR

This study shows that Cyclophilin D (CypD) influences the fat-forming ability of bone marrow stem cells, impacting bone loss and fat accumulation during aging.

Contribution

The study reveals a novel role of CypD in regulating mitochondrial metabolism and adipogenesis in mesenchymal stem cells.

Findings

CypD loss-of-function impairs BMSC adipogenesis, while gain-of-function enhances it.

CypD regulates metabolic reprogramming during adipogenesis, affecting glycolysis and OXPHOS.

CypD's role is linked to age-related bone loss and marrow fat accumulation.

Abstract

During aging, bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSCs) 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) at least in part 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 and MPTP, activate glycolysis and inhibit OXPHOS. To further study the role of CypD in BMSC bioenergetics, adipogenesis and bone marrow fat accumulation, we used CypD loss-of-function (LOF) or gain-of-function (GOF) models in osteo-adipoprogenitors in vitro and in vivo. We found that CypD LOF and GOF are associated with impaired and enhanced BMSC adipogenesis, respectively, both in vitro and in ectopic bone grafts in vivo. In addition, bioenergetic profiling and metabolomic analyses show evidence of corresponding metabolic reprogramming in CypD LOF and GOF cells. In summary, our study demonstrates the role of CypD-regulated mitochondrial metabolism during BMSC adipogenesis, facilitating the understanding of stem cell fate determination and the molecular mechanism of age-related bone loss as well as bone marrow fat accumulation.

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