Role of the Mitochondrial Permeability Transition in Bone Metabolism and Aging

The mitochondrial permeability transition pore (MPTP) and its positive regulator, cyclophilin D (CypD), play important pathophysiological roles in aging. In bone tissue, higher CypD expression and pore activity are found in aging; however, a causal relationship between CypD/MPTP and bone degeneration needs to be established. We previously reported that CypD expression and MPTP activity are downregulated during osteoblast (OB) differentiation and that manipulations in CypD expression affect OB differentiation and function. Using a newly developed OB-specific CypD/MPTP gain-of-function (GOF) mouse model, we here present evidence that overexpression of a constitutively active K166Q mutant of CypD (caCypD) impairs OB energy metabolism and function, and bone morphological and biomechanical parameters. Specifically, in a spatial-dependent and sex-dependent manner, OB-specific CypD GOF led to a decrease in oxidative phosphorylation (OxPhos) levels, higher oxidative stress, and general metabolic adaptations coincident with the decreased bone organic matrix content in long bones. Interestingly, accelerated bone degeneration was present in vertebral bones regardless of sex. Overall, our work confirms CypD/MPTP overactivation as an important pathophysiological mechanism leading to bone degeneration and fragility in aging. (c) 2023 American Society for Bone and Mineral Research (ASBMR).

Automated summary

CypD/MPTP overactivation plays an important role in bone aging, and overexpression of CypD impairs bone cell energy metabolism and function. Spatial-dependent and sex-dependent studies found that CypD GOF leads to a decrease in oxidative phosphorylation levels, increased oxidative stress, and decreased bone organic matrix content, ultimately resulting in bone aging. This study confirms the important pathological mechanism of CypD/MPTP overactivation in bone aging and osteoporosis.