Role of the Mitochondrial Permeability Transition in Bone Metabolism and Aging

ABSTRACT 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 de...

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Published in:Journal of bone and mineral research 2023-04, Vol.38 (4), p.522-540
Main Authors: Sautchuk, Rubens, Yu, Chen, McArthur, Matthew, Massie, Christine, Brookes, Paul S., Porter, George A., Awad, Hani, Eliseev, Roman A.
Format: Article
Language:English
Subjects:
Adaptation
AGING
Animals
Bone matrix
Bone turnover
Bones
Degeneration
DISEASES AND DISORDERS OF/RELATED TO BONE
Energy metabolism
Long bone
Membrane permeability
Metabolism
Mice
MITOCHONDRIA
Mitochondrial Membrane Transport Proteins - genetics
Mitochondrial Membrane Transport Proteins - metabolism
Mitochondrial Permeability Transition Pore
Mitochondrial Transmembrane Permeability-Driven Necrosis
Osteoblastogenesis
OSTEOBLASTS
OSTEOPOROSIS
Oxidative phosphorylation
Oxidative stress
Peptidyl-Prolyl Isomerase F
Permeability
Phosphorylation
Vertebrae
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Summary:ABSTRACT 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. © 2023 American Society for Bone and Mineral Research (ASBMR).
ISSN:0884-0431
1523-4681
DOI:10.1002/jbmr.4787