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Disrupted mitochondrial function in the Opa3L122P mouse model for Costeff Syndrome impairs skeletal integrity

Navein, Alice E., Cooke, Esther J., Davies, Jennifer R., Smith, Terence G., Wells, Lois H. M., Ohazama, Atsushi, Healy, Christopher, Sharpe, Paul T., Evans, Samuel Lewin, Evans, Bronwen Alice James, Votruba, Marcela and Wells, Timothy 2016. Disrupted mitochondrial function in the Opa3L122P mouse model for Costeff Syndrome impairs skeletal integrity. Human Molecular Genetics 25 (12) , pp. 2404-2416. 10.1093/hmg/ddw107

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Abstract

Mitochondrial dysfunction connects metabolic disturbance with numerous pathologies, but the significance of mitochondrial activity in bone remains unclear. We have, therefore, characterized the skeletal phenotype in the Opa3L122P mouse model for Costeff syndrome, in which a missense mutation of the mitochondrial membrane protein, Opa3, impairs mitochondrial activity resulting in visual and metabolic dysfunction. Although widely expressed in the developing normal mouse head, Opa3 expression was restricted after E14.5 to the retina, brain, teeth, and mandibular bone. Opa3 was also expressed in adult tibiae, including at the trabecular surfaces and in cortical osteocytes, epiphyseal chondrocytes, marrow adipocytes and mesenchymal stem cell rosettes. Opa3L122P mice displayed craniofacial abnormalities, including undergrowth of the lower mandible, accompanied in some individuals by cranial asymmetry and incisor malocclusion. Opa3L122P mice showed an 8-fold elevation in tibial marrow adiposity, due largely to increased adipogenesis. In addition, femoral length and cortical diameter and wall thickness were reduced, the weakening of the calcified tissue and the geometric component of strength reducing overall cortical strength in Opa3L122P mice by 65%. In lumbar vertebrae reduced vertebral body area and wall thickness were accompanied by a proportionate reduction in marrow adiposity. Although the total biomechanical strength of lumbar vertebrae was reduced by 35%, the strength of the calcified tissue (σmax) was proportionate to a 38% increase in trabecular number. Thus, mitochondrial function is important for the development and maintenance of skeletal integrity, impaired bone growth and strength, particularly in limb bones, representing a significant new feature of the Costeff syndrome phenotype.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Biosciences
Engineering
Medicine
Optometry and Vision Sciences
Publisher: Oxford University Press
ISSN: 0964-6906
Date of First Compliant Deposit: 26 April 2016
Date of Acceptance: 31 March 2016
Last Modified: 26 Nov 2017 03:26
URI: http://orca.cf.ac.uk/id/eprint/90071

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