Disrupted mitochondrial function in the Opa3L122P mouse model for Costeff Syndrome impairs skeletal integrity.
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 Opa3L122Pmouse 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. Opa3L122Pmice displayed craniofacial abnormalities, including undergrowth of the lower mandible, accompanied in some individuals by cranial asymmetry and incisor malocclusion. Opa3L122Pmice 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 Opa3L122Pmice 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.
School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
Alice E
AE
Navein
School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
Esther J
EJ
Cooke
School of Optometry and Vision Sciences, Cardiff University, Cardiff CF24 4LU, UK.
Jennifer R
JR
Davies
School of Optometry and Vision Sciences, Cardiff University, Cardiff CF24 4LU, UK.
Terence G
TG
Smith
School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.|Caerleon Comprehensive School, Caerleon, Newport NP18 1NF, UK.
Lois H M
LH
Wells
Department of Craniofacial Development and Stem Cell Biology, King's College London, Guy's Hospital, London SE1 9RT, UK.
Atsushi
A
Ohazama
Department of Craniofacial Development and Stem Cell Biology, King's College London, Guy's Hospital, London SE1 9RT, UK.
Christopher
C
Healy
Department of Craniofacial Development and Stem Cell Biology, King's College London, Guy's Hospital, London SE1 9RT, UK.
Paul T
PT
Sharpe
School of Engineering, Cardiff University, The Parade, Cardiff CF24 3AA, UK.
Sam L
SL
Evans
Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
Bronwen A J
BA
Evans
School of Optometry and Vision Sciences, Cardiff University, Cardiff CF24 4LU, UK.|Cardiff Eye Unit, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK.
Marcela
M
Votruba
School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK wellst@cardiff.ac.uk.
Timothy
T
Wells
D000818:Animals; D001846:Bone Development / Q000235:genetics*; D001921:Brain / Q000254:growth & development / Q000503:physiopathology; D002819:Chorea / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D006257:Head / Q000254:growth & development / Q000503:physiopathology; D006801:Humans; D008334:Mandible / Q000254:growth & development / Q000503:physiopathology; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D009896:Optic Atrophy / Q000235:genetics* / Q000503:physiopathology; D011506:Proteins / Q000235:genetics*; D012160:Retina / Q000254:growth & development / Q000503:physiopathology; D012863:Skeleton / Q000254:growth & development / Q000503:physiopathology; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000503:physiopathology; D014070:Tooth / Q000254:growth & development / Q000503:physiopathology
C528268:Opa3 protein, mouse; D011506:Proteins