Disrupted mitochondrial function in the Opa3^L122Pmouse model for Costeff Syndrome impairs skeletal integrity

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.

Unacylated ghrelin promotes adipogenesis in rodent bone marrow via ghrelin O-acyl transferase and GHS-R1a activity: evidence for target cell-induced acylation

“…Our data indicate that the balance between bone forming and fat storing cells in the marrow is likely to be nutritionally regulated, and that AG and UAG may defend marrow fat from utilisation during starvation 40 . However, it is also becoming clear that the relationship between marrow adipocytes and bone integrity in different bone types is not uniform 41 .…”

Optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy caused by a de novo OPA3 mutation

“…Whether she has true lipodystrophy (abnormal growth and/or loss of adipose tissue due to a primary, intrinsic defect of the tissue) as opposed to lipoatrophy (loss of adipose tissue secondary to hypermetabolism) could not be established with certainty, though her relatively high metabolic rate suggests the possibility of the former. Mouse models with a homozygous mutation in Opa3 showed a 60% reduction in body weight and profound intra-abdominal leanness, suggesting that the patient's loss of adipose tissue may be caused by her OPA3 mutation (Davies et al 2008; Wells et al 2012; Navein et al 2016). The atypical set of phenotypes observed in this case expands the phenotypic spectrum of autosomal dominant mutations in OPA3 and identifies a de novo mutation, which we believe to be pathogenic for these phenotypes.…”

Thermoneutrality improves skeletal impairment in adult Prader–Willi syndrome mice

“…These forces promote the remodelling of the bone to enhance diameter and weightbearing capacity (David et al, 2007;Luu et al, 2009). Although muscle mass was not quantified in the current study, muscle hypoplasia in the Magel2 del mouse model for PWS/Schaaf-Yang syndrome (SYS) (Kamaludin et al, 2016), indicates that this could represent a possible transduction mechanism. Secondly, such profound reductions in abdominal fat mass are likely to cause a dramatic reduction in circulating leptin.…”

“…For example, there is a bi-directional relationship between fat and bone (Leiben et al, 2009), with bone marrow adipocytes and the bone-forming osteoblasts arising from the same mesenchymal stem cells (MSCs) (Beresford et al, 1992, Di Iorgi et al, 2008 and osteogenesis being influenced by leptin (Thomas et al, 1999, Hamrick et al, 2005, Evans et al, 2011. Although several studies have examined the effects of the loss of specific PWS interval regions/genes on bone (Khor et al, 2016, Kamaludin et al, 2016, Baraghithy et al, 2019, a study of the impact of losing all of the genes in the PWS locus is lacking. We have therefore conducted a study of the growth, morphology, microarchitecture and biomechanical properties of the appendicular bones of PWS-IC del mice and characterised the underlying endocrine phenotype.…”