Opa3, a novel regulator of mitochondrial function, controls thermogenesis and abdominal fat mass in a mouse model for Costeff syndrome.

The interrelationship between brown adipose tissue (BAT) and white adipose tissue (WAT) is emerging as an important factor in obesity, but the effect of impairing non-shivering thermogenesis in BAT on lipid storage in WAT remains unclear. To address this, we have characterized the metabolic phenotype of a mouse model for Costeff syndrome, in which a point mutation in the mitochondrial membrane protein Opa3 impairs mitochondrial activity. Opa3(L122P) mice displayed an 80% reduction in insulin-like growth factor 1, postnatal growth retardation and hepatic steatosis.

Specific deficits in visual electrophysiology in a mouse model of dominant optic atrophy.

Autosomal dominant optic atrophy (ADOA) is a slowly progressive optic neuropathy caused by mutations in the OPA1 gene. OPA1 is ubiquitously expressed and plays a key role in mitochondrial fusion. Heterozygous Opa1 mutant mice (B6; C3-Opa1(Q285STOP)), have previously been reported to develop visual defects and optic nerve changes.

Secondary mtDNA defects do not cause optic nerve dysfunction in a mouse model of dominant optic atrophy.

Purpose: The majority of patients with autosomal dominant optic atrophy (DOA) harbor pathogenic OPA1 mutations and certain missense mutations, mostly within the GTPase domain, have recently been shown to cause multiple mitochondrial DNA (mtDNA) deletions in skeletal muscle. This raises the possibility that the optic neuropathy could be the result of secondary mtDNA defects accumulating within retinal ganglion cells (RGCs). To explore this hypothesis, the authors looked for evidence of mitochondrial dysfunction in a mouse model of DOA and documented the visual and neurologic progression in aging mutant mice.

OPA1 deficiency associated with increased autophagy in retinal ganglion cells in a murine model of dominant optic atrophy.

Purpose: To examine retinal ganglion cell (RGC) and axonal abnormalities in an ENU-induced mutant mouse carrying a protein-truncating nonsense mutation in OPA1. Mutations in the OPA1 gene cause autosomal dominant optic atrophy (ADOA) in which loss of RGCs followed by myelin degeneration in the optic nerve leads to progressive decrease in visual acuity.

Methods: Ultrastructure of the optic nerve was examined in heterozygous mutants and wild-type littermate controls at 6, 9, and 24 months using electron microscopy.

A missense mutation in the murine Opa3 gene models human Costeff syndrome.

Opa3 mRNA is expressed in all tissues examined to date, but currently the function of the OPA3 protein is unknown. Intriguingly, various mutations in the OPA3 gene lead to two similar diseases in humans: autosomal dominant inherited optic atrophy and cataract (ADOAC) and a metabolic condition; type 3-methylglutaconic aciduria (MGA). Early onset bilateral optic atrophy is a common characteristic of both disorders; retinal ganglion cells are lost and visual acuity is impaired from an early age.

Impaired processing of local geometric features during navigation in a water maze following hippocampal lesions in rats.

Hippocampal damage impairs navigation with respect to information provided by the shape of an arena. Recent evidence has suggested that normal rats use local geometric information, as opposed to a global geometric representation, to navigate to a correct corner. One implication of this pattern of results is that hippocampal lesions may impair processing of 1 or more of the local geometric features of an environment.

Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function.

OPA1 is a ubiquitously expressed, nuclear dynamin-related GTPase, targeted to the inner mitochondrial membrane, which plays a role in mitochondrial fusion. Mutations in the OPA1 gene on chromosome 3q28-qter are associated with autosomal dominant optic atrophy (ADOA), the most common inherited optic neuropathy, in which retinal ganglion cells (RGCs) are lost and visual acuity is impaired from an early age. We have generated a novel ENU-induced mutant mouse carrying a protein-truncating nonsense mutation in opa1 in order to explore the pathophysiology of ADOA.