Journal
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
Volume 58, Issue 2, Pages -Publisher
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.16-21116
Keywords
dominant optic atrophy; optic neuropathy; OPA1; metabolomics; mitochondria
Categories
Funding
- INSERM
- CNRS
- University of Angers
- University Hospital of Angers
- Region Pays de Loire
- Angers Loire Metropole
- Fondation VISIO
- Ouvrir les Yeux
- Union Nationale des Aveugles et Deficients Visuels
- Association contre les Maladies Mitochondriales
- Retina France
- Kjer France
- Fondation Berthe Fouassier
- Fondation pour la Recherche Medicale
- Association Point de Mire
Ask authors/readers for more resources
PURPOSE. Dominant optic atrophy (MIM No. 165500) is a blinding condition related to mutations in OPA1, a gene encoding a large GTPase involved in mitochondrial inner membrane dynamics. Although several mouse models mimicking the disease have been developed, the pathophysiological mechanisms responsible for retinal ganglion cell degeneration remain poorly understood. METHODS. Using a targeted metabolomic approach, we measured the concentrations of 188 metabolites in nine tissues, that is, brain, three types of skeletal muscle, heart, liver, retina, optic nerve, and plasma in symptomatic 11-month-old Opa1(delTTAG/-) mice. RESULTS. Significant metabolic signatures were found only in the optic nerve and plasma of female mice. The optic nerve signature was characterized by altered concentrations of phospholipids, amino acids, acylcarnitines, and carnosine, whereas the plasma signature showed decreased concentrations of amino acids and sarcosine associated with increased concentrations of several phospholipids. In contrast, the investigation of 3-month-old presymptomatic Opa1(delTTAG/-) mice showed no specific plasma signature but revealed a significant optic nerve signature in both sexes, although with a sex effect. The Opa1(delTTAG/-) versus wild-type optic nerve signature was characterized by the decreased concentrations of 10 sphingomyelins and 10 lysophosphatidylcholines, suggestive of myelin sheath alteration, and by alteration in the concentrations of metabolites involved in neuroprotection, such as dimethylarginine, carnitine, spermine, spermidine, carnosine, and glutamate, suggesting a concomitant axonal metabolic dysfunction. CONCLUSIONS. Our comprehensive metabolomic investigations revealed in symptomatic as well as in presymptomatic Opa1(delTTAG/-) mice, a specific sensitiveness of the optic nerve to Opa1 insufficiency, opening new routes for protective therapeutic strategies.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available