A Plasma Metabolomic Signature Involving Purine Metabolism in Human Optic Atrophy 1 (OPA1)-Related Disorders.

Purpose: Dominant optic atrophy (DOA; MIM [Mendelian Inheritance in Man] 165500), resulting in retinal ganglion cell degeneration, is mainly caused by mutations in the optic atrophy 1 (OPA1) gene, which encodes a dynamin guanosine triphosphate (GTP)ase involved in mitochondrial membrane processing. This work aimed at determining whether plasma from OPA1 pathogenic variant carriers displays a specific metabolic signature. Methods: We applied a nontargeted clinical metabolomics pipeline based on ultra-high-pressure liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) allowing the exploration of 500 polar metabolites in plasma. We compared the plasma metabolic profiles of 25 patients with various OPA1 pathogenic variants and phenotypes to those of 20 healthy controls. Statistical analyses were performed using univariate and multivariate (principal component analysis [PCA], orthogonal partial least-squares discriminant analysis [OPLS-DA]) methods and a machine learning approach, the Biosigner algorithm. Results: A robust and relevant predictive model characterizing OPA1 individuals was obtained, based on a complex panel of metabolites with altered concentrations. An impairment of the purine metabolism, including significant differences in xanthine, hypoxanthine, and inosine concentrations, was at the foreground of this signature. In addition, the signature was characterized by differences in urocanate, choline, phosphocholine, glycerate, 1-oleoyl-rac-glycerol, rac-glycerol-1-myristate, aspartate, glutamate, and cystine concentrations. Conclusions: This first metabolic signature reported in the plasma of patient carrying OPA1 pathogenic variants highlights the unexpected involvement of purine metabolism in the pathophysiology of DOA.

A novel ADOA-associated OPA1 mutation alters the mitochondrial function, membrane potential, ROS production and apoptosis.

Autosomal dominant optic atrophy (ADOA) is a dominantly inherited optic neuropathy, affecting the specific loss of retinal ganglion cells (RGCs). The majority of affected cases of ADOA are associated with mutations in OPA1 gene. Our previous investigation identified the c.1198C > G (p.P400A) mutation in the OPA1 in a large Han Chinese family with ADOA. In this report, we performed a functional characterization using lymphoblostoid cell lines derived from affected members of this family and control subjects. Mutant cell lines exhibited the aberrant mitochondrial morphology. A ~24.6% decrease in the mitochondrial DNA (mtDNA) copy number was observed in mutant cell lines, as compared with controls. Western blotting analysis revealed the variable reductions (~45.7%) in four mtDNA-encoded polypeptides in mutant cell lines. The impaired mitochondrial translation caused defects in respiratory capacity. Furthermore, defects in mitochondrial ATP synthesis and mitochondrial membrane potential (ΔΨm) were observed in mutant cell lines. These abnormalities resulted in the accumulation of oxidative damage and increasing of apoptosis in the mutant cell lines, as compared with controls. All those alterations may cause the primary degeneration of RGCs and subsequent visual loss. These data provided the direct evidence for c.1198C > G mutation leading to ADOA. Our findings may provide new insights into the understanding of pathophysiology of ADOA.