A plasma metabolomic signature of Leber hereditary optic neuropathy showing taurine and nicotinamide deficiencies

Abstract

Leber's hereditary optic neuropathy (LHON) is the most common disorder due to mitochondrial DNA mutations and complex I deficiency. It is characterized by an acute vision loss, generally in young adults, with a higher penetrance in males. How complex I dysfunction induces the peculiar LHON clinical presentation remains an unanswered question. To gain an insight into this question, we carried out a non-targeted metabolomic investigation using the plasma of 18 LHON patients, during the chronic phase of the disease, comparing them to 18 healthy controls. A total of 500 metabolites were screened of which 156 were accurately detected. A supervised Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) highlighted a robust model for disease prediction with a Q2 (cum) of 55.5%, with a reliable performance during the permutation test (cross-validation analysis of variance, P-value = 5.02284e-05) and a good prediction of a test set (P = 0.05). This model highlighted 10 metabolites with variable importance in the projection (VIP) > 0.8. Univariate analyses revealed nine discriminating metabolites, six of which were the same as those found in the Orthogonal Projections to Latent Structures Discriminant Analysis model. In total, the 13 discriminating metabolites identified underlining dietary metabolites (nicotinamide, taurine, choline, 1-methylhistidine and hippurate), mitochondrial energetic substrates (acetoacetate, glutamate and fumarate) and purine metabolism (inosine). The decreased concentration of taurine and nicotinamide (vitamin B3) suggest interesting therapeutic targets, given their neuroprotective roles that have already been demonstrated for retinal ganglion cells. Our results show a reliable predictive metabolomic signature in the plasma of LHON patients and highlighted taurine and nicotinamide deficiencies.

Figure 1

Metabolomics workflow. Steps of sample processing and statistical analysis are indicated with the corresponding figure or table number in bold type. Key elements of the principal features are shown in italics.

Figure 2

LHON metabolomic signature. (a) Unsupervised PCA score plot of LHON (blue circles) and CTRL (control) (green squares) individuals. An outlier is highlighted (red circle). (b) Supervised OPLS-DA score plot of LHON (blue circle, n = 17) and CTRL (green squares, n = 18) individuals. The model, constructed with 28 molecules (shown in c) discriminates LHON patients on the t [1]*1.02032 axis. (c) VIP plot showing the contribution of each metabolite to the model (described in b). Molecules emphasized in red squares were significant during univariate analysis (Wilcoxon test and FC > 1.2). The horizontal red dotted line corresponds to the threshold of VIP = 0.8.

Figure 3

Metabolic position of the LHON discriminant metabolites.