A Metabolomics Profiling of Glaucoma Points to Mitochondrial Dysfunction, Senescence, and Polyamines Deficiency

Abstract

Our results highlight a systemic and age-related mitochondrial defect in the pathogenesis of POAG.

A Data Mining Metabolomics Exploration of Glaucoma

“…The increased arginine concentration in POAG plasma was evidenced by three of the four data methods and was already reported in the targeted metabolomics study [7], together with that of methionine and tyrosine, which were also identified here by the univariate analysis, thus attesting the reproducibility of the results obtained with two different mass spectrometry approaches. Modification of arginine concentration may be related to the altered arginine/nitric oxide regulatory pathway that characterize glaucoma [20].…”

“…Indeed, a study of the mouse DBA/2J model with high intra-ocular pressure has recently established the proof of concept of vitamin B3 therapeutic interest [15] to prevent glaucoma. Our current investigations in humans [7] together with the recent report in mice, argues in favor of a mitochondrial-related nicotinamide deficiency, contributing to the age-related vulnerability of the optic nerve in glaucoma pathogenesis. This statement is further reinforced by the fact that mitochondrial complex I deficiency was also reported in lymphoblasts from glaucoma patients [16], a fact that could be related to the decrease level of nicotinamide adenine dinucleotide (reduced form) (NADH) in these cells [17].…”

“…In the absence of an exhaustive method to explore the whole metabolome, combinations of different approaches are required to progress the deciphering the extensive blood metabolic signature of glaucoma. To complete the two studies previously published [6,7] that evidenced 41 and 18 discriminant metabolites, using non-targeted and targeted metabolomics, respectively, we here carried out a non-targeted method, allowing the precise identification of 500 metabolites [8]. Among the 160 metabolites accurately detected using this approach, univariate analysis highlighted 28 discriminant metabolites, with FDR below 5%, whereas the combination of multivariate analysis, LASSO tests and machine learning approaches restricted this list to the nine most discriminating metabolites.…”

“…The second one, performed by our group, compared the metabolomics profiles of plasma from POAG individuals (n = 36) with age-and sex-matched controls with cataract (n = 27) using a targeted metabolomics approach. This study revealed 18 discriminant metabolites disclosing mitochondrial dysfunction with energetic substrates accumulation (hexoses and short-and medium-chain acyl-carnitines), senescence (increased phosphatidylcholines and decreased spermine, spermidine, and long-chain acyl-carnitines), and deficiency of polyamines (spermine and spermidine) known to be protective of retinal ganglion cells [7].…”

Nicotinamide Deficiency in Primary Open-Angle Glaucoma

“…In this respect, the lymphoblasts of patients with POAG showed a mitochondrial complex I deficiency reflecting a systemic mitochondrial impairment 4,5 . In addition, using targeted metabolomics on the plasma of POAG patients compared to controls, we have recently shown a metabolic profile combining the impaired utilization of energetic substrates and decreased levels of polyamines, attesting to mitochondrial dysfunction, and premature ageing 22 . Since nicotinamide is one of the main contributors to the regeneration of NAD through a salvage metabolic pathway, nicotinamide deficiency could reflect excessive age-related NAD consumption, which subsequently leads to complex I deficiency, and the energetic failure responsible for the degeneration of RGCs.…”