Assessing
metabolomic alterations in age-related macular degeneration
(AMD) can provide insights into its pathogenesis. We compared
the metabolomic profiles of the aqueous humor between wet AMD patients
(n = 26) and age- and sex-matched patients undergoing
cataract surgery without AMD as controls (n = 20).
A global untargeted metabolomics study was performed using ultra-high-performance
liquid chromatography tandem mass spectrometry. Univariate analysis
after the false discovery correction showed 18 significantly altered
metabolites among the 291 metabolites measured. These differential
metabolomic profiles pointed to three interconnected metabolic pathways:
a compromised carnitine-associated mitochondrial oxidation pathway
(carnitine, deoxycarnitine, N6-trimethyl-l-lysine), an altered
carbohydrate metabolism pathway (cis-aconitic acid,
itaconatic acid, and mesaconic acid), which plays a role in senescence
and immunity, and an activated osmoprotection pathway (glycine betaine,
creatine), which potentially contributes to the pathogenesis of the
disease. These results suggested that metabolic dysfunction in AMD
is mitochondrial-centered and may provide new insights into the pathophysiology
of wet AMD and novel therapeutic strategies.
Purpose
Energy compromise underpins wet age-related macular degeneration (wAMD) pathogenesis, but the relationship between glucose metabolism and the disease remains unclear. Here, we characterized aqueous humor (AH) to elucidate glucose-related metabolic signatures in patients with wAMD.
Methods
In total, 25 eyes of 25 patients with wAMD were divided into phakic (15 eyes), pseudophakic (10 eyes), and intravitreal injections of ranibizumab (13 eyes) wAMD groups. Twenty patients with cataract (21 eyes) served as controls. Ultrahigh-performance liquid chromatography tandem mass spectrometry was used to quantitatively characterize AH.
Results
Twenty-one metabolites related to glucose metabolism were identified in AH from 45 patients. Tricarboxylic acid (TCA)-related metabolic substrates, including citrate, were detected in AH and were significantly increased in AMD (
P
< 0.01) and AMD pseudophakic groups (
P
< 0.05). In contrast,
α
-ketoglutarate levels were decreased in the AMD group (
P
< 0.05). The
α
-ketoglutarate/citrate ratio was significantly decreased, corresponding to 71.71% and 93.6% decreases in the AMD (phakic and pseudophakic) groups as compared with controls (
P
< 0.001), revealing a significant positive correlation with glutamine. A lower mean glutamine and higher glutamate level were detected in AMD cases compared with controls. No significant differences were observed for lactic acid or other Krebs cycle metabolites. Intravitreal injection significantly alleviated mean central foveal thickness but did not significantly alter metabolites.
Conclusions
Compromised glucose TCA cycle and altered glutamine metabolism are implicated in the AH metabolism in wAMD. These findings highlight potential treatments for alleviating wAMD from a metabolic perspective.
Age-related macular degeneration is a metabolic compromise disorder whose main pathological feature is choroidal neovascularization (CNV) formation. Using untargeted metabolomics analysis, we determined to assess the metabolomic alterations in a CNV rat model to provide an insight into its pathogenesis. In the CNV model, there were 24 significantly changed metabolites in the plasma and 71 in various ocular tissues. Pathway analysis showed that certain metabolic pathways changed in interrelated tissues: for instance, in terms of the altered urea cycle, arginine and proline metabolism were increased in the plasma, while spermidine and spermine biosynthesis activities were increased in the retinal pigment epithelium (RPE)/choroid. The retina and RPE/choroid shared the same changed metabolites of branched-chain amino acid metabolism. Fatty acid metabolism was found to be the significant altered metabolic pathway in the retina of this CNV model. Although the metabolism pattern of different substances is specific for each ocular tissue, there is also a certain material exchange between different tissues. Dysregulated metabolomic profiles in differential tissues may point to an interconnected pathway, oxidative stress response, which may lead to RPE cell degeneration and, ultimately, CNV development.
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