Targeted LC-MS profiling reveals dysregulated glycolytic flux and TCA cycle stalling in POAG plasma

Abstract

Glaucoma is the leading cause of irreversible blindness. Primary open-angle glaucoma (POAG) is the most common form globally and has been linked to mitochondrial dysfunction and energy deficiency. Plasma was used to investigate the energy metabolomic profiles of patients with POAG and controls, and to determine the metabolite flux within the core interconnected energy pathways. Targeted liquid chromatography-mass spectrometry (LC-MS) was used to analyze plasma energy metabolism in POAG patients and controls. Differential metabolite expression analysis, correlation analysis, and pathway flux analysis were then conducted to elucidate the metabolic alterations and the mechanisms underlying POAG. Our findings reveal elevated levels of D-Glucose-6-phosphate(G6P), 6-Phosphogluconic acid(6PGA), Adenosine diphosphate(ADP), Adenosine monophosphate(AMP), Adenosine triphosphate(ATP), Guanosine diphosphate(GDP), Inosine monophosphate(IMP), Phosphoenolpyruvic acid(PEP), Phosphorylethanolamine(pEtN), and uridine diphosphate N-acetylglucosamine(UDP-GlcNAc) in POAG patients. Conversely, POAG patients showed reduced ratios of ATP/ADP, Glycerol-3-phosphate(G3P)/ Dihydroxyacetone phosphate(DHAP), 1,3-Bisphosphoglyceric acid(BPG)/DHAP, PYR/PEP, Fumarate/Succinate, Arginine/ASA, and Citrulline/Ornithine. These findings collectively suggest disrupted flux in glycolysis, the TCA cycle, urea cycle, and tyrosine metabolism, offering new insights into POAG mechanisms and potential therapeutic strategies targeting energy metabolic pathways.