Abstract
Leber's Hereditary Optic Neuropathy (LHON) is a neurodegenerative mitochondrial disease characterized by retinal ganglionic cell death and eventual loss of central vision. Specific mtDNA mutations in respiratory complex I subunits (ND4/ND6/ND1) coding genes have been identified in most of LHON patients, and these mutations have been shown to cause mitochondrial dysfunctions leading to increased oxidative stress and bioenergetics failure in cell models and LHON patients. In this study, we investigated the alterations in metabolic profiling of various pathways converging to mitochondria. We aim to identify metabolic signatures of LHON associated with complex I defects.We utilized trans-mitochondrial hybrids (cybrids) of LHON carrying ND4/ND6/ND1 mutations grown in regular and mitochondrial challenged conditions. We investigated polar metabolites profiling in the cell extracts using LC-MS approach and found alterations in various metabolic intermediates of pentose phosphate pathway, amino acid metabolism, fatty acid metabolism, purine metabolism, glycolysis, and TCA cycle.Our studies indicated downregulations of some important metabolites involved in the antioxidant defense and neuro-protective mechanism, and accumulations of other metabolites involved in tryptophan degradation and protein glycation. Further investigations would provide mechanistic insights on how mtDNA mutations lead to retinal ganglionic cell death in LHON patients and may help to develop metabolic markers for disease diagnostics and to explore novel intervention approaches for treatment.
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call