By Xu Qiuwei
Mitochondria are important for bioenergetics and critical sources of biosynthetic pathways including amino acid, urea, heme, and bile acid. Mitochondrial dysfunction is often a cause of many human diseases including neuronal Parkinson’s disease. Mitochondrial toxicity is an undesirable side effect sometimes encountered in drug development. Mitochondrial DNA polymerase gamma (POLG) plays an integral role in mitochondrial DNA replication and repair. Rare mutation in Polg causes mitochondrial dysfunction leading to disease such as parkinsonism. Mutation in PolgD257A impairs DNA replication “proofreading” and leads to progressive accumulation of mutation in mitochondrial DNA. The PolgD257A mouse provides an opportunity as an animal model for mitochondrial neuronal disease target validation and sensitive system for evaluating drug candidates with potential mitochondrial toxicity. We have applied NMR metabolomics to identify metabolites and pathways related to mitochondrial toxicities in vivo or in vitro. High field quantitative NMR is unique in identifying water soluble endogenous metabolites in deuterated buffer solution with an internal reference standard for both chemical shift and quantification. Our internal library of 700 endogenous metabolites provides an opportunity of quick chemical identification and shifts our refocus on biochemical interpretation and pathway analysis. In this presentation, we will present our preliminary work of metabolomics profiling of PolgD256A mutant mouse model and analysis of pathways under which significant changes were observed in identified metabolites.