Identification of bioactive metabolites in human iPSC-derived dopaminergic neurons with PARK2 mutation: altered mitochondrial and energy metabolism.

PARK2 (parkin) mutations cause early onset of autosomal recessively inherited Parkinson9s disease (PD). Parkin is an ubiquitin E3 ligase and has been reported to participate in several cellular functions, including mitochondrial homeostasis. However, the specific metabolomic changes caused by parkin depletion remain largely unknown. Human induced pluripotent stem cells (iPSCs) with PARK2 knockout (KO) provide a valuable model for studying parkin dysfunction in dopaminergic neurons. In the current study, we used isogenic iPSCs to investigate the effect of parkin loss-of-function by comparative metabolomics analysis. The metabolomic profile of the PARK2 KO neurons differed substantially from that of healthy controls. We found increased tricarboxylic acid (TCA) cycle activity, perturbed mitochondrial ultrastructure connected with ATP depletion, glycolysis dysregulation with lactate accumulation, and elevated levels of short- and long-chain carnitines. These mitochondrial and energy perturbations in the PARK2 KO neurons were combined with increased levels of oxidative stress and a decreased anti-oxidative response. In conclusion, our data describe a unique metabolomic profile associated with parkin dysfunction, demonstrating several PD-related cellular defects. Our findings support and expand previously described PD phenotypic features and show that combining metabolomic analysis with an iPSC-derived dopaminergic neuronal model of PD is a valuable approach to obtain novel insight into the disease pathogenesis.