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

Stem Cell Reports. 2021 Jun 8;16(6):1510-1526. doi: 10.1016/j.stemcr.2021.04.022. Epub 2021 May 27.

Abstract

PARK2 (parkin) mutations cause early-onset Parkinson's disease (PD). Parkin is an ubiquitin E3 ligase that participates in several cellular functions, including mitochondrial homeostasis. However, the specific metabolomic changes caused by parkin depletion remain unknown. Here, we used isogenic human induced pluripotent stem cells (iPSCs) with and without PARK2 knockout (KO) to investigate the effect of parkin loss of function by comparative metabolomics supplemented with ultrastructural and functional analyses. PARK2 KO neurons displayed increased tricarboxylic acid (TCA) cycle activity, perturbed mitochondrial ultrastructure, ATP depletion, and dysregulation of glycolysis and carnitine metabolism. These perturbations were combined with increased oxidative stress and a decreased anti-oxidative response. Key findings for PARK2 KO cells were confirmed using patient-specific iPSC-derived neurons. Overall, our data describe a unique metabolomic profile associated with parkin dysfunction and show that combining metabolomics with an iPSC-derived dopaminergic neuronal model of PD is a valuable approach to obtain novel insight into the disease pathogenesis.

Keywords: Parkinson's disease; induced pluripotent stem cells; metabolomics; mitochondria; oxidative stress; parkin.