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

Abstract

<jats:p>PARK2 (parkin) mutations cause early onset of autosomal recessively inherited Parkinson's 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.</jats:p>

Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation

“…PGC1‐α gene expression and protein deacetylation is regulated by the NAD + ‐dependent energy sensor SIRT1 28,29 . Moreover, our and a published metabolic study in parkin‐deficient neurons revealed increased lactate:pyruvate ratios, suggesting lower levels of freely accessible NAD + as a result of metabolic remodeling from oxidative phosphorylation to glycolysis 30,37 …”

Midbrain on Fire: mtDNA Ignites Neuroinflammation in PRKN‐P

“…12 Notably, a similar elevation in TCA intermediate metabolites was recently observed in PRKN KO iDA neurons, which also have an OXPHOS deficit and a low NAD + /NADH ratio. 11 This is consistent with an OXPHOS defect driving the low NAD + /NADH ratio as well as metabolites in NAD + -dependent reactions in the setting of PRKN deficiency.…”

“…Lowered NAD + suppresses PGC1-α signaling by decreasing the activity of SIRT1, an NAD +dependent deacetylase. 10 Although Wasner et al 8 do not directly measure NAD + and NADH, a recent study found that the NAD + /NADH ratio is decreased in PRKN KO and patient iDA neurons, 11 and both studies found an increase in the lactate/pyruvate ratio, 8,11 which is metabolically coupled to the NAD + /NADH ratio. Based on these findings, the authors suggest that Parkin deficiency may decrease mitochondrial biogenesis through lowered NAD + , via the SIRT1-PGC1-α/NRF1-TFAM signaling axis.…”

Modeling of Alpha-1 Antitrypsin Deficiency with Syngeneic Human iPSC-Hepatocytes Reveals Metabolic Dysregulation and Cellular Heterogeneity in PiMZ and PiZZ Hepatocytes

“…In addition to structural differences, we identified alterations of the global transcriptome and metabolome in both MZ and ZZ iHeps, some of which have been previously associated with ER stress or mitochondrial dysfunction (35)(36)(37)42). Among these were enrichment for metabolites significant in the citric acid cycle, glutathione metabolism, and branched chain amino acid and tRNA biosynthesis.…”