期刊
STEM CELL REPORTS
卷 16, 期 6, 页码 1510-1526出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2021.04.022
关键词
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资金
- Danish Agency for Science, Technology and Innovation
- University of Southern Denmark
- Innovation Fund Denmark (BrainStem) [410800008A]
- H. Lundbeck A/S
- Danish Parkinson Foundation
- Jascha Foundation
- A.P. MOller Foundation for the Advancement of Medical Science [15396, 14427]
- Faculty of Health Sciences at the University of Southern Denmark
- Monument Trust Discovery Award from Parkinson's UK - European Union's Seventh Framework Program (FP7/2007-2013)
- Oxford Martin School - European Union's Seventh Framework Program (FP7/2007-2013) [LC0910004]
- Innovative Medicines Initiative Joint Undertaking - European Union's Seventh Framework Program (FP7/2007-2013) [115439]
- EFPIA
- Wellcome Trust [090532/Z/09/Z]
- MRC Hub grant [G0900747 91070]
- European Union's Seventh Framework Program (FP7/2007-2013)
PARK2 knockout cells exhibit increased TCA cycle activity, disturbed mitochondrial ultrastructure, ATP depletion, and dysregulation of glycolysis and carnitine metabolism. These perturbations are associated with elevated oxidative stress and reduced anti-oxidative response. Key findings were validated using patient-specific iPSC-derived neurons.
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.
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