High-Resolution Respirometry Reveals MPP+ Mitochondrial Toxicity Mechanism in a Cellular Model of Parkinson's Disease.

Abstract

MPP+ is the active metabolite of MPTP, a molecule structurally similar to the herbicide Paraquat, known to injure the dopaminergic neurons of the nigrostriatal system in Parkinson's disease models. Within the cells, MPP+ accumulates in mitochondria where it inhibits complex I of the electron transport chain, resulting in ATP depletion and neuronal impairment/death. So far, MPP+ is recognized as a valuable tool to mimic dopaminergic degeneration in various cell lines. However, despite a large number of studies, a detailed characterization of mitochondrial respiration in neuronal cells upon MPP+ treatment is still missing. By using high-resolution respirometry, we deeply investigated oxygen consumption related to each respiratory state in differentiated neuroblastoma cells exposed to the neurotoxin. Our results indicated the presence of extended mitochondrial damage at the inner membrane level, supported by increased LEAK respiration, and a drastic drop in oxygen flow devoted to ADP phosphorylation in respirometry measurements. Furthermore, prior to complex I inhibition, an enhancement of complex II activity was observed, suggesting the occurrence of some compensatory effect. Overall our findings provide a mechanistic insight on the mitochondrial toxicity mediated by MPP+, relevant for the standardization of studies that employ this neurotoxin as a disease model.

• Authors: Pierpaolo Risiglione, Loredana Leggio, Salvatore A M Cubisino, Simona Reina, Greta Paternò, Bianca Marchetti, Andrea Magrì, Nunzio Iraci, Angela Messina
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 21 (Oct 22 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33105548 (Publication Type: Journal Article)

Chemical References

• Adenosine Diphosphate
• Electron Transport Complex III
• 1-Methyl-4-phenylpyridinium
• Oxygen

Topics

• 1-Methyl-4-phenylpyridinium (toxicity)
• Adenosine Diphosphate (metabolism)
• Cell Death (drug effects)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Electron Transport Complex III (metabolism)
• Humans
• Mitochondria (drug effects, metabolism, pathology)
• Mitochondrial Membranes (drug effects, pathology)
• Neurons (drug effects, metabolism, pathology)
• Oxidative Phosphorylation (drug effects)
• Oxygen (metabolism)
• Parkinson Disease (pathology)
• Respiration