High-Resolution Respirometry Reveals MPP<sup>+</sup> Mitochondrial Toxicity Mechanism in a Cellular Model of Parkinson’s Disease
MPP<sup>+</sup> 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<sup>+</sup> accumulates in mitochondria where...
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doaj-4e512fe284c840d5b644b197e0c7ee322020-11-25T03:36:36ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-01217809780910.3390/ijms21217809High-Resolution Respirometry Reveals MPP<sup>+</sup> Mitochondrial Toxicity Mechanism in a Cellular Model of Parkinson’s DiseasePierpaolo Risiglione0Loredana Leggio1Salvatore A. M. Cubisino2Simona Reina3Greta Paternò4Bianca Marchetti5Andrea Magrì6Nunzio Iraci7Angela Messina8Department of Biomedical and Biotechnological Sciences, University of Catania, V.le Andrea Doria 6, 95125 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia 97, 95125 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, V.le Andrea Doria 6, 95125 Catania, ItalyDepartment of Biological, Geological and Environmental Sciences, University of Catania, V.le Andrea Doria 6, 95125 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia 97, 95125 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia 97, 95125 Catania, ItalyDepartment of Biological, Geological and Environmental Sciences, University of Catania, V.le Andrea Doria 6, 95125 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia 97, 95125 Catania, ItalyDepartment of Biological, Geological and Environmental Sciences, University of Catania, V.le Andrea Doria 6, 95125 Catania, ItalyMPP<sup>+</sup> 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<sup>+</sup> accumulates in mitochondria where it inhibits complex I of the electron transport chain, resulting in ATP depletion and neuronal impairment/death. So far, MPP<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup>, relevant for the standardization of studies that employ this neurotoxin as a disease model.https://www.mdpi.com/1422-0067/21/21/7809MPP<sup>+</sup>mitochondriaParkinson’s diseasehigh-resolution respirometrySH-SY5Y cells |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Pierpaolo Risiglione Loredana Leggio Salvatore A. M. Cubisino Simona Reina Greta Paternò Bianca Marchetti Andrea Magrì Nunzio Iraci Angela Messina |
spellingShingle |
Pierpaolo Risiglione Loredana Leggio Salvatore A. M. Cubisino Simona Reina Greta Paternò Bianca Marchetti Andrea Magrì Nunzio Iraci Angela Messina High-Resolution Respirometry Reveals MPP<sup>+</sup> Mitochondrial Toxicity Mechanism in a Cellular Model of Parkinson’s Disease International Journal of Molecular Sciences MPP<sup>+</sup> mitochondria Parkinson’s disease high-resolution respirometry SH-SY5Y cells |
author_facet |
Pierpaolo Risiglione Loredana Leggio Salvatore A. M. Cubisino Simona Reina Greta Paternò Bianca Marchetti Andrea Magrì Nunzio Iraci Angela Messina |
author_sort |
Pierpaolo Risiglione |
title |
High-Resolution Respirometry Reveals MPP<sup>+</sup> Mitochondrial Toxicity Mechanism in a Cellular Model of Parkinson’s Disease |
title_short |
High-Resolution Respirometry Reveals MPP<sup>+</sup> Mitochondrial Toxicity Mechanism in a Cellular Model of Parkinson’s Disease |
title_full |
High-Resolution Respirometry Reveals MPP<sup>+</sup> Mitochondrial Toxicity Mechanism in a Cellular Model of Parkinson’s Disease |
title_fullStr |
High-Resolution Respirometry Reveals MPP<sup>+</sup> Mitochondrial Toxicity Mechanism in a Cellular Model of Parkinson’s Disease |
title_full_unstemmed |
High-Resolution Respirometry Reveals MPP<sup>+</sup> Mitochondrial Toxicity Mechanism in a Cellular Model of Parkinson’s Disease |
title_sort |
high-resolution respirometry reveals mpp<sup>+</sup> mitochondrial toxicity mechanism in a cellular model of parkinson’s disease |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-10-01 |
description |
MPP<sup>+</sup> 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<sup>+</sup> accumulates in mitochondria where it inhibits complex I of the electron transport chain, resulting in ATP depletion and neuronal impairment/death. So far, MPP<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup>, relevant for the standardization of studies that employ this neurotoxin as a disease model. |
topic |
MPP<sup>+</sup> mitochondria Parkinson’s disease high-resolution respirometry SH-SY5Y cells |
url |
https://www.mdpi.com/1422-0067/21/21/7809 |
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