TY - JOUR
T1 - High-resolution respirometry reveals mpp+ mitochondrial toxicity mechanism in a cellular model of parkinson’s disease
AU - Risiglione, Pierpaolo
AU - Leggio, Loredana
AU - Cubisino, Salvatore A.M.
AU - Reina, Simona
AU - Paternò, Greta
AU - Marchetti, Bianca
AU - Magrì, Andrea
AU - Iraci, Nunzio
AU - Messina, Angela
N1 - Funding Information:
Funding: This research was funded by AIM Linea 1 Salute (AIM1833071) to A. Magrì, Brains2South (Fondazione con il Sud—Bando Capitale Umano ad Alta Qualificazione 2015, grant no. 2015-PDR-0219) to N.I., PIACERI (grant no. ARVEST) and Proof of Concept (grant no. PEPSLA POC 01_00054) to A. Mess.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
KW - High-resolution respirometry
KW - Mitochondria
KW - MPP
KW - Parkinson’s disease
KW - SH-SY5Y cells
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U2 - 10.3390/ijms21217809
DO - 10.3390/ijms21217809
M3 - Article
C2 - 33105548
AN - SCOPUS:85094140558
VL - 21
SP - 1
EP - 15
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 21
M1 - 7809
ER -