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Role of Mitochondrial Protein, mitoNEET, in Impaired Intracellular Cholesterol Metabolism-Induced Neuronal Cell Death
Ayana Nakata1, Tsugumi Takeo1, Hideya Mizuno1
1School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien Kyuban-cho, Nishinomiya, Hyogo 663-8179, Japan.
Abstract:
Parkinson's disease (PD) is a progressive neurological disorder with an unclear etiology. Nonetheless, abnormal cholesterol metabolism is considered an environmental risk factor. MitoNEET (mNT) is an iron-sulfur cluster protein located in the outer mitochondrial membrane. mNT dysfunction is involved in the pathology of several diseases, including PD. However, the cause of mNT dysfunction remains unclear. Therefore, we hypothesized that increased intracellular cholesterol levels may reduce mNT function and increase reactive oxygen species (ROS) levels, resulting in neuronal cell death and PD progression. In this study, we investigated the effects of cholesterol on cell viability and mNT levels in human neuroblastoma (SH-SY5Y) cells. Cholesterol reduced cell viability and mNT protein levels and increased ROS generation. Pioglitazone, an mNT activator, decreased cholesterol-induced ROS generation but did not rescue cell viability, suggesting that reduced mNT levels may be involved but are not the sole cause of cholesterol-induced cell death. Additionally, the viability of cells treated with rotenone, 6-hydroxydopamine, and 1-methyl-4-phenylpyridinium in the presence of cholesterol was measured. However, no significant enhancement in cell death was observed. Moreover, the toxic compounds did not reduce mNT levels, indicating that mNT is not involved in toxic compound-induced cell death. In summary, these results indicate that cholesterol induces cell death, reduces mNT protein levels without suppressing transcription, and increases ROS generation, which may affect PD development. Further assessment of the mechanisms associated with abnormal intracellular cholesterol metabolism, reduced mNT levels, and cell death may lead to the discovery of novel treatments for PD.
Insights
High cholesterol levels may contribute to Parkinson's disease (PD) by reducing MitoNEET protein and increasing oxidative stress, leading to neuronal cell death. Further research into cholesterol's role in PD is warranted.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Parkinson's disease (PD) is a progressive neurodegenerative disorder with an unknown cause, though abnormal cholesterol metabolism is a suspected environmental risk factor.
- MitoNEET (mNT), an outer mitochondrial membrane protein, is implicated in PD pathology, but the reasons for its dysfunction are unclear.
Purpose of the Study:
- To investigate the hypothesis that elevated intracellular cholesterol reduces mNT function, increases reactive oxygen species (ROS), and contributes to neuronal cell death in PD.
- To examine the effects of cholesterol on cell viability, mNT levels, and ROS generation in human neuroblastoma (SH-SY5Y) cells.
Main Methods:
- Human neuroblastoma (SH-SY5Y) cells were treated with cholesterol to assess its impact on cell viability, mNT protein levels, and ROS generation.
- The effects of pioglitazone (an mNT activator) on cholesterol-induced ROS and cell viability were evaluated.
- Cell viability was also assessed for cells treated with rotenone, 6-hydroxydopamine, and 1-methyl-4-phenylpyridinium in the presence of cholesterol.
Main Results:
- Cholesterol exposure significantly reduced SH-SY5Y cell viability and mNT protein levels while increasing ROS generation.
- Pioglitazone mitigated cholesterol-induced ROS but did not restore cell viability, suggesting mNT reduction is involved but not the sole cause of cell death.
- Cholesterol did not enhance cell death induced by rotenone, 6-hydroxydopamine, or 1-methyl-4-phenylpyridinium, and these toxins did not reduce mNT levels.
Conclusions:
- Cholesterol induces neuronal cell death by reducing mNT protein levels (without affecting transcription) and increasing ROS generation, potentially contributing to PD development.
- Reduced mNT levels are implicated in cholesterol-induced neurotoxicity, but other factors also contribute to cell death.
- Understanding the interplay between abnormal cholesterol metabolism, mNT levels, and cell death pathways may reveal novel therapeutic strategies for Parkinson's disease.
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