title: MicroRNA-7 Regulates the Function of Mitochondrial Permeability Transition Pore by Targeting VDAC1 Expression.
abstract: Mitochondrial dysfunction is one of the major contributors to neurodegenerative disorders including Parkinson disease. The mitochondrial permeability transition pore is a protein complex located on the mitochondrial membrane. Under cellular stress, the pore opens, increasing the release of pro-apoptotic proteins, and ultimately resulting in cell death. MicroRNA-7 (miR-7) is a small non-coding RNA that has been found to exhibit a protective role in the cellular models of Parkinson disease. In the present study, miR-7 was predicted to regulate the function of mitochondria, according to gene ontology analysis of proteins that are down-regulated by miR-7. Indeed, miR-7 overexpression inhibited mitochondrial fragmentation, mitochondrial depolarization, cytochrome c release, reactive oxygen species generation, and release of mitochondrial calcium in response to 1-methyl-4-phenylpyridinium (MPP(+)) in human neuroblastoma SH-SY5Y cells. In addition, several of these findings were confirmed in mouse primary neurons. Among the mitochondrial proteins identified by gene ontology analysis, the expression of voltage-dependent anion channel 1 (VDAC1), a constituent of the mitochondrial permeability transition pore, was down-regulated by miR-7 through targeting 3'-untranslated region of VDAC1 mRNA. Similar to miR-7 overexpression, knockdown of VDAC1 also led to a decrease in intracellular reactive oxygen species generation and subsequent cellular protection against MPP(+). Notably, overexpression of VDAC1 without the 3'-UTR significantly abolished the protective effects of miR-7 against MPP(+)-induced cytotoxicity and mitochondrial dysfunction, suggesting that the protective effect of miR-7 is partly exerted through promoting mitochondrial function by targeting VDAC1 expression. These findings point to a novel mechanism by which miR-7 accomplishes neuroprotection by improving mitochondrial health.
authors.affiliation: From the Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors.forename: Amrita Datta
authors.initials: AD
authors.lastname: Chaudhuri
authors.affiliation: From the Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors.forename: Doo Chul
authors.initials: DC
authors.lastname: Choi
authors.affiliation: From the Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors.forename: Savan
authors.initials: S
authors.lastname: Kabaria
authors.affiliation: From the Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors.forename: Alan
authors.initials: A
authors.lastname: Tran
authors.affiliation: From the Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, New Jersey 08854 junneu@rwjms.rutgers.edu.
authors.forename: Eunsung
authors.identifier: http://orcid.org/0000-0001-5694-2599
authors.initials: E
authors.lastname: Junn
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D015870:Gene Expression; D063990:Gene Ontology; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D053142:Mitochondrial Size; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D050995:Voltage-Dependent Anion Channel 1; C549242:MIRN7-1 microRNA, human; C494762:VDAC1 protein, human
keywords: 1-methyl-4-phenylpyridinium; Parkinson disease; microRNA (miRNA); mitochondrial membrane potential; mitochondrial permeability transition (MPT); voltage-dependent anion channel (VDAC)