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Live Imaging of Mitosis in the Developing Mouse Embryonic Cortex
Published on: June 4, 2014
miR-351-5p/Miro2 axis contributes to hippocampal neural progenitor cell death via unbalanced mitochondrial fission
Ha-Na Woo1,2, Sujeong Park1,3, Hae Lin Kim1,3
1Department of Microbiology, University of Ulsan College of Medicine, Seoul 05505, Korea.
Abstract:
Adult hippocampal neurogenesis supports the structural and functional plasticity of the brain, while its decline is associated with neurodegeneration common in Alzheimer's disease (AD). Although the dysregulation of certain microRNAs (miRNAs) in AD have been observed, the effects of miRNAs on hippocampal neurogenesis are largely unknown. In this study, we demonstrated miR-351-5p as a causative factor in hippocampal neural progenitor cell death through modulation of the mitochondrial guanosine triphosphatase (GTPase), Miro2. Downregulation of Miro2 by siMiro2 induced cell death, similar to miR-351-5p, whereas ectopic Miro2 expression using an adenovirus abolished these effects. Excessively fragmented mitochondria and dysfunctional mitochondria were indexed by decreased mitochondrial potential, and increased reactive oxygen species were identified in miR-351-5p-induced cell death. Moreover, subsequent induction of mitophagy via Pink1 and Parkin was observed in the presence of miR-351-5p and siMiro2. The suppression of mitochondrial fission by Mdivi-1 completely inhibited cell death by miR-351-5p. miR-351-5p expression increased whereas the level of Miro2 decreased in the hippocampus of AD model mice, emulating expression in AD patients. Collectively, the data indicate the mitochondrial fission and accompanying mitophagy by miR-351-5p/Miro2 axis as critical in hippocampal neural progenitor cell death, and a potential therapeutic target in AD.
Insights
MicroRNA-351-5p causes neural progenitor cell death in Alzheimer's disease (AD) by disrupting mitochondrial function. Targeting this miR-351-5p/Miro2 pathway may offer a new therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Adult hippocampal neurogenesis is vital for brain plasticity.
- Declining neurogenesis is linked to neurodegeneration in Alzheimer's disease (AD).
- The role of microRNAs (miRNAs) in hippocampal neurogenesis in AD is largely unknown.
Purpose of the Study:
- To investigate the role of miR-351-5p in hippocampal neural progenitor cell death.
- To elucidate the molecular mechanisms underlying miR-351-5p-induced cell death.
- To explore the miR-351-5p/Miro2 axis as a potential therapeutic target for AD.
Main Methods:
- Investigated miR-351-5p effects on hippocampal neural progenitor cells.
- Utilized siRNA (siMiro2) and adenovirus for Miro2 modulation.
- Assessed mitochondrial function (potential, ROS), mitophagy markers (Pink1, Parkin), and mitochondrial fission.
- Administered Mdivi-1 to inhibit mitochondrial fission.
- Analyzed miR-351-5p and Miro2 levels in AD model mice hippocampus.
Main Results:
- miR-351-5p induced hippocampal neural progenitor cell death by targeting Miro2.
- Miro2 downregulation mimicked miR-351-5p effects; Miro2 overexpression rescued cell death.
- miR-351-5p triggered mitochondrial fragmentation, decreased mitochondrial potential, and increased reactive oxygen species.
- Mitophagy was induced by miR-351-5p via Pink1 and Parkin.
- Inhibition of mitochondrial fission blocked miR-351-5p-induced cell death.
- miR-351-5p was upregulated and Miro2 downregulated in the hippocampus of AD model mice.
Conclusions:
- The miR-351-5p/Miro2 axis drives hippocampal neural progenitor cell death through mitochondrial fission and mitophagy.
- This pathway is dysregulated in Alzheimer's disease models.
- Targeting the miR-351-5p/Miro2 axis presents a potential therapeutic strategy for AD.
