Integrative analysis of microRNA-mediated mitochondrial dysfunction in hippocampal neural progenitor cell death in relation with Alzheimer’s disease
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Adult hippocampal neurogenesis plays a pivotal role in maintainingcognitive brain function. However, this process diminisheswith age, particularly in patients with neurodegenerative disorders. While small, non-coding microRNAs (miRNAs) arecrucial for hippocampal neural stem (HCN) cell maintenance,their involvement in neurodegenerative disorders remains unclear. This study aimed to elucidate the mechanisms throughwhich miRNAs regulate HCN cell death and their potentialinvolvement in neurodegenerative disorders. We performed acomprehensive microarray-based analysis to investigate changesin miRNA expression in insulin-deprived HCN cells as an invitro model for cognitive impairment. miR-150-3p, miR-323-5p,and miR-370-3p, which increased significantly over time followinginsulin withdrawal, induced pronounced mitochondrialfission and dysfunction, ultimately leading to HCN cell death. These miRNAs collectively targeted the mitochondrial fusionprotein OPA1, with miR-150-3p also targeting MFN2. Data-drivenanalyses of the hippocampi and brains of human subjects revealedsignificant reductions in OPA1 and MFN2 in patients withAlzheimer’s disease (AD). Our results indicate that miR-150-3p,miR-323-5p, and miR-370-3p contribute to deficits in hippocampalneurogenesis by modulating mitochondrial dynamics. Our findings provide novel insight into the intricate connectionsbetween miRNA and mitochondrial dynamics, sheddinglight on their potential involvement in conditions characterizedby deficits in hippocampal neurogenesis, such as AD.
Abstract
Adult hippocampal neurogenesis plays a pivotal role in maintainingcognitive brain function. However, this process diminisheswith age, particularly in patients with neurodegenerative disorders. While small, non-coding microRNAs (miRNAs) arecrucial for hippocampal neural stem (HCN) cell maintenance,their involvement in neurodegenerative disorders remains unclear. This study aimed to elucidate the mechanisms throughwhich miRNAs regulate HCN cell death and their potentialinvolvement in neurodegenerative disorders. We performed acomprehensive microarray-based analysis to investigate changesin miRNA expression in insulin-deprived HCN cells as an invitro model for cognitive impairment. miR-150-3p, miR-323-5p,and miR-370-3p, which increased significantly over time followinginsulin withdrawal, induced pronounced mitochondrialfission and dysfunction, ultimately leading to HCN cell death. These miRNAs collectively targeted the mitochondrial fusionprotein OPA1, with miR-150-3p also targeting MFN2. Data-drivenanalyses of the hippocampi and brains of human subjects revealedsignificant reductions in OPA1 and MFN2 in patients withAlzheimer’s disease (AD). Our results indicate that miR-150-3p,miR-323-5p, and miR-370-3p contribute to deficits in hippocampalneurogenesis by modulating mitochondrial dynamics. Our findings provide novel insight into the intricate connectionsbetween miRNA and mitochondrial dynamics, sheddinglight on their potential involvement in conditions characterizedby deficits in hippocampal neurogenesis, such as AD.
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