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miR-129-3p Targeting of MCU Protects Against Glucose Fluctuation-Mediated Neuronal Damage via a
Bo Wang1,2, Yang Li3, Chao You1
1Department of Neurosurgery, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
Introduction:
Glucose fluctuations have an adverse effect on several diabetes-related complications, especially for the nervous system, but the underlying mechanisms are not clear. MicroRNAs are critical regulators of posttranscription in many physiological processes, such as apoptosis. Our study clarified the neuroprotective effects of miR-129-3p targeting mitochondrial calcium uniporter (MCU) in glucose fluctuation-mediated neuronal damage and the specific mechanisms involved.
Methods:
The expression of MCU and miR-129-3p was examined by real-time PCR and Western blot in the glucose fluctuation cell model. Dual-luciferase reporter assay was performed to confirm the transcriptional regulation of miR-129-3p by MCU. Fluorescent probe and assay kit assay was used to determine oxidative stress condition. Mitochondrial-dependent intrinsic apoptotic factors were examined by flow cytometry assay, enzyme-linked immunosorbent assay (ELISA), and gene and protein expression assays.
Results:
We found an upregulation of MCU and downregulation of miR-129-3p in glucose fluctuation-treated primary hippocampal neuronal cells, and miR-129-3p directly targeted MCU. miR-129-3p overexpression produced a dramatic reduction in calcium overload, reactive oxygen species (ROS) generation, GSH-to-GSSG ratio, MMP-2 expression in the mitochondrial-dependent intrinsic apoptosis pathway and an increase in MnSOD activity. Increasing MCU expression rescued the effects of miR-129-3p overexpression. miR-129-3p downregulation produced a significant increase in calcium overload, reactive oxygen species (ROS) generation, MMP-2 expression, cytochrome c release and cell apoptosis, and antioxidant N-acetyl cysteine (NAC) rescued the effects of miR-129-3p downregulation.
Conclusion:
Therefore, miR-129-3p suppressed glucose fluctuation-mediated neuronal damage by targeting MCU via a mitochondrial-dependent intrinsic apoptotic pathway. The miR-129-3p/MCU axis may be a promising therapeutic target for glucose fluctuation-mediated neuronal damage.
Insights
MicroRNA-129-3p protects neurons from glucose fluctuations by targeting the mitochondrial calcium uniporter (MCU). This discovery offers a potential therapeutic target for neurological damage caused by unstable blood sugar levels.
Area of Science:
- Neuroscience
- Molecular Biology
- Endocrinology
Background:
- Glucose fluctuations negatively impact diabetes complications, particularly neurological damage.
- The precise mechanisms underlying this neurotoxicity remain unclear.
- MicroRNAs (miRNAs) are key post-transcriptional regulators involved in physiological processes like apoptosis.
Purpose of the Study:
- To investigate the neuroprotective role of miR-129-3p in neuronal damage induced by glucose fluctuations.
- To elucidate the specific molecular mechanisms involving the mitochondrial calcium uniporter (MCU).
Main Methods:
- Real-time PCR and Western blot to assess MCU and miR-129-3p expression in a glucose fluctuation cell model.
- Dual-luciferase reporter assay to confirm the targeting relationship between miR-129-3p and MCU.
- Assays for oxidative stress, mitochondrial function, and apoptosis markers (e.g., calcium overload, ROS, MMP-2, cytochrome c release).
Main Results:
- Upregulation of MCU and downregulation of miR-129-3p were observed in glucose fluctuation-treated neurons.
- miR-129-3p directly targeted MCU, reducing calcium overload, reactive oxygen species (ROS), and apoptosis.
- Overexpression of MCU counteracted the protective effects of miR-129-3p, while antioxidant treatment rescued the effects of miR-129-3p downregulation.
Conclusions:
- miR-129-3p mitigates glucose fluctuation-induced neuronal injury by targeting MCU through the mitochondrial-dependent intrinsic apoptotic pathway.
- The miR-129-3p/MCU pathway represents a potential therapeutic target for managing neuronal damage associated with glucose instability.
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