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Published on: August 4, 2022
MicroRNA-29b-3p degenerates terminally differentiated dopaminergic SH-SY5Y cells by perturbation of mitochondrial
Sana Sarkar1,2, Anuj Pandey1,3, Sanjeev Kumar Yadav1
1Systems Toxicology Group, Food, Drug & Chemical, Environment and Systems Toxicology (FEST) Division, CSIR- Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, UP, India.
Abstract:
Mitochondrial dysfunction is the main cause of gradual deterioration of structure and function of neuronal cells, eventually resulting in neurodegeneration. Studies have revealed a complex interrelationship between neurotoxicant exposure, mitochondrial dysfunction, and neurodegenerative diseases. Alteration in the expression of microRNAs (miRNAs) has also been linked with disruption in mitochondrial homeostasis and bioenergetics. In our recent research (Cellular and Molecular Neurobiology (2023) https://doi.org/10.1007/s10571-023-01362-4), we have identified miR-29b-3p as one of the most significantly up-regulated miRNAs in the blood of Parkinson's patients. The findings of the present study revealed that neurotoxicants of two different natures, that is, arsenic or rotenone, dramatically increased miR-29b-3p expression (18.63-fold and 12.85-fold, respectively) in differentiated dopaminergic SH-SY5Y cells. This dysregulation of miR-29b-3p intricately modulated mitochondrial morphology, induced oxidative stress, and perturbed mitochondrial membrane potential, collectively contributing to the degeneration of dopaminergic cells. Additionally, using assays for mitochondrial bioenergetics in live and differentiated SH-SY5Y cells, a reduction in oxygen consumption rate (OCR), maximal respiration, basal respiration, and non-mitochondrial respiration was observed in cells transfected with mimics of miR-29b-3p. Inhibition of miR-29b-3p by transfecting inhibitor of miR-29b-3p prior to exposure to neurotoxicants significantly restored OCR and other respiration parameters. Furthermore, we observed that induction of miR-29b-3p activates neuronal apoptosis via sirtuin-1(SIRT-1)/YinYang-1(YY-1)/peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α)-regulated Bcl-2 interacting protein 3-like-dependent mechanism. Collectively, our studies have shown the role of miR-29b-3p in dysregulation of mitochondrial bioenergetics during degeneration of dopaminergic neurons via regulating SIRT-1/YY-1/PGC-1α axis.
Insights
Neurotoxicants increase miR-29b-3p, a microRNA linked to Parkinson's disease. This dysregulation impairs mitochondrial function and causes dopaminergic neuron degeneration by affecting key regulatory pathways.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Mitochondrial dysfunction is a key factor in neurodegeneration, with links to neurotoxicant exposure and altered microRNA (miRNA) expression.
- MiRNAs play a role in regulating mitochondrial homeostasis and bioenergetics.
- miR-29b-3p is significantly upregulated in Parkinson's disease patients' blood.
Purpose of the Study:
- To investigate the role of miR-29b-3p in neurotoxicant-induced dopaminergic cell degeneration.
- To elucidate the mechanisms by which miR-29b-3p affects mitochondrial function and neuronal apoptosis.
Main Methods:
- Differentiated dopaminergic SH-SY5Y cells were exposed to neurotoxicants (arsenic or rotenone).
- miR-29b-3p expression levels were measured.
- Mitochondrial morphology, oxidative stress, membrane potential, and bioenergetics (oxygen consumption rate) were assessed.
- Apoptosis pathways involving SIRT-1/YY-1/PGC-1α were investigated.
Main Results:
- Neurotoxicants significantly increased miR-29b-3p expression in dopaminergic cells.
- Elevated miR-29b-3p impaired mitochondrial morphology, increased oxidative stress, and reduced mitochondrial membrane potential.
- Overexpression of miR-29b-3p decreased mitochondrial respiration parameters (OCR, maximal, basal, and non-mitochondrial respiration).
- Inhibition of miR-29b-3p restored mitochondrial respiration.
- miR-29b-3p induced apoptosis via the SIRT-1/YY-1/PGC-1α pathway.
Conclusions:
- miR-29b-3p is a critical mediator of neurotoxicant-induced mitochondrial dysfunction and dopaminergic neuron degeneration.
- The study identifies miR-29b-3p as a potential therapeutic target for Parkinson's disease and related neurodegenerative disorders.
- The findings highlight the intricate regulation of mitochondrial bioenergetics by miRNAs in neurodegeneration.
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