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Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress.

ABSTRACT: Tobacco smoking is a risk factor for several human diseases. Conversely, smoking also reduces the prevalence of Parkinson's disease, whose hallmark is degeneration of substantia nigra dopaminergic neurons (DNs). We use C. elegans as a model to investigate whether tobacco-derived nicotine activates nicotinic acetylcholine receptors (nAChRs) to selectively protect DNs. Using this model, we demonstrate conserved functions of DN-expressed nAChRs. We find that DOP-2, a D3-receptor homolog; MCU-1, a mitochondrial calcium uniporter; PINK-1 (PTEN-induced kinase 1); and PDR-1 (Parkin) are required for nicotine-mediated protection of DNs. Together, our results support involvement of a calcium-modulated, mitochondrial stress-activated PINK1/Parkin-dependent pathway in nicotine-induced neuroprotection. This suggests that nicotine-selective protection of substantia nigra DNs is due to the confluence of two factors: first, their unique vulnerability to mitochondrial stress, which is mitigated by increased mitochondrial quality control due to PINK1 activation, and second, their specific expression of D3-receptors.

SUBMITTER: Nourse JB

PROVIDER: S-EPMC7900352 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress.

Nourse J Brucker JB Harshefi Gilad G Marom Adi A Karmi Abdelrahaman A Cohen Ben-Ami Hagit H Caldwell Kim A KA Caldwell Guy A GA Treinin Millet M

iScience 20210204 3

Tobacco smoking is a risk factor for several human diseases. Conversely, smoking also reduces the prevalence of Parkinson's disease, whose hallmark is degeneration of <i>substantia nigra</i> dopaminergic neurons (DNs). We use <i>C. elegans</i> as a model to investigate whether tobacco-derived nicotine activates nicotinic acetylcholine receptors (nAChRs) to selectively protect DNs. Using this model, we demonstrate conserved functions of DN-expressed nAChRs. We find that DOP-2, a D3-receptor homol ...[more]

PMID: 33665559

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Project description:BACKGROUND:Mitochondrial dysfunction causes or contributes to a wide variety of pathologies, including neurodegenerative diseases, cancer, metabolic diseases, and aging. Cells actively surveil a number of mitochondrial readouts to ensure that cellular homeostasis is maintained. RESULTS:In this article, we characterize the role of the ethanol and stress response element (ESRE) pathway in mitochondrial surveillance and show that it is robustly activated when the concentration of reactive oxygen species (ROS) in the cell increases. While experiments were mostly performed in Caenorhabditis elegans, we observed similar gene activation profile in human cell lines. The linear relationship between ROS and ESRE activation differentiates ESRE from known mitochondrial surveillance pathways, such as the mitochondrial unfolded protein response (UPRmt), which monitor mitochondrial protein import. The ability of the ESRE network to be activated by increased ROS allows the cell to respond to oxidative and reductive stresses. The ESRE network works in tandem with other mitochondrial surveillance mechanisms as well, in a fashion that suggests a partially redundant hierarchy. For example, mutation of the UPRmt pathway results in earlier and more robust activation of the ESRE pathway. Interestingly, full expression of ATFS-1, a key transcription factor for the UPRmt, requires the presence of an ESRE motif in its promoter region. CONCLUSION:The ESRE pathway responds to mitochondrial damage by monitoring ROS levels. This response is conserved in humans. The ESRE pathway is activated earlier when other mitochondrial surveillance pathways are unavailable during mitochondrial crises, potentially to mitigate stress and restore health. However, the exact mechanisms of pathway activation and crosstalk remain to be elucidated. Ultimately, a better understanding of this network, and its role in the constellation of mitochondrial and cellular stress networks, will improve healthspan.

Project description:Activation of the Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and consequent induction of phase 2 antioxidant enzymes is known to afford neuroprotection. Here, we present a series of novel electrophilic compounds that protect neurons via this pathway. Natural products, such as carnosic acid (CA), are present in high amounts in the herbs rosemary and sage as ortho-dihydroquinones, and have attracted particular attention because they are converted by oxidative stress to their active form (ortho-quinone species) that stimulate the Keap1/Nrf2 transcriptional pathway. Once activated, this pathway leads to the production of a series of antioxidant phase 2 enzymes. Thus, such dihydroquinones function as redox-activated 'pro-electrophiles'. Here, we explored the concept that related para-dihydroquinones represent even more effective bioactive pro-electrophiles for the induction of phase 2 enzymes without producing toxic side effects. We synthesized several novel para-hydroquinone-type pro-electrophilic compounds (designated D1 and D2) to analyze their protective mechanism. DNA microarray, PCR, and western blot analyses showed that compound D1 induced expression of heat-shock proteins (HSPs), including HSP70, HSP27, and DnaJ, in addition to phase 2 enzymes such as hemeoxygenase-1 (HO-1), NADP(H) quinine-oxidoreductase1, and the Na(+)-independent cystine/glutamate exchanger (xCT). Treatment with D1 resulted in activation of Nrf2 and heat-shock transcription factor-1 (HSF-1) transcriptional elements, thus inducing phase 2 enzymes and HSPs, respectively. In this manner, D1 protected neuronal cells from both oxidative and endoplasmic reticulum (ER)-related stress. Additionally, D1 suppressed induction of 78 kDa glucose-regulated protein (GRP78), an ER chaperone protein, and inhibited hyperoxidation of peroxiredoxin 2 (PRX2), a molecule that is in its reduced state can protect from oxidative stress. These results suggest that D1 is a novel pro-electrophilic compound that activates both the Nrf2 and HSF-1 pathways, and may thus offer protection from oxidative and ER stress.

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Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress.

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Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress.

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