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Sigma-1 Receptor Agonists Induce Oxidative Stress in Mitochondria and Enhance Complex I Activity in Physiological
Nino Goguadze1,2, Elene Zhuravliova2, Didier Morin3
1MMDN, Université Montpellier, EPHE, INSERM, UMR-S1198, CC 105, place Eugene Bataillon, 34095, Montpellier cedex 5, France.
Abstract:
The sigma1 receptor (σ1R) is a chaperone protein residing at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), where it modulates Ca2+ exchange between the ER and mitochondria by interacting with inositol-1,4,5 trisphosphate receptors (IP3Rs). The σ1R is highly expressed in the central nervous system and its activation stimulates neuromodulation and neuroprotection, for instance in Alzheimer's disease (AD) models in vitro and in vivo. σ1R effects on mitochondria pathophysiology and the downstream signaling are still not fully understood. We here evaluated the impacts of σ1R ligands in mouse mitochondria preparations on reactive oxygen species (ROS) production, mitochondrial respiration, and complex activities, in physiological condition and after direct application of amyloid Aβ1-42 peptide. σ1R agonists (2-(4-morpholinethyl)-1-phenylcyclohexanecarboxylate hydrochloride (PRE-084), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine (ANAVEX1-41, AN1-41), (S)-1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one (ANAVEX3-71, AN3-71), dehydroepiandrosterone-3 sulfate (DHEA), donepezil) increased mitochondrial ROS in a σ1R antagonist-sensitive manner but decreased Aβ1-42-induced increase in ROS. σ1R ligands (agonists or antagonists) did not impact respiration but attenuated Aβ1-42-induced alteration. σ1R agonists (PRE-084, AN1-41, tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73, AN2-73), AN3-71) increased complex I activity, in a Ca2+-dependent and σ1R antagonist-sensitive manner. σ1R ligands failed to affect complex II, III, and IV activities. The increase in complex I activity explain the σ1R-induced increase in ROS since ligands failed to affect other sources of ROS accumulation in mitochondria and homogenates, namely NADPH oxidase (NOX) and superoxide dismutase (SOD) activities. Furthermore, Aβ1-42 significantly decreased the activity of complexes I and IV and σ1R agonists attenuated the Aβ1-42-induced complex I and IV dysfunctions. σ1R activity in mitochondria therefore results in a Ying-Yang effect, by triggering moderate ROS increase acting as a physiological signal and promoting a marked anti-oxidant effect in pathological (Aβ) conditions.
Insights
Sigma-1 receptor (σ₁R) agonists boost mitochondrial ROS and Complex I activity, offering neuroprotection against amyloid-beta in Alzheimer
Area of Science:
- Mitochondrial pathophysiology
- Neuropharmacology
- Neurodegenerative diseases
Background:
- The sigma-1 receptor (σ₁R) is a chaperone protein at mitochondria-associated ER membranes (MAMs), crucial for Ca²⁺ signaling.
- σ₁R activation in the CNS promotes neuromodulation and neuroprotection, relevant to Alzheimer's disease (AD).
- The precise role of σ₁R in mitochondrial dysfunction and downstream signaling, especially in AD, remains unclear.
Purpose of the Study:
- To investigate the impact of σ₁R ligands on mitochondrial function in the presence of amyloid-beta (Aβ) peptides.
- To evaluate the effects of σ₁R agonists and antagonists on reactive oxygen species (ROS) production, mitochondrial respiration, and electron transport chain complex activities.
- To elucidate the mechanisms underlying σ₁R-mediated neuroprotection in the context of AD-related mitochondrial damage.
Main Methods:
- Utilized mouse mitochondria preparations to assess ROS production, mitochondrial respiration, and electron transport chain complex activities.
- Applied σ₁R agonists and antagonists, alongside amyloid-beta (Aβ)1-42 peptide.
- Measured Complex I, II, III, and IV activities, NADPH oxidase (NOX), and superoxide dismutase (SOD) activities.
Main Results:
- σ₁R agonists increased mitochondrial ROS and Complex I activity in a Ca²⁺-dependent and σ₁R antagonist-sensitive manner.
- σ₁R ligands attenuated Aβ1-42-induced increases in ROS and protected against Aβ1-42-induced Complex I and IV dysfunction.
- Mitochondrial respiration and activities of Complexes II, III, IV, NOX, and SOD were not significantly affected by σ₁R ligands alone.
Conclusions:
- σ₁R activation exhibits a dual role: inducing moderate ROS as a physiological signal and providing significant antioxidant protection in pathological conditions like Aβ exposure.
- σ₁R ligands, particularly agonists, enhance mitochondrial Complex I activity and mitigate Aβ-induced mitochondrial damage, suggesting therapeutic potential for AD.
- σ₁R's influence on mitochondrial Ca²⁺ handling and Complex I function is key to its neuroprotective effects in Alzheimer's disease models.
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