Sigma-1 Receptor Agonists Induce Oxidative Stress in Mitochondria and Enhance Complex I Activity in Physiological Condition but Protect Against Pathological Oxidative Stress

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 Aβ_1-42 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 Aβ_1-42-induced increase in ROS. σ₁R ligands (agonists or antagonists) did not impact respiration but attenuated Aβ_1-42-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, Aβ_1-42 significantly decreased the activity of complexes I and IV and σ₁R agonists attenuated the Aβ_1-42-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.

Keywords: Amyloid toxicity; Mitochondria; Oxidative stress; Sigma-1 receptor.