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

The sigma(1) receptor (sigma R-1) 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 (IP(3)Rs). The sigma R-1 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. sigma R-1 effects on mitochondria pathophysiology and the downstream signaling are still not fully understood. We here evaluated the impacts of sigma R-1 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 A(1-42) peptide. sigma R-1 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 sigma R-1 antagonist-sensitive manner but decreased A(1-42)-induced increase in ROS. sigma R-1 ligands (agonists or antagonists) did not impact respiration but attenuated A(1-42)-induced alteration. sigma R-1 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 sigma R-1 antagonist-sensitive manner. sigma R-1 ligands failed to affect complex II, III, and IV activities. The increase in complex I activity explain the sigma R-1-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, A(1-42) significantly decreased the activity of complexes I and IV and sigma R-1 agonists attenuated the A(1-42)-induced complex I and IV dysfunctions. sigma R-1 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 (A) conditions.