MMDN, Université Montpellier, EPHE, INSERM, UMR-S1198, CC 105, place Eugene Bataillon, 34095, Montpellier cedex 5, France.
Institute of Chemical Biology, Ilia State University, 0162, Tbilisi, Georgia.
Neurotox Res. 2019 Jan;35(1):1-18. doi: 10.1007/s12640-017-9838-2. Epub 2017 Nov 10.
The sigma receptor (σR) is a chaperone protein residing at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), where it modulates Ca exchange between the ER and mitochondria by interacting with inositol-1,4,5 trisphosphate receptors (IPRs). The σR 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. σR effects on mitochondria pathophysiology and the downstream signaling are still not fully understood. We here evaluated the impacts of σR 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 peptide. σR 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 σR antagonist-sensitive manner but decreased Aβ-induced increase in ROS. σR ligands (agonists or antagonists) did not impact respiration but attenuated Aβ-induced alteration. σR 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 Ca-dependent and σR antagonist-sensitive manner. σR ligands failed to affect complex II, III, and IV activities. The increase in complex I activity explain the σR-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 significantly decreased the activity of complexes I and IV and σR agonists attenuated the Aβ-induced complex I and IV dysfunctions. σR 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.
σ 型受体（σR）是一种位于线粒体相关内质网（ER）膜（MAMs）上的伴侣蛋白，通过与肌醇 1,4,5-三磷酸受体（IPR）相互作用，调节 ER 和线粒体之间的 Ca 交换。σR 在中枢神经系统中高度表达，其激活刺激神经调节和神经保护，例如在体外和体内的阿尔茨海默病（AD）模型中。σR 对线粒体病理生理学和下游信号的影响仍不完全清楚。我们在这里评估了 σR 配体在小鼠线粒体制剂中的作用，包括对活性氧（ROS）产生、线粒体呼吸和复合物活性的影响，这些作用是在生理条件下和直接应用淀粉样蛋白 Aβ 肽后产生的。σR 激动剂（2-（4-吗啉乙基）-1-苯基环己烷甲羧酸盐盐酸盐（PRE-084）、四氢-N，N-二甲基-5,5-二苯基-3-呋喃甲胺（ANAVEX1-41、AN1-41）、（S）-1-（2,8-二甲基-1-硫代-3,8-二氮杂螺[4.5]癸-3-基）-3-（1H-吲哚-3-基）丙-1-酮（ANAVEX3-71、AN3-71）、脱氢表雄酮-3-硫酸盐（DHEA）、多奈哌齐）以 σR 拮抗剂敏感的方式增加线粒体 ROS，但降低 Aβ 诱导的 ROS 增加。σR 配体（激动剂或拮抗剂）不影响呼吸，但减轻 Aβ 诱导的改变。σR 激动剂（PRE-084、AN1-41、四氢-N，N-二甲基-2,2-二苯基-3-呋喃甲胺盐酸盐（ANAVEX2-73、AN2-73）、AN3-71）以 Ca 依赖性和 σR 拮抗剂敏感的方式增加复合物 I 活性。σR 配体未能影响复合物 II、III 和 IV 活性。复合物 I 活性的增加解释了 σR 诱导的 ROS 增加，因为配体未能影响线粒体和匀浆中 ROS 积累的其他来源，即 NADPH 氧化酶（NOX）和超氧化物歧化酶（SOD）活性。此外，Aβ 显著降低复合物 I 和 IV 的活性，而 σR 激动剂减轻 Aβ 诱导的复合物 I 和 IV 功能障碍。因此，线粒体中的 σR 活性产生了一种阴阳效应，通过触发适度的 ROS 增加作为生理信号，并在病理（Aβ）条件下促进显著的抗氧化作用。
