Sigma-1 Receptor Agonists Induce Oxidative Stress in Mitochondria and Enhance Complex I Activity in Physiological Condition but Protect Against Pathological Oxidative Stress
Sigma-1 Receptor Agonists Induce Oxidative Stress in Mitochondria and Enhance Complex I Activity in Physiological Condition but Protect Against Pathological Oxidative Stress
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DOI：
10.1007/s12640-017-9838-2
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发表时间：
2019-01-01
影响因子：
3.7
通讯作者：
Maurice, Tangui
中科院分区：
文献类型：
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作者：
Goguadze, Nino;Zhuravliova, Elene;Maurice, Tangui
sigma(1)受体（sigma R-1）是一种存在于线粒体相关内质网（ER）膜（MAMs）上的伴侣蛋白，它通过与肌醇-1,4,5三磷酸受体（IP(3)Rs）相互作用来调节ER和线粒体之间的Ca2+交换。sigma R-1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。sigma R-1对线粒体病理生理和下游信号的影响尚不完全清楚。我们在此评估了小鼠线粒体制剂中sigma R-1配体在生理条件下和直接应用淀粉样蛋白A（1-42）肽后对活性氧（ROS）产生、线粒体呼吸和复杂活性的影响。sigma R-1激动剂(2-(4-morpholinethyl)-1-phenylcyclohexanecarboxylate hydrochloride (pre084)，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-3,8-重氮斯匹罗[4.5]癸-3-基）-3-（1h -吲哚-3-基）propan-1-one （ANAVEX3-71, AN3-71)，脱氢表雄酮-3硫酸盐（DHEA），多奈哌齐））以sigma R-1拮抗剂敏感的方式增加线粒体ROS，但降低a（1-42）诱导的ROS增加。sigma R-1配体（激动剂或拮抗剂）不影响呼吸，但减弱A（1-42）诱导的改变。sigma R-1激动剂（pre084, 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Ca2+依赖性和sigma R-1拮抗剂敏感的方式增加复合物I的活性。sigma R-1配体不能影响配合物II、III和IV的活性。复合物I活性的增加解释了sigma r -1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，A（1-42）显著降低复合物I和IV的活性，sigma R-1激动剂减弱A（1-42）诱导的复合物I和IV功能障碍。因此，线粒体中的sigma R-1活性导致阴阳效应，通过触发适度的ROS增加，作为生理信号，并在病理(a)条件下促进显着的抗氧化作用。
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.