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Social isolation stress-resilient rats reveal energy shift from glycolysis to oxidative phosphorylation in hippocampal nonsynaptic mitochondria.
Life Sciences ( IF 5.2 ) Pub Date : 2020-05-13 , DOI: 10.1016/j.lfs.2020.117790 Dragana Filipović 1 , Ivana Perić 1 , Victor Costina 2 , Andrijana Stanisavljević 1 , Peter Gass 3 , Peter Findeisen 2
Life Sciences ( IF 5.2 ) Pub Date : 2020-05-13 , DOI: 10.1016/j.lfs.2020.117790 Dragana Filipović 1 , Ivana Perić 1 , Victor Costina 2 , Andrijana Stanisavljević 1 , Peter Gass 3 , Peter Findeisen 2
Affiliation
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AIMS
To examine the differences in the hippocampal proteome profiles of resilience or susceptibility to chronic social isolation (CSIS), animal model of depression, and to identify biomarkers that can distinguish the two.
MAIN METHODS
Comparative subproteomic approach was used to identify changes in hippocampal cytosol and nonsynaptic mitochondria (NSM) of CSIS-resilient compared to CSIS-sensitive or control rats. The resilient and sensitive phenotypes of CSIS rats were distinguished based on their sucrose preference values. Selected proteins were validated by Western blot or immunofluorescence.
KEY FINDINGS
Predominantly down-regulated processes such as cytosolic cytoskeleton organization, the calcium signaling pathway, ubiquitin proteasome degradation, redox system, malate/aspartate shuttling and glutamate metabolism in CSIS-resilient compared to CSIS-sensitive rats were found. Decreased protein expression of glycolytic enzymes with simultaneous increased expression of Aco2 involved in tricarboxylic acid cycle and expression of several subunits composing oxidative phosphorylation involved enzymes (Uqcrc2, Atp5f1a, Atp5f1b) were found, indicating shift in energy production from glycolysis to oxidative phosphorylation in NSM. The four-fold higher level of mitochondrial glyceraldehyde-3-phosphate dehydrogenase of resilient rats indicated its transfer from the cytosol to the NSM. An increased level of transketolase along with the reduced pyruvate kinase level suggested an activated pentose phosphate pathway in CSIS-resilient relative to control rats. Cytosolic up-regulated CSIS proteins were implicated in antioxidative and proteasomal systems, while down-regulated NSM protein was involved in oxidative phosphorylation.
SIGNIFICANCE
The identified altered activated pathways and potential biomarkers enhance understanding of molecular mechanisms underlying resilience or susceptibility to CSIS, crucial in developing new therapeutic strategies.
中文翻译：
社会隔离的抗应激大鼠揭示了海马非突触线粒体中能量从糖酵解转移到氧化磷酸化。
目的探讨海马蛋白质组概况的适应力或对慢性社交隔离（CSIS），抑郁症动物模型的敏感性的差异，并确定可以区分两者的生物标志物。主要方法与CSIS敏感或对照组相比，比较亚蛋白质组学方法可确定CSIS弹性的海马细胞质和非突触线粒体（NSM）的变化。根据CSIS大鼠的蔗糖偏爱值来区分其弹性和敏感表型。通过蛋白质印迹或免疫荧光验证所选蛋白。主要发现主要是下调过程，例如胞浆细胞骨架组织，钙信号传导途径，泛素蛋白酶体降解，氧化还原系统，与CSIS敏感的大鼠相比，在CSIS弹性的大鼠中发现了苹果酸/天冬氨酸的穿梭和谷氨酸代谢。发现糖酵解酶的蛋白质表达降低，同时参与三羧酸循环的Aco2表达增加，同时一些氧化亚磷酸化酶（Uqcrc2，Atp5f1a，Atp5f1b）的亚基表达也升高，这表明NSM中能量产生从糖酵解转变为氧化磷酸化。弹性大鼠线粒体甘油醛-3-磷酸脱氢酶的水平高四倍，表明其从胞浆转移到NSM。相对于对照大鼠，转酮醇酶水平的增加以及丙酮酸激酶水平的降低表明CSIS弹性中的活化戊糖磷酸途径。胞质上调的CSIS蛋白与抗氧化和蛋白酶体系统有关，而下调的NSM蛋白与氧化磷酸化有关。意义鉴定出的改变的激活途径和潜在的生物标记物可增强对潜在的CSIS抵抗力或敏感性的分子机制的了解，这对于开发新的治疗策略至关重要。
更新日期：2020-05-19
中文翻译：
社会隔离的抗应激大鼠揭示了海马非突触线粒体中能量从糖酵解转移到氧化磷酸化。
目的探讨海马蛋白质组概况的适应力或对慢性社交隔离（CSIS），抑郁症动物模型的敏感性的差异，并确定可以区分两者的生物标志物。主要方法与CSIS敏感或对照组相比，比较亚蛋白质组学方法可确定CSIS弹性的海马细胞质和非突触线粒体（NSM）的变化。根据CSIS大鼠的蔗糖偏爱值来区分其弹性和敏感表型。通过蛋白质印迹或免疫荧光验证所选蛋白。主要发现主要是下调过程，例如胞浆细胞骨架组织，钙信号传导途径，泛素蛋白酶体降解，氧化还原系统，与CSIS敏感的大鼠相比，在CSIS弹性的大鼠中发现了苹果酸/天冬氨酸的穿梭和谷氨酸代谢。发现糖酵解酶的蛋白质表达降低，同时参与三羧酸循环的Aco2表达增加，同时一些氧化亚磷酸化酶（Uqcrc2，Atp5f1a，Atp5f1b）的亚基表达也升高，这表明NSM中能量产生从糖酵解转变为氧化磷酸化。弹性大鼠线粒体甘油醛-3-磷酸脱氢酶的水平高四倍，表明其从胞浆转移到NSM。相对于对照大鼠，转酮醇酶水平的增加以及丙酮酸激酶水平的降低表明CSIS弹性中的活化戊糖磷酸途径。胞质上调的CSIS蛋白与抗氧化和蛋白酶体系统有关，而下调的NSM蛋白与氧化磷酸化有关。意义鉴定出的改变的激活途径和潜在的生物标记物可增强对潜在的CSIS抵抗力或敏感性的分子机制的了解，这对于开发新的治疗策略至关重要。
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