8月23日,，國際知名學(xué)術(shù)期刊Molecular and Cellular Proteomics在線發(fā)表了生化細胞所曾嶸研究組工作：運用蛋白質(zhì)組學(xué)策略，研究了大鼠肝臟線粒體蛋白質(zhì)組表達,、蛋白質(zhì)磷酸化修飾以及羥基化修飾從前糖尿病期到糖尿病初期的動態(tài)變化。
已有研究表明,，在2型糖尿病發(fā)病過程中,，細胞線粒體的生理功能發(fā)生了顯著變化，線粒體的功能受損也是進一步促進糖尿病發(fā)展的重要因素,。了解糖尿病發(fā)病過程中線粒體蛋白質(zhì)組及其修飾的動態(tài)變化,，掌握這些變化所影響的生理活動和調(diào)控網(wǎng)絡(luò)，對于闡明2型糖尿病的致病過程有著重要的意義,。
中國科學(xué)院上海生命科學(xué)研究院生化與細胞研究所/系統(tǒng)生物學(xué)重點實驗室博士生鄧文君等人在曾嶸研究員的指導(dǎo)下,，運用蛋白質(zhì)組學(xué)策略和該實驗室發(fā)明的陰陽多維色譜-質(zhì)譜方法,，研究了大鼠肝臟線粒體的蛋白質(zhì)組表達,、蛋白質(zhì)磷酸化修飾以及羥基化修飾從前糖尿病期到糖尿病初期的動態(tài)變化。研究發(fā)現(xiàn)在2型糖尿病發(fā)病早期，肝細胞通過不斷增強能量代謝,，激活三羧酸循環(huán),、脂肪酸β氧化等物質(zhì)代謝途徑以適應(yīng)不斷升高的血糖和血脂。該工作發(fā)現(xiàn)這些代謝途徑在糖尿病發(fā)生過程中不僅存在著蛋白質(zhì)表達水平的調(diào)控,，還存在著蛋白質(zhì)磷酸化修飾水平的調(diào)控,。此外，隨著線粒體能量代謝的加強,，其副產(chǎn)物活性氧物質(zhì)（Reactive Oxygen Species,，ROS）的含量也隨之上升，對細胞形成氧化壓力,。該工作檢測到線粒體蛋白質(zhì)羥基化修飾水平隨著糖尿病的進展而升高,，這正是細胞氧化壓力增強的一種體現(xiàn)。但另一方面,，線粒體內(nèi)抗氧化壓力以及抗凋亡蛋白質(zhì)的表達卻隨糖尿病的進展明顯降低,，進一步反映出隨著2型糖尿病的發(fā)生，細胞清除氧化物質(zhì)的能力降低,，細胞凋亡指數(shù)不斷上升,。這一工作首次系統(tǒng)地揭示了糖尿病發(fā)生發(fā)展過程中肝臟線粒體各個功能模塊在蛋白質(zhì)表達水平，蛋白質(zhì)磷酸化修飾水平和羥基化修飾水平的動態(tài)變化,，這些變化相互影響,、相互調(diào)節(jié)，最終促進了一種穩(wěn)定病理狀態(tài)-2型糖尿病的形成,。這一工作為進一步研究2型糖尿病的致病機理,，篩選糖尿病的診斷標(biāo)志物和治療靶點提供了分子基礎(chǔ)。
該項工作得到了國家科技部,，基金委,，中科院和歐盟第六框架的經(jīng)費支持。（生物谷Bioon.com）
生物谷推薦原始出處：
Mol. Cell. Proteomics, Aug 2009; doi:10.1074/mcp.M900020-MCP200
Proteome, phosphoproteome and hydroxyproteome of liver mitochondria in diabetic rats at early pathogenic stages
Wen-Jun Deng, Song Nie, JIe Dai, Jia-Rui Wu, and Rong Zeng
Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai 200031
It has been proposed that mitochondrial dysfunction is involved in the pathogenesis of type 2 diabetes (T2D). To dissect the underlying mechanisms, we performed a multiplexed proteomics study on liver mitochondria isolated from a spontaneous diabetic rat model before/after they are rendered diabetic. All together we identified 1091 mitochondrial proteins, 228 phosphoproteins and 355 hydroxyproteins. Mitochondrial proteins were found to undergo expression changes in a highly correlated fashion during T2D development. For example, proteins involved in ?-oxidation, TCA cycle, oxidative phosphorylation (OXPHOS) and other bioenergetic processes were coordinately up-regulated, indicating that liver cells confront T2D by increasing energy expenditure and activating pathways that rid themselves of the constitutively increased flux of glucose and lipid. Notably, activation of OXPHOS is immediately related to the overproduction of reactive oxygen species (ROS), which causes oxidative stress within the cells. Increased oxidative stress was also evidenced by our post-translational modification profiles, such that mitochondrial proteins were heavier hydroxylated during T2D development. Moreover, we observed a distinct depression of anti-apoptosis and anti-oxidative stress proteins, which might reflect higher apoptotic index under diabetic stage. We suggest that such changes in systematic metabolism are causally linked to the development of T2D. Comparing proteomics data against microarray data, we demonstrated that many T2D-related alterations were unidentifiable by either proteomic or genomic approaches alone, underscoring the importance of integrating different approaches. Our compendium could help to unveil pathogenic events in mitochondria leading to T2D, and be useful for the discovery of diagnosis biomarker and therapeutic targets of T2D.
