A mitochondria-targeted mass spectrometry probe to detect glyoxals: implications for diabetes.
A mitochondria-targeted mass spectrometry probe to detect glyoxals: implications for diabetes.
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线粒体靶向质谱探针以检测乙二醇：对糖尿病的影响。
DOI：
10.1016/j.freeradbiomed.2013.11.025
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发表时间：
2014-02
影响因子：
7.4
通讯作者：
Murphy, Michael P.
中科院分区：
文献类型：
--
作者：
Pun, Pamela Boon Li;Logan, Angela;Darley-Usmar, Victor;Chacko, Balu;Johnson, Michelle S.;Huang, Guang W.;Rogatti, Sebastian;Prime, Tracy A.;Methner, Carmen;Krieg, Thomas;Fearnley, Ian M.;Larsen, Lesley;Larsen, David S.;Menger, Katja E.;Collins, Yvonne;James, Andrew M.;Kumar, G. D. Kishore;Hartley, Richard C.;Smith, Robin A. J.;Murphy, Michael P.
由于高血糖症而发生的蛋白质和核酸的糖化破坏细胞功能并导致许多病理学，包括与糖尿病和衰老相关的那些病理学。细胞内糖基化发生在反应性1，2-二羰基甲基乙二醛和乙二醛生成之后，线粒体功能的破坏与高血糖症相关。然而，这些反应性二羰基化合物在病理学中对线粒体损伤的贡献尚不清楚，因为它们在细胞和体内线粒体内的水平不确定。为了解决这个问题，我们开发了一种靶向线粒体的试剂（MitoG），旨在评估细胞内线粒体二羰基化合物的水平。MitoG包含亲脂性三苯基鳞阳离子官能团和邻苯二胺部分，所述亲脂性三苯基鳞阳离子官能团将分子引导至细胞内的线粒体，所述邻苯二胺部分与二羰基反应以产生独特且稳定的产物。这些诊断性杂环产物的积累程度可以通过液相色谱-串联质谱法容易且灵敏地定量，从而能够确定变化。使用基于MitoG的分析，我们评估了体内培养的细胞和糖尿病秋田小鼠模型中响应高血糖症的甲基乙二醛和乙二醛的形成。这些发现表明，在细胞和体内高血糖期间，线粒体内的甲基乙二醛和乙二醛水平增加，表明它们可能导致糖尿病和衰老中发生的病理性线粒体功能障碍。已经开发了一种以丙酮酸为靶向的质谱探针MitoG来测量乙二醛和甲基乙二醛。使用MitoG，我们表明，线粒体乙二醛和甲基乙二醛可以在高血糖细胞中测量。MitoG也可以在体内用于推断I型糖尿病小鼠模型中线粒体乙二醛和甲基乙二醛的产生。这些发现表明，乙二醛和甲基乙二醛在线粒体内的积累可能有助于糖尿病中线粒体功能障碍。
The glycation of protein and nucleic acids that occurs as a consequence of hyperglycemia disrupts cell function and contributes to many pathologies, including those associated with diabetes and aging. Intracellular glycation occurs after the generation of the reactive 1,2-dicarbonyls methylglyoxal and glyoxal, and disruption of mitochondrial function is associated with hyperglycemia. However, the contribution of these reactive dicarbonyls to mitochondrial damage in pathology is unclear owing to uncertainties about their levels within mitochondria in cells and in vivo. To address this we have developed a mitochondria-targeted reagent (MitoG) designed to assess the levels of mitochondrial dicarbonyls within cells. MitoG comprises a lipophilic triphenylphosphonium cationic function, which directs the molecules to mitochondria within cells, and an o-phenylenediamine moiety that reacts with dicarbonyls to give distinctive and stable products. The extent of accumulation of these diagnostic heterocyclic products can be readily and sensitively quantified by liquid chromatography–tandem mass spectrometry, enabling changes to be determined. Using the MitoG-based analysis we assessed the formation of methylglyoxal and glyoxal in response to hyperglycemia in cells in culture and in the Akita mouse model of diabetes in vivo. These findings indicated that the levels of methylglyoxal and glyoxal within mitochondria increase during hyperglycemia both in cells and in vivo, suggesting that they can contribute to the pathological mitochondrial dysfunction that occurs in diabetes and aging. A mitochondria-targeted mass spectrometric probe, MitoG, has been developed to measure glyoxal and methylglyoxal. Using MitoG we show that mitochondrial glyoxal and methylglyoxal can be measured in hyperglycemic cells. MitoG can also be used in vivo to infer mitochondrial glyoxal and methylglyoxal production in a mouse model of type I diabetes. These findings suggest that the accumulation of glyoxal and methylglyoxal within mitochondria may contribute to mitochondrial dysfunction in diabetes.
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影响因子：
29
作者：
Cochemé HM;Quin C;McQuaker SJ;Cabreiro F;Logan A;Prime TA;Abakumova I;Patel JV;Fearnley IM;James AM;Porteous CM;Smith RA;Saeed S;Carré JE;Singer M;Gems D;Hartley RC;Partridge L;Murphy MP
通讯作者：
Murphy MP
影响因子：
3.7
作者：
Hill BG;Benavides GA;Lancaster JR Jr;Ballinger S;Dell'Italia L;Jianhua Z;Darley-Usmar VM
通讯作者：
Darley-Usmar VM
影响因子：
2.9
作者：
Chaplen, FWR;Fahl, WE;Cameron, DC
通讯作者：
Cameron, DC
影响因子：
2.2
作者：
Kingkeohoi, S;Chaplen, FWR
通讯作者：
Chaplen, FWR
影响因子：
4.5
作者：
FEDORONKO, M;KONIGSTEIN, J;LINEK, K
通讯作者：
LINEK, K