Mercer University School of Medicine, Macon, GA, USA.
Vanderbilt University Medical Center, Nashville, TN, USA.
Redox Biol. 2019 Sep;26:101300. doi: 10.1016/j.redox.2019.101300. Epub 2019 Aug 14.
Inflammation is a major cause of morbidity and mortality in Western societies. Despite use of multiple drugs, both chronic and acute inflammation still represent major health burdens. Inflammation produces highly reactive dicarbonyl lipid peroxidation products such as isolevuglandins which covalently modify and cross-link proteins via lysine residues. Mitochondrial dysfunction has been associated with inflammation; however, its molecular mechanisms and pathophysiological role are still obscure. We hypothesized that inflammation-induced isolevuglandins contribute to mitochondrial dysfunction and mortality. To test this hypothesis, we have (a) investigated the mitochondrial dysfunction in response to synthetic 15-E-isolevuglandin (IsoLG) and its adducts; (b) developed a new mitochondria-targeted scavenger of isolevuglandins by conjugating 2-hydroxybenzylamine to the lipophilic cation triphenylphosphonium, (4-(4-aminomethyl)-3-hydroxyphenoxy)butyl)-triphenylphosphonium (mito2HOBA); (c) tested if mito2HOBA protects from mitochondrial dysfunction and mortality using a lipopolysaccharide model of inflammation. Acute exposure to either IsoLG or IsoLG adducts with lysine, ethanolamine or phosphatidylethanolamine inhibits mitochondrial respiration and attenuates Complex I activity. Complex II function was much more resistant to IsoLG. We confirmed that mito2HOBA markedly accumulates in isolated mitochondria and it is highly reactive with IsoLGs. To test the role of mitochondrial IsoLGs, we studied the therapeutic potential of mito2HOBA in lipopolysaccharide mouse model of sepsis. Mito2HOBA supplementation in drinking water (0.1 g/L) to lipopolysaccharide treated mice increased survival by 3-fold, improved complex I-mediated respiration, and histopathological analyses supported mito2HOBA-mediated protection of renal cortex from cell injury. These data support the role of mitochondrial IsoLG in mitochondrial dysfunction and inflammation. We conclude that reducing mitochondrial IsoLGs may be a promising therapeutic target in inflammation and conditions associated with mitochondrial oxidative stress and dysfunction.
炎症是西方社会发病率和死亡率的主要原因。尽管使用了多种药物，但慢性和急性炎症仍然是主要的健康负担。炎症会产生高度反应性的二羰基脂质过氧化产物，如异亮氨酸，它通过赖氨酸残基共价修饰和交联蛋白质。线粒体功能障碍与炎症有关；然而，其分子机制和病理生理作用仍不清楚。我们假设炎症诱导的异亮氨酸与线粒体功能障碍和死亡率有关。为了验证这一假设，我们已经（a）研究了合成 15-E-异亮氨酸（IsoLG）及其加合物对线粒体功能障碍的影响；（b）通过将 2-羟基苯甲胺与亲脂性阳离子三苯基膦偶联，开发了一种新的线粒体靶向异亮氨酸清除剂（（4-（4-氨基甲基）-3-羟基苯氧基）丁基）-三苯基膦（mito2HOBA）；（c）使用脂多糖炎症模型测试 mito2HOBA 是否能保护线粒体功能障碍和死亡率。急性暴露于异亮氨酸或异亮氨酸与赖氨酸、乙醇胺或磷脂酰乙醇胺的加合物会抑制线粒体呼吸并减弱复合物 I 的活性。复合物 II 的功能对异亮氨酸的抵抗力要强得多。我们证实 mito2HOBA 明显积聚在线粒体中，并且与 IsoLGs 高度反应。为了研究线粒体 IsoLGs 的作用，我们研究了 mito2HOBA 在脂多糖败血症小鼠模型中的治疗潜力。将 mito2HOBA 补充到饮用水中（0.1g/L），可使脂多糖处理的小鼠的存活率提高 3 倍，改善复合物 I 介导的呼吸，并通过组织病理学分析支持 mito2HOBA 介导的对肾皮质细胞损伤的保护。这些数据支持线粒体 IsoLG 在线粒体功能障碍和炎症中的作用。我们得出结论，减少线粒体 IsoLGs 可能是炎症和与线粒体氧化应激和功能障碍相关的疾病的有前途的治疗靶点。
