Targeting Mitochondrial Dysfunction with L-Alpha Glycerylphosphorylcholine

Background
We hypothesized that L-alpha-glycerylphosphorylcholine (GPC), a deacylatedphosphatidylcholine derivative, can influence the mitochondrial respiratory activity and in this way, may exert tissue protective effects.
Methods
Rat liver mitochondria were examined with high-resolution respirometry to analyze the effects of GPC on the electron transport chain in normoxic and anoxic conditions. Besides, Sprague-Dawley rats were subjected to sham operation or standardized liver ischemia-reperfusion (IR), with or without GPC administration. The reduced glutathione (GSH) and oxidized glutathione disulfide (GSSG), the tissue myeloperoxidase, xanthine oxidoreductase and NADPH oxidases activities were measured. Tissue malondialdehyde and nitrite/nitrate formation, together with blood superoxide and hydrogen-peroxide production were assessed.
Results
GPC increased the efficacy of complex I-linked mitochondrial oxygen consumption, with significantly lower in vitro leak respiration. Mechanistically, liver IR injury was accompanied by deteriorated mitochondrial respiration and enhanced ROS production and, as a consequence, by significantly increased inflammatory enzyme activities. GPC administration decreased the inflammatory activation in line with the reduced oxidative and nitrosative stress markers.
Conclusion
GPC, by preserving the mitochondrial complex I function respiration, reduced the biochemical signs of oxidative stress after an IR episode. This suggests that GPC is a mitochondria-targeted compound that indirectly suppresses the activity of major intracellular superoxide-generating enzymes.

背景
我们提出假说：脱酰磷脂酰胆碱衍生物L-α-甘油磷酸胆碱（L-alpha-glycerylphosphorylcholine, GPC）可影响线粒体呼吸活性，进而发挥组织保护作用。
方法
采用高分辨率呼吸测定法检测大鼠肝线粒体，分析GPC在常氧与缺氧条件下对电子传递链的影响。此外，将斯普拉格-道利（Sprague-Dawley）大鼠分为四组：假手术组、标准化肝脏缺血再灌注（IR）组、伴GPC给药的缺血再灌注组及不伴GPC给药的缺血再灌注组。检测指标包括：还原型谷胱甘肽（reduced glutathione, GSH）与氧化型谷胱甘肽二硫化物（oxidized glutathione disulfide, GSSG）水平，组织髓过氧化物酶、黄嘌呤氧化还原酶及NADPH氧化酶活性；同时测定组织丙二醛、亚硝酸盐/硝酸盐生成量，以及血液中超氧阴离子与过氧化氢的生成水平。
结果
GPC可提升复合体I偶联的线粒体氧消耗效率，并显著降低体外线粒体呼吸漏泄水平。机制层面，肝脏IR损伤伴随线粒体呼吸功能受损、活性氧（reactive oxygen species, ROS）生成增加，进而导致炎症相关酶活性显著升高；而GPC给药可抑制炎症活化，同时降低氧化与亚硝化应激标志物水平。
结论
GPC通过维持线粒体复合体I的呼吸功能，减轻缺血再灌注事件后氧化应激的生化异常表现。这表明GPC是一种靶向线粒体的化合物，可间接抑制主要细胞内超氧生成酶的活性。