Kristal B S, Vigneau-Callahan K E, Moskowitz A J, Matson W R
Dementia Research Service, Burke Medical Research Institute, White Plains, New York, 10605, USA.
Arch Biochem Biophys. 1999 Oct 1;370(1):22-33. doi: 10.1006/abbi.1999.1387.
Type I diabetes in rodents is associated with a spectrum of liver mitochondrial abnormalities ranging from evidence of oxidative stress and altered antioxidant defenses to frank defects in respiration rates and respiratory control ratios. To better address the myriad changes in redox metabolism in these mitochondria, we have applied new chromatographic techniques that enable simultaneous analysis of multiple components of pathways of interest (e.g., purine catabolites and oxidation by-products). We report here a portion of these results, which, in conjunction with other reported data, suggest that purine catabolism may contribute to mitochondrial antioxidant defenses by producing the antioxidant urate. In liver mitochondria from diabetic rats, increases in uric acid (threefold) and its direct precursor xanthine (sixfold) were observed in moderate diabetes, but levels fell essentially to normal in severe disease. Failure to maintain elevated xanthine and uric acid occurred contemporaneously with progressive mitochondrial dysfunction. Regression analysis revealed altered precursor-product relationships between xanthine, its precursors, and uric acid. An independent set of studies in isolated rat liver mitochondria showed that mitochondrial respiration was associated with essentially uniform decreases (approximately 30%) in all purine catabolites measured (urate, xanthine, hypoxanthine, guanine, guanosine, and xanthosine). That result suggests the potential for steady production of urate. Taken together, the two studies raise the possibility that purine catabolism may be a previously unappreciated component of the homeostatic response of mitochondria to oxidant stress and may play a critical role in slowing progressive mitochondrial dysfunction in certain disease states.
啮齿动物的I型糖尿病与一系列肝脏线粒体异常有关，范围从氧化应激证据和抗氧化防御改变到呼吸速率和呼吸控制率的明显缺陷。为了更好地研究这些线粒体中氧化还原代谢的众多变化，我们应用了新的色谱技术，能够同时分析感兴趣途径的多个成分（例如嘌呤分解代谢产物和氧化副产物）。我们在此报告这些结果的一部分，结合其他已报道的数据表明，嘌呤分解代谢可能通过产生抗氧化剂尿酸来促进线粒体的抗氧化防御。在糖尿病大鼠的肝脏线粒体中，在中度糖尿病中观察到尿酸（增加三倍）及其直接前体黄嘌呤（增加六倍）增加，但在严重疾病中水平基本降至正常。未能维持黄嘌呤和尿酸升高与线粒体功能逐渐障碍同时发生。回归分析显示黄嘌呤、其前体和尿酸之间的前体-产物关系发生改变。在分离的大鼠肝脏线粒体中进行的另一组独立研究表明，线粒体呼吸与所测量的所有嘌呤分解代谢产物（尿酸、黄嘌呤、次黄嘌呤、鸟嘌呤、鸟苷和黄苷）的基本均匀下降（约30%）相关。该结果表明尿酸有稳定产生的潜力。综合来看，这两项研究提出了一种可能性，即嘌呤分解代谢可能是线粒体对氧化应激稳态反应中一个以前未被重视的组成部分，并且在某些疾病状态下减缓线粒体功能逐渐障碍方面可能起关键作用。
