Clinical Department and Laboratory of Intensive Care Medicine, Division Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Crit Care Med. 2013 Jan;41(1):182-94. doi: 10.1097/CCM.0b013e3182676657.
Increasing evidence implicates mitochondrial dysfunction as an early, important event in the pathogenesis of critical illness-induced multiple organ failure. We previously demonstrated that prevention of hyperglycemia limits damage to mitochondria in vital organs, thereby reducing morbidity and mortality. We now hypothesize that inadequate activation of mitochondrial repair processes (clearance of damaged mitochondria by autophagy, mitochondrial fusion/fission, and biogenesis) may contribute to accumulation of mitochondrial damage, persistence of organ failure, and adverse outcome of critical illness.
Prospective, randomized studies in a critically ill rabbit model.
University laboratory.
Three-month-old male rabbits.
We studied whether vital organ mitochondrial repair pathways are differentially affected in surviving and nonsurviving hyperglycemic critically ill animals in relation to mitochondrial and organ damage. Next, we investigated the impact of preventing hyperglycemia over time and of administering rapamycin as an autophagy activator.
In both liver and kidney of hyperglycemic critically ill rabbits, we observed signs of insufficient autophagy, including accumulation of p62 and a concomitant decrease in the microtubule-associated protein light-chain-3-II/microtubule-associated protein light-chain-3-I ratio. The phenotype of insufficient autophagy was more pronounced in nonsurviving than in surviving animals. Molecular markers of insufficient autophagy correlated with impaired mitochondrial function and more severe organ damage. In contrast, key players in mitochondrial fusion/fission or biogenesis were not significantly different regarding survival status. Therefore, we focused on autophagy to study the impact of preventing hyperglycemia. Both after 3 and 7 days of illness, autophagy was better preserved in normoglycemic than in hyperglycemic rabbits, which correlated with improved mitochondrial function and less organ damage. Stimulation of autophagy in kidney with rapamycin correlated with protection of renal function.
Our findings put forward insufficient autophagy as a potentially important contributor to mitochondrial and organ damage in critical illness and open perspectives for therapies that activate autophagy during critical illness.
越来越多的证据表明，线粒体功能障碍是导致危重病引起的多器官衰竭的早期重要事件。我们之前的研究表明，预防高血糖可限制重要器官中线粒体的损伤，从而降低发病率和死亡率。我们现在假设，线粒体修复过程（自噬清除受损线粒体、线粒体融合/裂变和生物发生）的激活不足可能导致线粒体损伤的积累、器官衰竭的持续存在以及危重病的不良结局。
危重病兔模型的前瞻性、随机研究。
大学实验室。
三个月大的雄性兔子。
我们研究了在与线粒体和器官损伤相关的存活和非存活高血糖危重病动物中，重要器官线粒体修复途径是否存在差异。接下来，我们研究了随着时间的推移预防高血糖和给予雷帕霉素作为自噬激活剂的影响。
在高血糖危重病兔的肝和肾中，我们观察到自噬不足的迹象，包括 p62 的积累和微管相关蛋白轻链 3-II/微管相关蛋白轻链 3-I 比值的相应下降。在非存活动物中，自噬不足的表型比存活动物更为明显。自噬不足的分子标志物与线粒体功能受损和更严重的器官损伤相关。相比之下，线粒体融合/裂变或生物发生的关键参与者在生存状态方面没有显著差异。因此，我们专注于自噬来研究预防高血糖的影响。在患病的第 3 天和第 7 天，血糖正常的兔子的自噬比高血糖的兔子更好地保留，这与改善的线粒体功能和较少的器官损伤相关。雷帕霉素在肾脏中刺激自噬与肾功能的保护相关。
我们的发现提出了自噬不足作为危重病中线粒体和器官损伤的一个潜在重要贡献因素，并为在危重病期间激活自噬的治疗方法开辟了新的前景。
