Carbamoyl phosphate synthase-1: A marker of mitochondrial damage and depletion in the liver during sepsis
Carbamoyl phosphate synthase-1: A marker of mitochondrial damage and depletion in the liver during sepsis
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DOI：
10.1097/01.ccm.0000230240.02216.21
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发表时间：
2006-09-01
影响因子：
8.8
通讯作者：
Cook, Charles H.
中科院分区：
文献类型：
--
作者：
Crouser, Elliott D.;Julian, Mark W.;Cook, Charles H.
客观的。线粒体损伤和功能障碍被认为在脓毒症引起的器官衰竭的发病机制中发挥重要作用。不幸的是，目前尚不存在重要器官中线粒体损伤的特定标记。最近，发现羧甲酰磷酸合酶（CPS）-1（一种主要定位于肝线粒体的蛋白质）在脓毒症患者的血浆中以高浓度存在。因此，我们假设在临床相关脓毒症模型中，CPS-1 的循环释放与肝脏中的线粒体损伤或线粒体功能受损相关。设计：前瞻性、随机、对照动物研究。设置：大学医学中心研究实验室。受试者：雄性，Balb/C 小鼠，年龄 10-12 周。干预：动物被分配接受盲肠 结扎和穿刺（CLP 脓毒症）或假手术，并与未治疗的对照进行比较。在手术后的不同时间点（8、24、48 小时和 6 天）评估血浆 CPS-1 水平和肝脏线粒体变量，包括形态、呼吸活动、质量（即心磷脂含量）和蛋白质羰基化。测量和主要结果：CLP 8 小时内检测到氧化应激（即羰基化），并持续至整个过程 48 小时。败血症组的血浆 CPS-1 水平在 24 小时时急剧增加，在 48 小时时保持显着升高，并在 6 天时恢复正常。肝脏线粒体形态和功能异常与血浆 CPS-1 水平升高同时发生。肝脏中的线粒体耗竭并非由于细胞死亡，而是与溶酶体清除率增加有关。到第 6 天，线粒体生物发生因子的表达增加，然后线粒体变量恢复和 CPS-1 水平正常化。结论：循环 CPS-1 是 CLP 脓毒症亚急性期肝脏线粒体损伤和消耗的标志物。从机制的角度来看，线粒体耗竭并不是由于细胞死亡，而是显然与溶酶体去除受损线粒体（即自噬）以及随后线粒体群体的补充有关。需要进一步的研究来确定 CPS-1 作为脓毒症严重程度标志物的临床效用。
Objective. Mitochondrial damage and dysfunction are thought to play an important role in the pathogenesis of sepsis-induced organ failures. Unfortunately, specific markers of mitochondrial damage in vital organs do not currently exist. Recently, carbomyl phosphate synthase (CPS)-1, a protein primarily localized to liver mitochondria, was found to be present in high concentrations in the plasma of septic humans. Thus, we hypothesized that the circulatory release of CPS-1 would correlate with mitochondrial damage or impaired mitochondrial function in the liver in a clinically relevant model of sepsis.Design: Prospective, randomized, controlled animal study.Setting: University medical center research laboratory.Subjects: Male, Balb/C mice, aged 10-12 wks.Interventions: Animals were assigned to receive cecal ligation and puncture (CLP sepsis) or sham operation and compared with untreated controls. Plasma CPS-1 levels and liver mitochondrial variables, including morphology, respiratory activity, mass (i.e., cardiolipin content), and protein carbonylation, were assessed at various time points (8, 24, and 48 hrs and 6 days) after surgery.Measurements and Main Results: Oxidant stress (i.e., carbonylation) was detected within 8 hrs of CLP and persisted through 48 hrs. Plasma CPS-1 levels increased dramatically at 24 hrs, remained significantly elevated at 48 hrs, and normalized by 6 days in the sepsis group. Abnormalities of liver mitochondrial morphology and function coincided with increased plasma CPS-1 levels. Mitochondrial depletion in the liver was not due to cell death but was associated with increased lysosomal clearance. Increased expression of mitochondrial biogenesis factors preceded restoration of mitochondrial variables and normalization of CPS-1 levels by day 6.Conclusions: Circulating CPS-1 is a marker of mitochondrial damage and depletion in the liver during the subacute phase of CLP sepsis. From a mechanistic standpoint, mitochondrial depletion is not due to cell death but is apparently related to the removal of damaged mitochondria by lysosomes (i.e., autophagy), followed by repletion of mitochondrial populations. Further studies are needed to determine the clinical utility of CPS-1 as a marker of sepsis severity.