Department of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand.
Mitochondrion. 2019 Jul;47:1-9. doi: 10.1016/j.mito.2019.04.006. Epub 2019 Apr 20.
Biliary atresia (BA) is a chronic obstructive liver disease, leading to advanced liver failure. Mitochondria dysfunction-mediated aberrant telomere length has been implicated in various pathological processes including cholestasis. Herein, we aimed to investigate associations between mitochondrial DNA (mtDNA) copy number, oxidative DNA damage, telomere length, and disease severity in BA patients. mtDNA copy number and relative telomere length (RTL) were assessed using real-time PCR. Circulating 8-hydroxy-2'-deoxyguanosine (8-OHdG) was measured using ELISA. Our findings showed that BA patients had significantly lower mtDNA copy number and RTL than healthy controls, whereas plasma 8-OHdG levels were significantly elevated in BA patients. mtDNA copy number was remarkably reduced in advanced BA patients. Furthermore, mtDNA copy number was independently associated with age and degree of liver fibrosis in BA patients. Decreased mtDNA copy number was significantly associated with elevated risks of BA, severe fibrosis, jaundice, and hepatic dysfunction. Low mtDNA copy number can be utilized to distinguish patients with poor-outcome from those with good-outcome. Survival curve analysis revealed that low mtDNA copy number was significantly associated with poor survival of BA patients. Interestingly, there was a positive association between mtDNA copy number and plasma 8-OHdG in BA patients, while a negative association of mtDNA copy number with RTL was observed in BA patients. Alternatively, RTL was negatively correlated with plasma 8-OHdG in BA patients. These data demonstrated relationships between leukocytes mtDNA copy number, oxidative stress, telomere length, and clinical parameters in BA patients. Accordingly, our findings indicate that mtDNA copy number may serve as a potential biomarker reflecting BA severity.
先天性胆道闭锁（BA）是一种慢性阻塞性肝病，可导致晚期肝功能衰竭。线粒体功能障碍导致的端粒长度异常与包括胆汁淤积在内的各种病理过程有关。在此，我们旨在研究 BA 患者中线粒体 DNA（mtDNA）拷贝数、氧化 DNA 损伤、端粒长度与疾病严重程度之间的关系。使用实时 PCR 评估 mtDNA 拷贝数和相对端粒长度（RTL）。使用 ELISA 测量循环 8-羟基-2'-脱氧鸟苷（8-OHdG）。我们的研究结果表明，BA 患者的 mtDNA 拷贝数和 RTL 明显低于健康对照组，而 BA 患者的血浆 8-OHdG 水平明显升高。晚期 BA 患者的 mtDNA 拷贝数显著降低。此外，mtDNA 拷贝数与 BA 患者的年龄和肝纤维化程度独立相关。mtDNA 拷贝数降低与 BA 的发生风险、严重纤维化、黄疸和肝功能障碍显著相关。低 mtDNA 拷贝数可用于区分预后不良和预后良好的患者。生存曲线分析显示，低 mtDNA 拷贝数与 BA 患者的不良生存显著相关。有趣的是，BA 患者 mtDNA 拷贝数与血浆 8-OHdG 呈正相关，而 mtDNA 拷贝数与 BA 患者 RTL 呈负相关。相反，BA 患者 RTL 与血浆 8-OHdG 呈负相关。这些数据表明，BA 患者白细胞 mtDNA 拷贝数、氧化应激、端粒长度与临床参数之间存在关系。因此，我们的研究结果表明，mtDNA 拷贝数可能作为反映 BA 严重程度的潜在生物标志物。
