Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Circ Heart Fail. 2011 Nov;4(6):707-13. doi: 10.1161/CIRCHEARTFAILURE.111.961474. Epub 2011 Aug 12.
The outcome of the surgical repair in congenital heart disease correlates with the degree of myocardial damage. In this study, we determined whether mitochondrial DNA depletion is a sensitive marker of right ventricular (RV) damage and whether impaired mitochondrial DNA (mtDNA) replication contributes to the transition from compensated hypertrophy to failure.
RV samples obtained from 31 patients undergoing cardiac surgery were compared with 5 RV samples from nonfailing hearts (control). Patients were divided into compensated hypertrophy and failure groups, based on preoperative echocardiography, catheterization, and/or MRI data. Mitochondrial enzyme activities (citrate synthase and succinate dehydrogenase) were maintained during hypertrophy and decreased by ≈40% (P<0.05 versus control) at the stage of failure. In contrast, mtDNA content was progressively decreased in the hypertrophied RV through failure (by 28±8% and 67±11%, respectively, P<0.05 for both), whereas mtDNA-encoded gene expression was sustained by increased transcriptional activity during compensated hypertrophy but not in failure. Mitochondrial DNA depletion was attributed to reduced mtDNA replication in both hypertrophied and failing RV, and it was independent of PGC-1 downregulation but was accompanied by reduced expression of proteins constituting the mtDNA replication fork. Decreased mtDNA content in compensated hypertrophy was also associated with pathological changes of mitochondria ultrastructure.
Impaired mtDNA replication causes early and progressive depletion of mtDNA in the RV of the patients with congenital heart disease during the transition from hypertrophy to failure. Decreased mtDNA content probably is a sensitive marker of mitochondrial injury in this patient population.
先天性心脏病的手术修复结果与心肌损伤程度相关。在这项研究中，我们确定线粒体 DNA 耗竭是否是右心室（RV）损伤的敏感标志物，以及受损的线粒体 DNA（mtDNA）复制是否有助于从代偿性肥厚向衰竭的转变。
比较了 31 例接受心脏手术的患者的 RV 样本和 5 例非衰竭心脏（对照）的 RV 样本。根据术前超声心动图、导管插入术和/或 MRI 数据，将患者分为代偿性肥厚和衰竭组。线粒体酶活性（柠檬酸合酶和琥珀酸脱氢酶）在肥厚期得以维持，但在衰竭期下降了约 40%（P<0.05 与对照组相比）。相比之下，mtDNA 含量在肥厚性 RV 中通过衰竭而逐渐下降（分别下降 28±8%和 67±11%，均 P<0.05），而 mtDNA 编码基因的表达在代偿性肥厚期间通过增加转录活性得以维持，但在衰竭时则不能。线粒体 DNA 耗竭归因于肥厚和衰竭 RV 中 mtDNA 复制减少，且与 PGC-1 下调无关，但伴随着构成 mtDNA 复制叉的蛋白质表达减少。代偿性肥厚中 mtDNA 含量的降低也与线粒体超微结构的病理变化有关。
在先天性心脏病患者从肥厚向衰竭的转变过程中，受损的 mtDNA 复制导致 RV 中线粒体 DNA 的早期和进行性耗竭。减少的 mtDNA 含量可能是该患者群体中线粒体损伤的敏感标志物。
