Mitochondrial and glycolysis-regulatory gene expression profiles are associated with intrauterine growth restriction

<b>Introduction:</b> Intrauterine growth restriction (IUGR) is a major pregnancy complication with significant postnatal implications. IUGR is characterized by high placental oxidative stress (OS) and increased mitochondrial DNA (mtDNA) abundance that altogether alter the placental metabolism. Such alterations may be captured by changes in the expression of mitochondrial-encoded oxidative phosphorylation genes and glycolysis-regulatory genes. <b>Study design:</b> We aimed here to determine the association between the placental expression of all 13 protein-coding mitochondrial-encoded genes and seven key nuclear glycolysis-regulatory genes, <i>PDK1</i>, <i>PDK2</i>, <i>PDK3</i>, <i>PDK4</i>, <i>PKLR</i>, <i>PKM</i>, <i>OGT</i>, with IUGR, within a case-control study including 50 IUGR and 100 control pregnancies. We additionally assessed placental mtDNA abundance and OS. <b>Results:</b> Three mitochondrial genes, <i>MT-ND5</i>, <i>MT-ND6</i>, and <i>MT-ATP6</i> were found negatively associated with IUGR, while one glycolysis-regulatory gene, <i>PDK1</i> was positively associated with IUGR. mtDNA abundance and OS were positively associated with IUGR. Our study confirmed the existing data on IUGR inducing increased placental OS and mtDNA abundance. Further, our data highlighted the significant involvement of mitochondria and glucose metabolism in the OS-challenged IUGR placentas, which might modulate the placental expression of genes affecting the OXPHOS and promoting glycolysis. <b>Brief rationale:</b> By using banked placenta samples available at Icahn School of Medicine at Mount Sinai, this study aims at laying the foundation for the characterization of the role of mitochondria epi/genetics in IUGR. IUGR is a highly prevalent pregnancy outcome with long-term effects on the progeny that, at present, has limited tools that can be used for its diagnosis and characterization, thus limiting the efficacy of both clinical and public health interventions. The alterations of mitochondrial copy number, OS and mitochondrial and glycolysis-regulatory gene expression that we detected, together, provide the first evidence that these phenomena are playing an important role in the pathophysiology of IUGR. These findings suggest possible new research paths for the full characterization of mitochondrial biomarkers of IUGR.<b>研究背景：</b>宫内生长受限（Intrauterine Growth Restriction, IUGR）是一类严重的妊娠并发症，对产后结局具有显著影响。该疾病以胎盘氧化应激（oxidative stress, OS）水平升高及线粒体DNA（mitochondrial DNA, mtDNA）拷贝数增加为特征，二者共同扰乱胎盘代谢。此类代谢改变可通过线粒体编码的氧化磷酸化（oxidative phosphorylation, OXPHOS）基因以及糖酵解调控基因的表达变化得以体现。<b>研究设计：</b>本研究为一项病例对照研究，纳入50例IUGR病例及100例正常妊娠对照，旨在明确全部13种蛋白编码线粒体编码基因，以及<i>PDK1</i>、<i>PDK2</i>、<i>PDK3</i>、<i>PDK4</i>、<i>PKLR</i>、<i>PKM</i>、<i>OGT</i>这7种关键细胞核编码糖酵解调控基因的胎盘表达水平与IUGR的关联。本研究同时检测了胎盘mtDNA拷贝数及OS水平。<b>研究结果：</b>研究发现，<i>MT-ND5</i>、<i>MT-ND6</i>及<i>MT-ATP6</i>这3种线粒体基因的胎盘表达水平与IUGR呈负相关，而<i>PDK1</i>这1种糖酵解调控基因的表达水平与IUGR呈正相关。胎盘mtDNA拷贝数及OS水平亦与IUGR呈正相关。本研究验证了已有研究结论：IUGR可导致胎盘OS水平升高及mtDNA拷贝数增加。此外，本研究数据显示，线粒体及糖代谢在氧化应激状态下的IUGR胎盘组织中发挥了重要作用，这可能会调控影响OXPHOS并促进糖酵解的基因的胎盘表达。<b>研究依据简述：</b>本研究依托西奈山伊坎医学院（Icahn School of Medicine at Mount Sinai）留存的胎盘样本库，旨在为阐明线粒体表观遗传与遗传学（epi/genetics）在IUGR中的作用奠定基础。IUGR是一种高发的妊娠不良结局，可对子代产生长期影响，而目前临床用于其诊断及特征分型的工具十分有限，这也限制了临床与公共卫生干预措施的实施效果。本研究检测到的线粒体拷贝数、OS水平以及线粒体与糖酵解调控基因表达的改变，共同首次证实了这些现象在IUGR病理生理过程中发挥了重要作用。本研究结果为全面解析IUGR的线粒体生物标志物提供了全新的研究方向。