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.