Laboratory of Metabolism and Exercise (LaMetEx), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Laboratory for Integrative and Translational Research in Population Health (ITR), Faculty of Sports, University of Porto, 4200-450 Porto, Portugal.
CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
Int J Mol Sci. 2023 Oct 14;24(20):15192. doi: 10.3390/ijms242015192.
Intra-uterine growth restriction (IUGR) is a common cause of fetal/neonatal morbidity and mortality and is associated with increased offspring predisposition for cardiovascular disease (CVD) development. Mitochondria are essential organelles in maintaining cardiac function, and thus, fetal cardiac mitochondria could be responsive to the IUGR environment. In this study, we investigated whether in utero fetal cardiac mitochondrial programming can be detectable in an early stage of IUGR pregnancy. Using a well-established nonhuman IUGR primate model, we induced IUGR by reducing by 30% the maternal diet (MNR), both in males (MNR-M) and in female (MNR-F) fetuses. Fetal cardiac left ventricle (LV) tissue and blood were collected at 90 days of gestation (0.5 gestation, 0.5 G). Blood biochemical parameters were determined and heart LV mitochondrial biology assessed. MNR fetus biochemical blood parameters confirm an early fetal response to MNR. In addition, we show that in utero cardiac mitochondrial MNR adaptations are already detectable at this early stage, in a sex-divergent way. MNR induced alterations in the cardiac gene expression of oxidative phosphorylation (OXPHOS) subunits (mostly for complex-I, III, and ATP synthase), along with increased protein content for complex-I, -III, and -IV subunits only for MNR-M in comparison with male controls, highlight the fetal cardiac sex-divergent response to MNR. At this fetal stage, no major alterations were detected in mitochondrial DNA copy number nor markers for oxidative stress. This study shows that in 90-day nonhuman primate fetuses, a 30% decrease in maternal nutrition generated early in utero adaptations in fetal blood biochemical parameters and sex-specific alterations in cardiac left ventricle gene and protein expression profiles, affecting predominantly OXPHOS subunits. Since the OXPHOS system is determinant for energy production in mitochondria, our findings suggest that these early IUGR-induced mitochondrial adaptations play a role in offspring's mitochondrial dysfunction and can increase predisposition to CVD in a sex-specific way.
胎儿/新生儿发病率和死亡率的常见原因是宫内生长受限（IUGR），并与后代患心血管疾病（CVD）的风险增加有关。线粒体是维持心脏功能的重要细胞器，因此胎儿心脏线粒体可能对 IUGR 环境有反应。在这项研究中，我们研究了宫内胎儿心脏线粒体编程是否可以在 IUGR 妊娠的早期阶段被检测到。我们使用了一种成熟的非人类 IUGR 灵长类动物模型，通过减少 30%的母体饮食（MNR）来诱导 IUGR，这种方法既适用于雄性（MNR-M）胎儿，也适用于雌性（MNR-F）胎儿。在妊娠 90 天时（0.5 妊娠，0.5 G）收集胎儿心脏左心室（LV）组织和血液。测定血液生化参数，并评估心脏 LV 线粒体生物学。MNR 胎儿血液生化参数证实了 MNR 对胎儿的早期反应。此外，我们还表明，在这个早期阶段，已经可以以性别差异的方式检测到宫内心脏线粒体 MNR 的适应。MNR 诱导了心脏氧化磷酸化（OXPHOS）亚基的基因表达改变（主要是复合物-I、III 和 ATP 合酶），同时仅在雄性对照中，MNR-M 胎儿的复合物-I、-III 和 -IV 亚基的蛋白含量增加，这突出了胎儿心脏对 MNR 的性别差异反应。在这个胎儿阶段，线粒体 DNA 拷贝数或氧化应激标志物没有检测到主要变化。这项研究表明，在 90 天的非人类灵长类胎儿中，母体营养减少 30%会导致胎儿血液生化参数的早期宫内适应，以及心脏左心室基因和蛋白质表达谱的性别特异性改变，主要影响 OXPHOS 亚基。由于 OXPHOS 系统是线粒体产生能量的决定因素，我们的研究结果表明，这些早期 IUGR 诱导的线粒体适应在后代的线粒体功能障碍中发挥作用，并以性别特异性的方式增加患 CVD 的风险。
