Louwagie Eli J, Larsen Tricia D, Wachal Angela L, Gandy Tyler C T, Eclov Julie A, Rideout Todd C, Kern Katherine A, Cain Jacob T, Anderson Ruthellen H, Mdaki Kennedy S, Baack Michelle L
University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105, USA.
Environmental Influences on Health and Disease Group, Sanford Research, Sioux Falls, SD 57104, USA.
iScience. 2020 Oct 28;23(11):101746. doi: 10.1016/j.isci.2020.101746. eCollection 2020 Nov 20.
Infants of diabetic mothers are at risk of cardiomyopathy at birth and myocardial infarction in adulthood, but prevention is hindered because mechanisms remain unknown. We previously showed that maternal glucolipotoxicity increases the risk of cardiomyopathy and mortality in newborn rats through fuel-mediated mitochondrial dysfunction. Here we demonstrate ongoing cardiometabolic consequences by cross-fostering and following echocardiography, cardiomyocyte bioenergetics, mitochondria-mediated turnover, and cell death following metabolic stress in aged adults. Like humans, cardiac function improves by weaning with no apparent differences in early adulthood but declines again in aged diabetes-exposed offspring. This is preceded by impaired oxidative phosphorylation, exaggerated age-related increase in mitochondrial number, and higher oxygen consumption. Prenatally exposed male cardiomyocytes have more mitolysosomes indicating high baseline turnover; when exposed to metabolic stress, mitophagy cannot increase and cardiomyocytes have faster mitochondrial membrane potential loss and mitochondria-mediated cell death. Details highlight age- and sex-specific roles of mitochondria in developmentally programmed adult heart disease.
患有糖尿病母亲的婴儿在出生时患心肌病的风险较高，成年后患心肌梗死的风险也较高，但由于发病机制尚不清楚，预防工作受到阻碍。我们之前的研究表明，母体糖脂毒性通过燃料介导的线粒体功能障碍增加新生大鼠患心肌病和死亡的风险。在此，我们通过交叉寄养以及对老年成年大鼠进行代谢应激后的超声心动图、心肌细胞生物能量学、线粒体介导的更新和细胞死亡情况进行跟踪，证明了持续存在的心脏代谢后果。与人类一样，断奶后心脏功能会改善，成年早期没有明显差异，但在暴露于糖尿病的老年后代中会再次下降。在此之前，氧化磷酸化受损，与年龄相关的线粒体数量增加过度，耗氧量更高。产前暴露的雄性心肌细胞有更多的线粒体溶酶体，表明基线更新率较高；当受到代谢应激时，线粒体自噬无法增加，心肌细胞的线粒体膜电位丧失更快，线粒体介导的细胞死亡也更快。详细情况突出了线粒体在发育编程性成年心脏病中的年龄和性别特异性作用。
