Maternal diabetes causes mitochondrial dysfunction and meiotic defects in murine oocytes.
The adverse effects of maternal diabetes on embryo development and pregnancy outcomes have recently been shown to occur as early as the one-cell zygote stage. The hypothesis of this study was that maternally inherited mitochondria in oocytes from diabetic mice are abnormal and thus responsible in part for this latency of developmental compromise. In ovulated oocytes from diabetic mice, transmission electron microscopy revealed an alteration in mitochondrial ultrastructure, and the quantitative analysis of mitochondrial DNA copy number demonstrated an increase. The levels of ATP and tricarboxylic acid cycle metabolites in diabetic oocytes were markedly reduced compared with controls, suggesting a mitochondrial metabolic dysfunction. Abnormal distribution of mitochondria within maturing oocytes also was seen in diabetic mice. Furthermore, oocytes from diabetic mice displayed a higher frequency of spindle defects and chromosome misalignment in meiosis, resulting in increased aneuploidy rates in ovulated oocytes. Collectively, our results suggest that maternal diabetes results in oocyte defects that are transmitted to the fetus by two routes: first, meiotic spindle and chromatin defects result in nondisjunction leading to embryonic aneuploidy; second, structural and functional abnormalities of oocyte mitochondria, through maternal transmission, provide the embryo with a dysfunctional complement of mitochondria that may be propagated during embryogenesis.
Wang
Qiang
Q
Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Ratchford
Ann M
AM
Chi
Maggie M-Y
MM
Schoeller
Erica
E
Frolova
Antonina
A
Schedl
Tim
T
Moley
Kelle H
KH
D000255:Adenosine Triphosphate / Q000378:metabolism; D000782:Aneuploidy; D000818:Animals; D033481:Chromosomes, Mammalian / Q000378:metabolism; D002952:Citric Acid Cycle; D004272:DNA, Mitochondrial / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D018628:Gene Dosage; D008540:Meiosis; D051379:Mice; D008928:Mitochondria / Q000473:pathology* / Q000648:ultrastructure; D009865:Oocytes / Q000473:pathology* / Q000648:ultrastructure; D010060:Ovulation; D011247:Pregnancy; D008941:Spindle Apparatus / Q000378:metabolism
D004272:DNA, Mitochondrial; D000255:Adenosine Triphosphate