Mitochondrial DNA, Age, and the "Good" Embryo

Abstract

Older women tend to generate blastocyst-stage embryos with elevated levels of mitochondrial DNA, which is associated with aneuploidy and poor implantation, according to a new a new study of embryos derived from IVF clinics [1]. The findings suggest that clinical tests to assess mitochondrial DNA levels could effectively help screen for ‘‘good’’ embryos during in vitro fertilization. The early embryo has high energy requirements as it divides and differentiates. Previous researchers have hypothesized that embryos under stress tend to be more metabolically active and less healthy, with poor developmental potential. And previous data have shown a link between ATP content of human oocytes and the outcome of IVF. In the new study, Elpida Fragouli et al. first assessed mitochondrial DNA content in 340 blastocysts from women who had undergone IVF and screening for chromosome abnormalities (preimplantation genetic screening). The researchers found that mitochondrial DNA content tended to be higher in blastocysts that did not implant, compared to blastocysts that implanted. Blastocysts from older women also tended to have higher levels of mitochondrial DNA. And, many of the blastocysts with elevated mitochondrial DNA levels also were aneuploid—an association that occurred independent of a woman’s age. With data from this retrospective study, the researchers established an ‘‘upper limit’’ of mitochondrial DNA content, above which embryos were not able to establish an ongoing pregnancy. They then examined the clinical utility of this limit in a prospective study of an additional 42 blastocyst-stage embryos derived from several different IVF clinics. They found that none of the blastocysts that met this cutoff implanted. The data suggest that up to one third of implantation failures in euploid embryos may be due to elevated mitochondrial DNA content. If these findings hold true in future studies, measurements of mitochondrial DNA content could join assessments of aneuploidy as standard clinical indicators of embryo quality during IVF. The study also suggests that changes in mitochondrial DNA content may be a major contributor to declining embryo quality with advancing maternal age. The researchers speculate that high levels of mitochondrial DNA replication might occur in embryos of underlying poor quality, perhaps to compensate for metabolic deficiencies. Future studies may delve further into this question, and also examine whether elevated mitochondrial DNA levels directly contribute to aneuploidy.