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Review
. 2013 Aug;19(8):486-94.
doi: 10.1093/molehr/gat026. Epub 2013 Apr 23.

Maternal obesity, infertility and mitochondrial dysfunction: potential mechanisms emerging from mouse model systems

Natalia M Grindler  1 , Kelle H Moley
Affiliations
Review

Maternal obesity, infertility and mitochondrial dysfunction: potential mechanisms emerging from mouse model systems

Natalia M Grindler et al. Mol Hum Reprod. 2013 Aug.

Abstract

Obesity is associated with ovulatory disorders, decreased rates of conception, infertility, early pregnancy loss and congenital abnormalities. Poor oocyte quality and reduced IVF success have also been reported in obese women. Recent attempts to understand the mechanism by which these defects occur have focused on mitochondria, essential organelles that are critical for oocyte maturation and subsequent embryo development. The oocyte relies on maternally supplied mitochondria until the resumption of mitochondrial replication in the peri-implantation period. Here we review current literature addressing the roles of mitochondria in oocyte function and how mitochondrial dysfunction can lead to fertility problems. The relationship between mitochondrial dysfunction and oocyte function is evaluated by examining the following examples of environmental exposures: tobacco smoke, aging, caloric restriction and hyperglycemia. Finally, we present new data from a mouse model of obesity that has demonstrated that oocyte mitochondria play a key role in obesity-associated reproductive disorders.

Keywords: infertility; mitochondria; obesity; oocyte.

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Figures

Figure 1
Figure 1
The impact of mitochondria on oocyte function and fertility: example of the effect of smoking and aging on fertility. PAHs are pathogenic chemicals found in tobacco smoke. PAHs bind to and activate the AHR. This action leads to the expression of the pro-apoptotic Bcl-2 mitochondrial protein, Bax, in oocytes, which subsequently leads to apoptosis. PAHs cause an accelerated loss of primordial follicles, leading to premature exhaustion of the ovarian pool. The addition of the AHR antagonist resveratrol rescues immature follicles from death. Inactivation of either the transcription factor Bax or AHR prevents ovarian damage. Bax deficiency leads to oocytes whose function is sustained into very old age, suggesting the importance of this mitochondrial protein on ovarian function and fertility in relation to aging.
Figure 2
Figure 2
Maternal HFD leads to changes in the mitochondria of oocytes. Oocytes of mice on the HFD differ in several ways from those of control mice: (i) these oocytes have mitochondria with fewer cristae, increased cristae disarray, decreased electron density of the mitochondrial matrix, increased swelling and a greater number of vacuoles. (ii) Diet-induced obesity leads to an aberration in the pattern of mitochondrial distribution: mitochondria from obese females are distributed in a clumping, clustering pattern. (iii) The HFD leads to an increase in mitochondrial potential and ROS, suggestive of mitochondrial damage. (iv) Oocytes from mice fed an HFD have lower citrate levels than mice fed the control diet but normal, but ATP levels are normal; this suggests abnormal metabolism related to the HFD. (v) Oocytes from mice on HFD have fragmented spindles with ectopic organizing centers with chromosomes that are misplaced from the metaphase plate. These oocyte spindle defects and chromosome misalignments can result in high levels of aneuploidy.
Figure 3
Figure 3
Oocyte mitochondrial ultrastructure. Compared with the mitochondria from oocytes of mice on a control diet (A), the mitochondria from oocytes of mice from the HFD group (B) have fewer cristae, increased cristae disarray, decreased electron density of the mitochondrial matrix, increased swelling and a greater number of vacuoles. Reproduced with permission from Luzzo et al. (2012).
Figure 4
Figure 4
Oocyte aneuploidy and spindle formation/chromosome alignment. (top left) The MII oocytes from control mice display a typical barrel-shaped spindle and organized chromosomes on the metaphase plate. Oocytes from HFD mice (top right) have abnormal fragmented spindles and clustered chromosomes. (lower panel) Quantitative analysis demonstrates that both spindle defects and chromosome misalignment are higher in obese mice than in control mice. Reproduced with permission from Luzzo et al. (2012).
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