Calorie restriction does not influence oocyte quality in oocytes from POLG mitochondrial mutator mice.

Christine Faraci,Dori C. Woods,Joyce Jin,Enrico Baruffini

doi:10.1371/journal.pone.0204373

Abstract

It has recently been demonstrated that moderate adult onset caloric restriction (e.g. calorie restriction; CR) has a positive impact on female fertility in aged mice, due in large to preventing the age-associated decline in the quality of oocytes available for fertilization. The impact of CR on oocyte quality has been attributed, at least in part, to mitochondrial functions. In mitochondrial DNA (mtDNA) mutator mice (PolgD257A/D257A), which harbor a mutation in the proofreading mtDNA polymerase-gamma (POLG), mitochondrial mutations rapidly accumulate, resulting in a premature aging phenotype and female infertility. As CR has been shown to extend both lifespan and ‘healthspan’ as well as improve oocyte quality in aged mice, we investigated whether adult onset CR could improve oocyte quality in the POLG mouse. Female PolgD257A/D257A mice exhibited infertility based on an inability to produce litters through natural mating. Analysis of oocytes from 8–9-month-old PolgD257A/D257A mice on CR following hormone stimulation revealed no improvement in the number of oocytes ovulated. Furthermore, CR did not result in a greater percentage of metaphase II oocytes, with the majority of the oocytes prematurely arrested at the germinal vesicle stage. Finally, CR did not improve the abnormal mitochondrial distribution or pronounced defects in meiotic spindle assembly and chromosomal distribution observed in the ad libitum fed PolgD257A/D257A. Taken together, these data suggest that although CR benefits oocyte quality and fertility outcomes in naturally aged female mice, it does not sufficiently improve oocyte quality in PolgD257A/D257A.

Highlights

The PolgD257A/D257A, or POLG mitochondrial DNA mutator mouse harbors a D257A mutation in the exonuclease domain of the gene encoding the sole mtDNA ‘proofreading’ polymerase, polymerase γ (Polg) [1,2,3]
Ovarian morphology was essentially normal with regard to follicle formation, there was a notable increase in diet (D57A/D57A-CR) denoted by black line
Ovarian cysts were present in approximately 50% ovaries collected from POLGD257A/257A mice, regardless of dietary status

Summary

Introduction

The PolgD257A/D257A, or POLG mitochondrial DNA (mtDNA) mutator mouse harbors a D257A mutation in the exonuclease domain of the gene encoding the sole mtDNA ‘proofreading’ polymerase, polymerase γ (Polg) [1,2,3]. Among the characteristics aligned with those that accompany naturally aging mice, PolgD257A/D257A exhibit alopecia, anemia, reduced subcutaneous fat, kyphosis, and osteoporosis by approximately 6 months of age, with a truncated life-span of approximately 12 months-of-age [2, 3]. Both sexes of PolgD257A/D257A mice have fertility defects, with male mice exhibiting small testicular size and reduced sperm production by 12 weeks of age, followed by testicular atrophy and complete loss of sperm by 40 weeks-of-age [3]. The exact mechanisms driving the specific fertility defect in the female PolgD257A/D257A have not been elucidated

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Results

Conclusion