The bottleneck: mitochondrial imperatives in oogenesis and ovarian follicular fate

https://doi.org/10.1016/S0303-7207(98)00173-7Get rights and content

Abstract

Molecular geneticists and ovarian physiologists today face the challenge of defining and reconciling two major biological imperatives that each center on oogenesis, folliculogenesis and competition between ovarian follicles: (1), defining how the mitochondrial genome—important in both aging and a number of serious mitochondrial diseases—is refreshed and purified as it passes, via the oocyte’s cytoplasm, from one generation to the next; and (2), endeavouring to discover what cytoplasmic factor(s) it is that permits some eggs but not others to produce viable embryos and ongoing pregnancies. We review here in detail the passage of mitochondria through the female germ cell line. For mitochondria, the processes of oogenesis, follicle formation and loss constitute a restriction/amplification/constraint event of the kind predicted by L. Chao for purification and refinement of a haploid genome. We argue that maintaining the integrity of mitochondrial inheritance is such a strong evolutionary imperative that we should expect at least some features of ovarian follicular formation, function and loss to be primarily adapted to this specific purpose. We predict, moreover, that to prevent accumulation of mild mitochondrial genomes in the population there is a need for physiological female sterility prior to total depletion of ovarian oocytes, a phenomenon for which there is empirical evidence and which we term the oöpause.

Introduction

The mitochondrial genome comprises a circular, histone-free ‘chromosome’ composed of 16.6 kilobases of DNA, present in one or more copies in every mitochondrion (Clayton, 1991, Wallace, 1995, Zeviani and Antozzi, 1997). This chromosome has been extraordinarily tightly conserved during evolution (Wolstenholme et al., 1985), coding in every multicellular animal so far investigated (vertebrate and invertebrate) (a) the same 13 protein subunits required for oxidative phosphorylation, (b) a component of each of the two mitochondrial ribosome subunits, and (c) the 22 transfer RNAs present within the mitochondrion.

Phylogenetically, the mitochondrion is ancient, predating the separation of multicellular animals and plants (Lang et al., 1997), perhaps 2 billion years ago. It is at the heart of what has recently been called the hydrogen hypothesis for the first eukaryote, by which, in the hydrogen-rich, reducing environment of the earth at that time a hydrogen and CO2-feeding autotrophic archeobacterium took on board a heterotrophic symbiotic organism that was not only capable of metabolizing complex carbohydrates but, as byproducts, produced the hydrogen and CO2 the host needed to live (Martin and Müller, 1998). With genomic rearrangement, this symbiosis persisted into a more aerobic, oxidizing world, so that, by the time the multicellular plants and animals took origin from a line of protists, pyruvate was the mitochondrion’s feedstock, and hydrogen, in the oxidized (electron-stripped) form of the hydrogen ion, was being pumped into an intramembranal space in such concentrations as to reverse an ATP-requiring Na+/H+ pump, generating ATP for the host cell.

Presumably for reasons of efficiency (and no doubt to rob the symbiont of replicative independence) most of the proto-mitochondrion’s genes were ceded to the nuclear genome. Why this transfer of genomic responsibility was left incomplete is a mystery, but a slight drift in the transfer RNA code for amino acids (Anderson et al., 1981) had taken place, locking forever into these cytoplasmic organelles an indelible genetic independence that every multicellular organism since has had to live with and protect.

The mitochondrial genome is special in other ways too:

  • the mitochondrial genome is not transmitted through Mendelian (diploid, or ‘sexual’) principles: rather it passes from one generation to the next by way of the egg’s cytoplasm, so that any individual’s mitochondrial DNA is entirely derived from his or her mother, paternal mtDNA having been expelled from the cleaving pre-embryo at the 2-cell stage (Kaneda et al., 1995, Sutovsky et al., 1996);

  • the mitochondrial genome deteriorates with age, through accumulation of point mutations and rearrangements (especially deletions), in most tissues (Wallace, 1995), including the ovary (Kitagawa et al., 1993);

  • at least partly because of an absence of histones, the mutation rate of mtDNA is almost 20 times greater than the mutation rate for nuclear DNA (Wallace et al., 1987);

  • the mitochondrial genome consists mostly of tightly packed exons; there are no introns between genes, so virtually every point mutation or deletion in a mtDNA circle is potentially capable of affecting that mitochondrion’s ability to support cellular respiration, thus accounting for at least some of the well known tissue weakness that is a normal part of the aging process, as well as for a serious group of familial neuromuscular diseases inherited maternally (Wallace, 1995, Zeviani and Antozzi, 1997);

  • for most cells most of the time, that is for non-embryonic somatic cells, mitochondria are polyploid, with multiple alleles present in each organelle (Satoh and Kuroiwa, 1991), enabling compensation for mutations as they occur with age (at least while they fall short of affecting all DNA circles within the particular mitochondrion); but

  • during oogenesis and early embryogenesis, mitochondria assume unique spherical profiles (Smith and Alcivar, 1993) and are haploid, containing mostly just one mtDNA molecule per organelle (Michaels et al., 1982, Pikó and Matsumoto, 1976, Pikó and Taylor, 1987), with somatic morphology (Smith and Alcivar, 1993) and normal replication patterns (Larsson et al., 1998) not being re-established until after implantation.

Ordinarily, all of an individual’s mtDNA will have the same nucleotide sequence (at least until age-related mutations occur in various tissues), a condition termed homoplasmy. When a non-lethal mutation occurs in the mtDNA of the germ line, the affected individual will have more than one mtDNA species, termed heteroplasmy. Heteroplasmy occurs within cells (and probably within mitochondria) as well as within and between tissues, and so could be considered to be the polyploid version of what for diploid genomics is termed heterozygosity. A feature of mitochondrial inheritance is that heteroplasmy reverts to homoplasmy very quickly, within a small number of generations. This rapid genetic drift is attributed to a tight restriction event (or ‘bottleneck’) in the population of mitochondria at some point or series of points in passage through the female germ line (Hauswirth and Laipis, 1985).

To better understand and appreciate the importance of this mitochondrial DNA population restriction event in humans, we have drawn systematic, quantitative inferences from previously published electron micrographs of the various stages of human oogenesis. We also summarize the qualitative cytoplasmic changes involving mitochondria during passage of the germ cell from the embryo yolk sac through its ovarian development, ovulation, cleavage, and formation of a new inner cell mass.

Section snippets

Observations on human germ cell mitochondria

Published electron micrographs of primordial germ cells (PGCs), oogonia and primary oocytes were studied in 17 works published between 1963 and 1995, covering human egg development from 3 weeks of embryonic life through to the adult resting primordial follicle (Stegner and Wartenberg, 1963, Lanzavecchia and Mangioni, 1964, Baker and Franchi, 1967, Hertig and Adams, 1967, Ruby et al., 1970, Gondos, 1971, Szollosi, 1972, Gondos, 1978, Van Blerkom and Motta, 1988, Gondos, 1984, Dvorak and Tesarik,

Discussion

During at least part of (but possibly throughout) their passage through the female germ cell cytoplasm, mitochondria are haploid, with one DNA circle per mitochondrion. During oogenesis, as the number of germ cells increases and also the mitochondrial number per germ cell increases, mitochondrial chromosomes must replicate extremely rapidly, but asexually, apparently without significant recombination (Howell, 1997). It can be useful in imagining this process to think of mitochondria as still

Acknowledgements

We thank Dr Andrew Speirs, Melbourne, for the formula for integrating mitochondrial profiles in cellular cross-sections to provide a three dimensional estimate of organelle numbers per cell.

References (52)

  • T.G. Baker et al.

    The fine structure of oogonia and oocytes in human ovaries

    J. Cell Sci.

    (1967)
  • T.G. Baker

    A quantitative and cytological study of germ cells in human ovaries

    Proc. R. Soc. Lond. B

    (1963)
  • L. Chao et al.

    The advantage of sex in the RNA virus phi6

    Genetics

    (1997)
  • X. Chen et al.

    Rearranged mitochondrial genomes are present in human oocytes

    Am. J. Hum. Genet.

    (1995)
  • D.A. Clayton

    Replication and transcription of vertebrate mitochondria DNA

    Ann. Rev. Cell Biol.

    (1991)
  • A.F. Davis et al.

    In situ localization of mitochondria DNA replication in intact mammalian cells

    J. Cell Biol.

    (1996)
  • M. Dvorak et al.

    Differentiation of mitchondria in the human preimplantation embryo grown in vitro

    Scripta Medica CHECK

    (1985)
  • M. Dvorak et al.

    Ultrastructure of human fertilization

  • M.J. Faddy et al.

    Accelerated disappearence of ovarian follicles in mid-life: implications for forecasting menopause

    Hum. Reprod.

    (1992)
  • D.K. Gardner et al.

    Mouse embryo cleavage, metabolism and viability: role of medium composition

    Hum. Reprod.

    (1993)
  • B. Gondos

    Ultrastructural observations on germ cells in human fetal ovaries

    Am. J. Obstet. Gynecol.

    (1971)
  • B. Gondos

    Oogonia and oocytes in mammals

  • B. Gondos

    Germ cell differentiation and intercellular bridges

  • B. Gondos

    Comparative studies of normal and neoplastic ovarian germ cells: I. Ultrastructure of ooonia and intercellular bridges in the fetal ovary

    Int. J. Gynecol. Path.

    (1987)
  • R.G. Gosden

    Ovulation 1: oocyte development throughout life

  • W.W. Hauswirth et al.

    Transmission genetics of mammalian mitochondria: a model and experimental evidence

  • Cited by (0)

    View full text