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F O R P H Y S I C I A N S – resources
Mitochondria in human oogenesis and preimplantation embryogenesis: engines of metabolism, ionic regulation and developmental competence
Jonathan Van Blerkom
Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA and Colorado Reproductive Endocrinology, Rose Medcial Center, Denver, Colorado 80220, USA
Abstract
Mitochondria are the most abundant organelles in the mammalian oocyte and early embryo. While their role in ATP production
has long been known, only recently has their contribution to oocyte and embryo competence been investigated in the
human. This review considers whether such factors as mitochondrial complement size, mitochondrial DNA copy numbers and
defects, levels of respiration, and stage-specific spatial distribution, influence the developmental normality and viability of
human oocytes and preimplantation-stage embryos. The finding that mitochondrial polarity can differ within and between
oocytes and embryos and that these organelles may participate in the regulation of intracellular Ca2+ homeostasis are discussed
in the context of how focal domains of differential respiration and intracellular-free Ca2+ regulation may arise in early
development and what functional implications this may have for preimplantation embryogenesis and developmental competence
after implantation.
Reproduction (2004) 128 269–280
Introduction
In clinical in vitro fertilization (IVF), current investigational
efforts are directed to understanding why a high proportion
of oocytes result in developmentally incompetent
embryos. Studies of embryo performance during the preimplantation
stages show high frequencies of abnormal
development and early demise, with further losses seen
after uterine transfer as measured by outcome per embryo.
There is a growing consensus of opinion that much of this
embryonic wastage originates from oocyte chromosomal
and subtle cytoplasmic defects whose adverse developmental
consequences are not expressed until well after
fertilization. The notion that mitochondrial dysfunctions or
abnormalities in the oocyte may be a critical determinant
of human embryo developmental competence has gained
currency from recent studies in which defects at the structural
and mitochondrial DNA (mtDNA) levels have been
identified. Likewise, the number of mtDNA copies has
been shown to differ between human oocytes (in the same
cohort) by over an order of magnitude, and for the early
embryonic stages developmentally significant differences
in mitochondrial numbers between blastomeres can result
from disproportionate inheritance during the cleavage
stages. Structural, spatial and genetic dysfunctions that
affect the capacity of mitochondria to produce ATP by oxidative
phosphorylation could have pleiotropic affects on
early human development that, as described below, may
include the normality of spindle organization and chromosomal
segregation, timing of the cell cycle, and morphodynamic
processes such as compaction, cavitation and
blastocyst hatching. Mitochondrial dysfunctions that may
initiate or contribute to the activation of apoptosis have
also been suggested to be a proximal cause of human
oocyte wastage and early embryo demise. Because the
normalcy of critical nuclear and cytoplasmic activities
may be determined by mitochondria, it is not surprising
that their role in early human development as related to
outcome in IVF treatments has become a subject of clinical
and basic research interest (Christodoulou 2000,
Howell et al. 2000, Jansen 2000a,b, Cummins 2002,
2004, Brenner 2004, Chinnery 2004, Eichenlaub-Ritter
et al. 2004). From a basic science viewpoint, the extent to
which mitochondria contribute to or actually determine
oocyte and embryo competence must be better understood
if proactive clinical therapies such as oocyte mitochondrial
donation/replacement (Cohen et al. 1997) are to
be considered acceptable treatments for certain types of
infertility in which a mitochondrial association has been
clearly identified (Brenner 2004, St John et al. 2004).
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