The Role of Mitochondrial Function in the Oocyte and Embryo

Rémi Dumollard*,,†; Michael Duchen*; John Carroll*    * Department of Physiology, University College London London WC1E 6BT, United Kingdom
† Laboratoire de Biologie du Développement, UMR 7009 CNRS/UPMC Station Zoologique, Observatoire, 06230 Villefranche-sur-Mer, France

I Introduction

Long known to be the “powerhouses” of the cell, mitochondria are now understood to be central to diverse cellular functions. The complexity and pervasiveness of mitochondrial activity is reflected in their contribution to diverse signaling pathways and intracellular processes. In fact, in addition to producing most of the cell’s ATP (Ernster and Schatz, 1981), mitochondria can sequester and release Ca2+, cytochrome c, and proteins (Duchen, 2000; Kroemer, 2003). They also produce reactive oxygen species (ROS), reducing equivalents [such as NAD(P)H/NAD(P)+] and intracellular metabolites (such as Krebs cycle intermediates) (Brookes et al., 2004; Duchen, 2000; MacDonald et al., 2005; Pagliarini and Dixon, 2006; Turrens, 2003). These mitochondrial activities ensure that mitochondria play a central role in cellular processes such as Ca2+ handling and Ca2+ signaling, the regulation of intracellular redox potential (IRP), and control of apoptosis, and they may well be the mediators of cellular and organismal aging (Balaban et al., 2005).

One peculiarity of mitochondria in development is that they are inherited maternally and independently of the nuclear genome (Cummins, 2000; Dawid and Blackler, 1972; Jansen, 2000; Shoubridge, 2000). Strikingly, the growth of the mitochondrial population in the embryo is discontinuous with a growing burst during oogenesis followed by an arrest of replication during cleavage stages until mitochondrial replication resumes after gastrulation (Dumollard et al., 2006a and references therein). Thus, embryonic mitochondria all originate from a restricted founder population present in the primordial germ cell, which is amplified during oogenesis. This pattern of mitochondrial replication provides a genetic “bottleneck” ensuring a homoplasmic population of mitochondria in the embryo even though mitochondrial DNA is prone to mutations (reviewed by Shoubridge and Wai in Chapter 4, this volume). Such homoplasmy is vital for the survival of each blastomere of the cleaving embryo, which depends on inheriting a functional complement of mitochondria from the egg.

Another consequence of such segregation of mitochondria during cleavage is that any heterogeneity in the distribution of mitochondria in the mature egg will be maintained during early development to give rise to blastomeres with different mitochondrial load, thereby potentially conferring a different developmental fate. An extreme example of this phenomenon is found in the determination of germ cells. Oocytes of many organisms (amphibians, fishes, insects, planarians, chaetognaths, nematodes, and some mammals) possess a cytoplasmic structure rich in mitochondria (called the germ plasm or nuage or Balbiani body or pole plasm) that segregates with the germ line and is necessary for its specification (Kloc et al., 2004). The mitochondria of the germ plasm are selected during oogenesis and aggregate with germ line determinants before they are relocated in the vegetal cortex of the egg (reviewed in Dumollard et al., 2006a; Kloc et al., 2004). Other eggs and embryos display gradients in the distribution of somatic mitochondria that may impact embryo patterning and such gradients may well be maternal factors influencing embryonic cell fate.

The activity of mitochondria in early mammalian embryos has been under investigation for many years. Oocytes and embryos have a relatively low oxygen consumption and electron microscopy shows that embryonic mitochondria have fewer and shorter cristae than mitochondria from metabolically active cells found in adult tissues (Trimarchi et al., 2000 and references therein). These observations led to the hypothesis that embryonic mitochondria are immature and with little capacity for respiratory activity (Houghton and Leese, 2004; Trimarchi et al., 2000). However, the pattern of consumption of energetic substrates seen in mammalian embryos (Biggers et al., 1967; Brinster, 1965; Johnson et al., 2003; Quinn and Wales, 1973) as well as pharmacological approaches undertaken on mammalian and ascidian embryos (Dumollard et al., 2003, 2004, 2006a) suggest that mitochondrial activity is crucial for the activation of development and for embryonic survival. Indeed, even though each mitochondrion may have a low level of metabolism, the concerted action of the large complement of embryonic mitochondria (from tens of thousands to tens of millions per egg or early embryo) is absolutely critical for the supply of energy in the embryo.

After being unanimously recognized in the 1990s as crucial players in intracellular Ca2+ signaling of somatic cells, mitochondria have been shown to be involved in the regulation of sperm-triggered Ca2+ oscillations during ascidian and mouse fertilization (reviewed in Dumollard et al., 2006a). These studies revealed intricate relationships between mitochondrial activity and Ca2+ dynamics. In particular, endoplasmic reticulum (ER) Ca2+ release stimulates mitochondrial respiration and, in return, mitochondrial activity supports long-lasting sperm-triggered Ca2+ oscillations (Dumollard et al., 2006a). Such interactions are advantageous to mitochondria by allowing a fine matching of energetic supply to energetic demand, which may be necessary for embryonic mitochondria to survive until mitochondrial renewal starts.

The oxidative metabolism associated with mitochondrial activity also confers a major role for mitochondria in the regulation of the IRP and oxidative load in the embryo. Mitochondria can have an impact on the IRP by regulating the NAD(P)H/NAD(P)+ ratio and by producing ROS (Brookes et al., 2004; Duchen,...