ReviewMitochondrial activity, embryogenesis, and the dialogue between the big and little brains of the cell
Introduction
There is an old, and more recent literature that implicates early embryonic asymmetries in developmental patterning and tissue specification (see Coffman, 2009, Coffman and Denegre, 2007 for reviews). For example, Barth (1944) reported differences in O2 consumption between different regions of the Amblyostoma punctatum (newt) embryo, while Marinos et al. (Marinos, 1986) and Yost et al. (1995) found asymmetries in mitochondrial numbers between the dorsal and ventral sides of the early Xenopus laevis (clawed frog) embryo. The Xenopus oocyte contains ~ 107 mitochondria (Marinos and Billett, 1981), which are originally arranged asymmetrically (Klymkowsky and Karnovsky, 1994). As oogenesis proceeds, one mitochondrial population remains associated with the germinal vesicle (the oocyte nucleus), while the other migrates with the germ plasm to the vegetal cortex/vegetal pole of the oocyte (Mignotte et al., 1987, Dent and Klymkowsky, 1989) (Fig. 1A). Cytoplasmic movements following sperm entry are known to play a critical role in the specification of the dorsal-anterior and ventral-posterior axes (Danilchik and Denegre, 1991, Vincent et al., 1986, Vincent and Gerhart, 1987). Fertilization-induced cytoplasmic reorganization then interacts with other maternally established asymmetries in Sox- and T-Box type transcription factors, Wnt signaling, and NF-κB, Nodal and Bone Morphogenic Protein (BMP)1 activities to further pattern the early embryo (Fig. 1).
Asymmetries in mitochondrial distribution may be expected to generate asymmetries in respiratory activity, which have been reported (Barth, 1944). On the other hand, using C14 labeled molecules (e.g. glucose and pyruvate, among others), Thoman and Gerhart (1979) found no apparent difference in metabolic activity between dorsal and ventral regions of X. laevis embryos. This leads us to consider other types of effects, associated with mitochondria. Here there are hints from recent studies in the sea urchin, where Coffman and colleagues (Coffman et al., 2009, Coffman and Davidson, 2001, Coffman et al., 2004) found evidence for a patterning role for reactive oxygen species (ROS). These are known to influence a number of signaling system (Coffman and Denegre, 2007, Covarrubias et al., 2008, Daiber, 2010, Dennery, 2007, Sun and Oberley, 1996). As an example, it is clear that NF-κB activity is influenced by ROS (see Glineur et al., 2000) and that NF-κB is required for normal mesoderm and neural crest formation in Xenopus (see Zhang et al., 2006 and references therein). That said, treatment of Xenopus embryos with the herbicide paraquat, which is known to increase ROS levels, does not dramatically influence either mesoderm or neural crest formation; it does, however, generate later stage defects in somites and myotomal muscle (Vismara et al., 2006), both mesodermal derivatives.
Section snippets
Thinking about mitochondrial–“host” interactions
Mitochondria are generally introduced to students during courses in cell biology. In the typical classroom, their endosymbiotic origins and role in aerobic respiration and ATP synthesis are typically stressed, but more recently their roles in the regulation of apoptosis, as well as intracellular [Ca2+] regulation, hypoxic signaling (Poyton et al., 2009a, Poyton et al., 2009b), nitric oxide production (Castello et al., 2006, Castello et al., 2008, Ghafourifar and Cadenas, 2005), and the
Reflections on localization studies
In general, the observation that provides the initial clue of mitochondrial involvement in various signaling/cellular response systems is the localization of relevant proteins to mitochondria or the mitochondrial fraction of cells. In this light, past studies on cytoskeletal/cell adhesion proteins can be illuminating. A classic example is the presence of actin and myosin within nuclei. Experimental studies using the Xenopus oocyte nuclei by Scheer et al. (1984) provided strong evidence for a
Bcl-2
My own interest in the role of mitochondria in the regulation of embryonic signaling began with a somewhat surprising result obtained in the course of studies on the role of the zinc-finger transcription factor Slug (Snail2) in Xenopus (Zhang et al., 2006, Carl et al., 1999). Snail2/Slug and the related protein Snail (Snail1) have been implicated in both the regulation of epithelial–mesenchymal transition (EMT) and apoptosis (Locascio et al., 2002). To disconnect these two functions, we
Summary
At this point, what is clear is that i) mitochondrial activity, particularly in the form of ROS/RNS can influence the activities of a wide range of proteins and signaling systems, ii) proteins not expected to be present in mitochondria have been found there (and vice versa); and iii) some of these observations will turn out to be molecular noise or epiphenomena, of little or subtle physiological significance, while others may be critical. The trick, experimentally, will be to examine what
Acknowledgement
Our work has been supported by grants from the NIH (GM 54001 and GM84113) and inspired by the unexpected weirdness of nature. We beg for forgiveness for limiting the scope of our review.
References (108)
- et al.
DeltaNp63 antagonizes p53 to regulate mesoderm induction in Xenopus laevis
Dev. Biol.
(2009) - et al.
Ikappa b-alpha, the NF-kappa B inhibitory subunit, interacts with ANT, the mitochondrial ATP/ADP translocator
J. Biol. Chem.
(2001) - et al.
APC shuttling to the membrane, nucleus and beyond
Trends Cell Biol.
(2008) - et al.
Mitochondrial targeting of adenomatous polyposis coli protein is stimulated by truncating cancer mutations: regulation of Bcl-2 and implications for cell survival
J. Biol. Chem.
(2008) - et al.
Differential modulation of BRCA1 and BARD1 nuclear localisation and foci assembly by DNA damage
Cell. Signal.
(2010) - et al.
Inhibition of neural crest migration in Xenopus using antisense slug RNA
Dev. Biol.
(1999) - et al.
Mitochondrial cytochrome oxidase produces nitric oxide under hypoxic conditions: implications for oxygen sensing and hypoxic signaling in eukaryotes
Cell Metab.
(2006) - et al.
Lipid-independent secretion of a Drosophila Wnt protein
J. Biol. Chem.
(2008) Mitochondria and metazoan epigenesis
Semin. Cell Dev. Biol.
(2009)- et al.
Oral–aboral axis specification in the sea urchin embryo III. Role of mitochondrial redox signaling via H2O2
Dev. Biol.
(2009)