Mitochondria and metazoan epigenesis

Abstract

In eukaryotes, mitochondrial activity controls ATP production, calcium dynamics, and redox state, thereby establishing physiological parameters governing the transduction of biochemical signals that regulate nuclear gene expression. However, these activities are commonly assumed to fulfill a 'housekeeping' function: necessary for life, but an epiphenomenon devoid of causal agency in the developmental flow of genetic information. Moreover, it is difficult to perturb mitochondrial function without generally affecting cell viability. For these reasons little is known about the extent of mitochondrial influence on gene activity in early development. Recent discoveries pertaining to the redox regulation of key developmental signaling systems together with the fact that mitochondria are often asymmetrically distributed in animal embryos suggests that they may contribute spatial information underlying differential specification of cell fate. In many cases such asymmetries correlate with localization of genetic determinants (i.e., mRNAs or proteins), particularly in embryos that rely heavily on cell-autonomous means of cell fate specification. In such embryos the localized genetic determinants play a dominant role, and any developmental information contributed by the mitochondria themselves is likely to be less obvious and more difficult to isolate experimentally. Hence, 'regulative' embryos that make more extensive use of conditional cell fate specification are better suited to experimental investigation of mitochondrial impacts on developmental gene regulation. Recent studies of the sea urchin embryo, which is a paradigmatic example of such a system, suggest that anisotropic distribution of mitochondria provides a source gradient of spatial information that directs epigenetic specification of the secondary axis via Nodal-Lefty signaling.

Figure 1

Mitochondrial influence on signal transduction in a metazoan cell. An idealized representation of redox-regulated information flow (red arrows) mediating the production of a transcriptional response to a signal (in this case, binding of an extracellular ligand to its transmembrane receptor). Note that signals impinging on gene expression might also originate intracellularly along these pathways.

Figure 2

Secondary axis specification in the sea urchin embryo. (A) Model of axis specification via a Gierer-Meinhardt type ‘reaction-diffusion’ system involving a short-range activator “A” that activates itself and its longer-range inhibitor “I” (redrawn from Gierer and Meinhardt, 1972: Figure 1c; [89]). “D_A” and “D_I” denote the respective rates of spatial redistribution (by diffusion or other means) of the activator and inhibitor. The final pattern of activator (green) and inhibitor (red) develops from an initially shallow source gradient of activator (blue). The vertical dashed line demarcates the boundary between final territories wherein the activator is ‘on’ and ‘off’. (B) Early sea urchin embryos labeled with indophenol blue, a specific indicator of cytochrome oxidase, showing asymmetry in mitochondrial distribution: (i) 8 cell embryo, lateral view; (ii) 8 cell embryo, polar view; (iii) 32 cell embryo, lateral view; (iv) mesenchyme blastula, polar view (from Czihak, 1963 [91]; reproduced with permission from Springer). (C) Time-lapse series of wide-field fluorescence micrographs showing the first two cleavages of a sea urchin zygote stained with MitoTracker Green FM. The arrowhead in the first panel points to the sperm entry point. An asymmetric distribution of mitochondria present in the egg produces a gradient of mitochondrial densities among the blastomeres, the high end of which specifies the oral pole of the embryo (from Coffman et al., 2004; [95]). (D) Schematic of oral-aboral axis specification in the sea urchin embryo showing relationships between mitochondrial gradient in the early embryo (blue), domains of dominance of Nodal (green) and Lefty (red) in blastula stage embryos, and the morphology of the pluteus larva (grey). The color scheme corresponds to that in (A). (E) Regulatory relationships of nodal and lefty that fulfill the activation and inhibition criteria shown in (A) (using the same color scheme), as discussed in the text. Mitochondrial inputs that contribute (or have the potential to contribute) to establishing the initial source gradient of nodal expression are shown in blue (modified from Coffman et al. [98]).