Nuclear-Mitochondrial Interactions
Mitochondrial function depends on the coordinated expression of genes encoded in the nucleus and mitochondrion. This is evident from the makeup of several mitochondrial complexes, including the translational machinery that involves nuclear-encoded polypeptides and mitochondrially-encoded rRNAs and tRNAs as well as the large respiratory complexes that have subunits encoded in each of the genomes.
Initial studies of the regulatory mechanisms that govern nuclear-mitochondrial interactions focused on the expression and import of nuclear genes involved in the respiratory gene complexes (Forsburg and Guarente 1989). In respiring yeast cells, expression of nuclear genes involved in mitochondrial function are under the control of the Hap transcription complex and respond to changes in oxygen level and carbon source (Poyton and McEwen 1996). This complex regulates genes involved in electron transport as well as enzymes involved in the tricarboxylic acid cycle (TCA) and biosynthetic pathways of heme, sterols and fatty acids.
More recently, it has been demonstrated that there is a bi-directional flow of information between the nucleus and mitochondrion and that mitochondria exert some control over nuclear genes (Parikh et al. 1987). Signaling from the mitochondrion to the nucleus, called retrograde regulation, usually involves metabolites as signals and is likely associated with multiple signal transduction pathways (Liu and Butow 1999; Epstein et al. 2001). This form of regulation is triggered by mitochondrial dysfunction and, in yeast, leads to the induction of genes involved in alternative metabolic pathways that appear to maintain vital components of the TCA cycle. The reallocation of resources to the anaplerotic pathways makes sense for yeast, as it is able to survive without mtDNA on fermentable carbon sources.
It has yet to be determined whether the same pathways are triggered in obligate aerobes and evidence exists that additional response pathways are present that control genes directly involved in mitochondrial function. For example, the alternative oxidase of N. crassa is induced by inhibitors of the cytochrome oxidase pathway, as are other nuclear-encoded mitochondrial genes, such as cytochrome c (Bertrand and Pittenger 1969; Lambowitz and Slayman 1971; Li et al. 1996). In addition, strains having mutant mtDNAs accumulate defective mitochondria relative to normal mitochondria (Bertrand 1994) and the proliferation of defective mitochondria is analogous to events associated with certain human mitochondrial myopathies (Wallace 1999). These findings suggest that the response pathways in obligate aerobic fungi may have relevance to events associated with human mitochondrial diseases.
REFERENCES
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| Epstein CB, Waddle JA, Hale Wt, Dave V, Thornton J, Macatee TL, Garner HR and Butow RA (2001). Genome-wide responses to mitochondrial dysfunction. Mol Biol Cell 12: 297-308. |
| Forsburg SL and Guarente L (1989). Communication between mitochondria and the nucleus in regulation of cytochrome genes in the yeast Saccharomyces cerevisiae. Annu Rev Cell Biol 5: 153-180. |
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| Parikh VS, Morgan MM, Scott R, Clements LS and Butow RA (1987). The mitochondrial genotype can influence nuclear gene expression in yeast. Science 235: 576-580. |
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