Copper-modulated gene expression and senescence in the filamentous fungus Podospora anserina

We have previously shown that the control of cellular copper homeostasis by the copper-modulated transcription factor GRISEA has an important impact o n the phenotype and lifespan of Podospora anserina. Here we demonstrate tha t copper depletion leads to the induction of an alternative respiratory pat hway and to an increase in lifespan. This response compensates mitochondria l dysfunctions via the expression of PaAox, a nuclear gene coding for an al ternative oxidase. It resembles the retrograde response in Saccharomyces ce revisiae, In P. anserina, this pathway appears to be induced by specific im pairments of the copper-dependent cytochrome c oxidase. It is not induced a s the result of a general decline of mitochondrial functions during senesce nce. We cloned and characterized PaAox. Transcript levels are decreased whe n cellular copper, superoxide, and hydrogen peroxide levels are raised. Cop per also controls transcript levels of PaSod2, the gene encoding the mitoch ondrial manganese superoxide dismutase (PaSOD2). PaSod2 is a target of tran scription factor GRISEA. During the senescence of wild-type strain s, the a ctivity of PaSOD2 decreases, whereas the activity of the cytoplasmic copper /zinc superoxide dismutase (PaSOD1) increases. Collectively, the data expla in the postponed senescence of mutant grisea as a defined consequence of co pper depletion, ultimately leading to a reduction of oxidative stress. More over, they suggest that during senescence of the wild-type strain, copper i s released from mitochondria. The involved mechanism is unknown. However, i t is striking that the permeability of mitochondrial membranes in animal sy stems changes during apoptosis and that mitochondrial proteins with an impo rtant impact on this type of cellular death are released.