Mitochondrial functions and aging.

Abstract

In the filamentous ascomycete Podospora anserina mitochondria play a major role in lifespan control. Since the function of these organelles depends on a large number of individual components it is no surprise that a complex network of interacting branches of individual molecular pathways is involved in this process. Recently, the nuclear encoded transcription factor GRISEA was found to significantly affect mitochondrial functions. GRISEA is involved in the control of cellular copper homeostasis. Most importantly, the high affinity uptake of copper from the environment is controlled by this transcription factor. Once copper has entered the cell, it becomes distributed to different compartments and different target molecules. This process depends on a group of proteins, termed copper chaperones. PaCOX17, a homologue of the yeast copper chaperone yCOX17, appears to be involved in copper delivery to mitochondria. Most importantly, the metal is crucial for the assembly and the function of complex IV of the respiratory chain. However, although P. anserina is an obligate aerobe and therefore depends on mitochondrial energy transduction, impairments in the copper delivery pathway are not lethal. This is due to the induction of a molecular back-up system able to compensate for deficiencies in complex IV. The system utilizes an alternative oxidase (PaAOX) which uses iron instead of copper as a cofactor. The alternative respiratory pathway is characterized by a decreased ATP generation but, most significantly, also a decrease in the production of reactive oxygen species. Consequently, molecular damage is reduced which contributes to an increased lifespan of this type of mutant. In addition, modifications in the availability of cellular copper have other relevant consequences. Most significantly, the characteristic age-related rearrangements occurring in the mitochondrial DNA of wild-type strains of P. anserina were found to be dependent on the availability of copper.