Age-Related Cellular Copper Dynamics in the Fungal Ageing Model Podospora anserina and in Ageing Human Fibroblasts

Abstract

In previous investigations an impact of cellular copper homeostasis on ageing of the ascomycete Podospora anserina has been demonstrated. Here we provide new data indicating that mitochondria play a major role in this process. Determination of copper in the cytosolic fraction using total reflection X-ray fluorescence spectroscopy analysis and eGfp reporter gene studies indicate an age-related increase of cytosolic copper levels. We show that components of the mitochondrial matrix (i.e. eGFP targeted to mitochondria) become released from the organelle during ageing. Decreasing the accessibility of mitochondrial copper in P. anserina via targeting a copper metallothionein to the mitochondrial matrix was found to result in a switch from a copper-dependent cytochrome-c oxidase to a copper-independent alternative oxidase type of respiration and results in lifespan extension. In addition, we demonstrate that increased copper concentrations in the culture medium lead to the appearance of senescence biomarkers in human diploid fibroblasts (HDFs). Significantly, expression of copper-regulated genes is induced during in vitro ageing in medium devoid of excess copper suggesting that cytosolic copper levels also increase during senescence of HDFs. These data suggest that the identified molecular pathway of age-dependent copper dynamics may not be restricted to P. anserina but may be conserved from lower eukaryotes to humans.

Comparison of global responses to mild deficiency and excess copper levels in Arabidopsis seedlings

“…59 Mitochondria Cu homeostasis has been proven a key player in senescence and life span in other organisms, such as Caernorhabditis elegans. 60 In agreement, our results indicate that mitochondria may be involved in the complex network of responses of higher plants to Cu status. Furthermore, these data indicate SDH1-2 as a new specific gene marker for mild Cu stress, which may prove useful for the detection of overdoses in Cu-containing agronomical treatments.…”

Cyclophilin D links programmed cell death and organismal aging in Podospora anserina

“…6a). Another inducer of oxidative stress with a role in aging and lifespan control is the micronutrient copper (Osiewacz & Borghouts, 2000;Stumpferl et al, 2004;Scheckhuber et al, 2009), an essential cofactor of different enzymes (e.g. cytochrome c oxidase, Cu ⁄ Zn superoxide dismutase).…”

Unopposed mitochondrial fission leads to severe lifespan shortening

“…[1][2][3][4][5][6] Several pathways are dedicated to ensure the uncompromised ability of mitochondria to cope with changing cellular demands. [7][8][9][10][11][12] One pathway that recently gained special interest is the regulation and execution of mitochondrial fusion and fission. These opposing events are normally balanced and, in addition to further accessory proteins, under the tight control of large dynamin-related GTPases.…”