title: 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.
authors.affiliation: Institute of Molecular Biosciences, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
authors.forename: Christian Q
authors.initials: CQ
authors.lastname: Scheckhuber
authors.forename: Jürgen
authors.initials: J
authors.lastname: Grief
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Boilan
authors.forename: Karin
authors.initials: K
authors.lastname: Luce
authors.forename: Florence
authors.initials: F
authors.lastname: Debacq-Chainiaux
authors.forename: Claudia
authors.initials: C
authors.lastname: Rittmeyer
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gredilla
authors.forename: Bernd O
authors.initials: BO
authors.lastname: Kolbesen
authors.forename: Olivier
authors.initials: O
authors.lastname: Toussaint
authors.forename: Heinz D
authors.initials: HD
authors.lastname: Osiewacz
mesh_terms: D000375:Aging / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D003300:Copper / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008136:Longevity; D008668:Metallothionein / Q000378:metabolism; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism; D048468:Podospora / Q000166:cytology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D015415:Biomarkers; D017382:Reactive Oxygen Species; D003300:Copper; D008668:Metallothionein