Mitochondria, Metals and Oxidative Stress

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Program: Molecular and Cellular Pathology

Group Leader: Jean-Michel CAMADRO

By studying the assimilation pathways of iron and its intracellular metabolism in a model organism, the yeast Saccharomyces cerevisiae, we can address some of the fundamental problems of biology whilst considering new applications within the field of therapeutics or furthering our knowledge and understanding of the molecular bases of human pathologies.

Indeed, the question of the cellular and molecular mechanisms that are brought into play to control the cellular homeostasis of iron, an element that is essential for cellular metabolism but potentially toxic as a vector of oxidative stress, must be broached in terms of the analysis of complex systems, which are very sensitive to variations in the parameters that control the responses to either a deficiency in or an excess of iron in the growth media and confer on cells an excellent capacity for adaptation. This adaptation can give rise to responses up to the supra-cellular level, as illustrated by the self-organization of yeast cells into colonies of differentiated morphology according to the bioavailability of iron in the growth medium (see photo)

We are using genetic and biochemical approaches to our studies, but we are also developing the important new methods now available in the field of genomics (DNA chips, Chromatin Immuno-precipitation, high density screening of collections of mutants, proteomic analyses, and measurement of molecular interactions).

Whilst studying the metabolism of iron in the model organism S. cerevisiae, we are also conducting similar work with another yeast, Candida albicans, putting emphasis in this case on the relationship between the metabolism of iron and pathogenicity. C. albicans, which is normally a human commensal, is known to be a major pathogen in hosts that are immunologically or physiologically compromised, and as such is responsible for a large number of nosocomial diseases that are often lethal.

Haemin-induced morphological change of C. albicans colonies.
(A) Colony of a wildtype strain (BWP17) grown with haemin as the sole iron source (YPD 1 mM BPS 50 mM haemin).
(B) Light microscope view of cells from the colony shown in (A).
(C) Colony of a wild-type strain (BWP17) grown in the presence of haemin (YPD 50 mM haemin).
(D) Colonies of the wild-type (1) and of mutant strains BWP17DCahmx1/CaHMX1 (2) and BWP17
DCahmx1/DCahmx1 (3) grown on YPD 25 mM haemin (upper view) or on YPD 75 mM haemin (lower view).

Selection of Publications

Friedreich's Ataxia: Molecular mechanisms, redox considerations and therapeutic opportunities
Santos R, Lefevre S, Sliwa D, Seguin A, Camadro JM, Lesuisse E.
Antioxid Redox Signal. 2010 Feb 16. [Epub ahead of print]. Review.
Abstract

KlAft, the Kluyveromyces lactis ortholog of Aft1 and Aft2, mediates activation of iron-responsive transcription through the PuCACCC Aft-type sequence.
Conde e Silva N, Gonçalves IR, Lemaire M, Lesuisse E, Camadro JM, Blaiseau PL.
Genetics. 2009 Sep;183(1):93-106.
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AutoClass@IJM: a powerful tool for Bayesian classification of heterogeneous data in biology.
Achcar F, Camadro JM, Mestivier D.
Nucleic Acids Res. 2009 Jul 1;37(Web Server issue):W63-7.
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Overexpression of the yeast frataxin homolog (Yfh1): contrasting effects on iron-sulfur cluster assembly, heme synthesis and resistance to oxidative stress.
Seguin A, Bayot A, Dancis A, Rogowska-Wrzesinska A, Auchère F, Camadro JM, Bulteau AL, Lesuisse E.
Mitochondrion. 2009 Apr;9(2):130-8.
Abstract

Glutathione-dependent redox status of frataxin-deficient cells in a yeast model of Friedreich's ataxia.
Auchère F, Santos R, Planamente S, Lesuisse E, Camadro JM.
Hum Mol Genet. 2008 Sep 15;17(18):2790-802. Epub 2008 Jun 18.
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