The effects of mitochondrial iron homeostasis on cofactor specificity of superoxide dismutase 2.
Many metalloproteins have the capacity to bind diverse metals, but in living cells connect only with their cognate metal cofactor. In eukaryotes, this metal specificity can be achieved through metal-specific metallochaperone proteins. Herein, we describe a mechanism whereby Saccharomyces cerevisiae manganese superoxide dismutase (SOD2) preferentially binds manganese over iron based on the differential bioavailability of these ions within mitochondria. The bulk of mitochondrial iron is normally unavailable to SOD2, but when mitochondrial iron homeostasis is disrupted, for example, by mutations in S. cerevisiae mtm1, ssq1 and grx5, iron accumulates in a reactive form that potently competes with manganese for binding to SOD2, inactivating the enzyme. Studies in mtm1 mutants indicate that iron inactivation of SOD2 involves the Mrs3p/Mrs4p mitochondrial carriers and iron-binding frataxin (Yfh1p). A small pool of SOD2-reactive iron also exists under normal iron homeostasis conditions and binds SOD2 when mitochondrial manganese is low. The ability to control this reactive pool of iron is critical to maintaining SOD2 activity and has important potential implications for oxidative stress in disorders of iron overload.
Yang
Mei
M
Division of Toxicological Sciences, Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Cobine
Paul A
PA
Molik
Sabine
S
Naranuntarat
Amornrat
A
Lill
Roland
R
Winge
Dennis R
DR
Culotta
Valeria C
VC
D027682:Cation Transport Proteins / Q000378:metabolism; D004789:Enzyme Activation; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000378:metabolism; D008345:Manganese / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000096923:Frataxin; D000099156:Superoxide Dismutase 2
D027682:Cation Transport Proteins; D007501:Iron; D033862:Iron-Binding Proteins; D008345:Manganese; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D013482:Superoxide Dismutase; D014157:Transcription Factors; D000096923:Frataxin; D000099156:Superoxide Dismutase 2; C090297:AFT1 protein, S cerevisiae; C066985:MRS3 protein, S cerevisiae; C066986:MRS4 protein, S cerevisiae