GTP in the mitochondrial matrix plays a crucial role in organellar iron homoeostasis.
Mitochondria are the major site of cellular iron utilization for the synthesis of essential cofactors such as iron-sulfur clusters and haem. In the present study, we provide evidence that GTP in the mitochondrial matrix is involved in organellar iron homoeostasis. A mutant of yeast Saccharomyces cerevisiae lacking the mitochondrial GTP/GDP carrier protein (Ggc1p) exhibits decreased levels of matrix GTP and increased levels of matrix GDP [Vozza, Blanco, Palmieri and Palmieri (2004) J. Biol. Chem. 279, 20850-20857]. This mutant (previously called yhm1) also manifests high cellular iron uptake and tremendous iron accumulation within mitochondria [Lesuisse, Lyver, Knight and Dancis (2004) Biochem. J. 378, 599-607]. The reason for these two very different phenotypic defects of the same yeast mutant has so far remained elusive. We show that in vivo targeting of a human nucleoside diphosphate kinase (Nm23-H4), which converts ATP into GTP, to the matrix of ggc1 mutants restores normal iron regulation. Thus the role of Ggc1p in iron metabolism is mediated by effects on GTP/GDP levels in the mitochondrial matrix.
Gordon
Donna M
DM
Department of Pharmacology and Physiology, UMDNJ, New Jersey Medical School, Newark, NJ 07103, USA.
Lyver
Elise R
ER
Lesuisse
Emmanuel
E
Dancis
Andrew
A
Pain
Debkumar
D
D000255:Adenosine Triphosphate / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009701:Nucleoside-Diphosphate Kinase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014170:Transformation, Genetic
D008565:Membrane Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; C105534:YHM1 protein, S cerevisiae; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D007501:Iron; D009701:Nucleoside-Diphosphate Kinase