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Originally published as Genetics Published Articles Ahead of Print on June 14, 2005.
Genetics, Vol. 171, 91-99, September 2005, Copyright © 2005
doi:10.1534/genetics.105.041517
Neurospora Strains Harboring Mitochondrial Disease-Associated Mutations in Iron-Sulfur Subunits of Complex I
Margarida Duarte*,
Ulrich Schulte
,
Alexandra V. Ushakova* and
Arnaldo Videira*,
,1
* Instituto de Biologia Molecular e Celular and Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, 4150-180 Porto, Portugal and Institute of Biochemistry, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany
1 Corresponding author: Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
E-mail: asvideir{at}icbas.up.pt
We subjected the genes encoding the 19.3-, 21.3c-, and 51-kDa iron-sulfur subunits of respiratory chain complex I from Neurospora crassa to site-directed mutagenesis to mimic mutations in human complex I subunits associated with mitochondrial diseases. The V135M substitution was introduced into the 19.3-kDa cDNA, the P88L and R111H substitutions were separately introduced into the 21.3c-kDa cDNA, and the A353V and T435M alterations were separately introduced into the 51-kDa cDNA. The altered cDNAs were expressed in the corresponding null-mutants under the control of a heterologous promoter. With the exception of the A353V polypeptide, all mutated subunits were able to promote assembly of a functional complex I, rescuing the phenotypes of the respective null-mutants. Complex I from these strains displays spectroscopic and enzymatic properties similar to those observed in the wild-type strain. A decrease in total complex I amounts may be the major impact of the mutations, although expression levels of mutant genes from the heterologous promoter were sometimes lower and may also account for complex I levels. We discuss these findings in relation to the involvement of complex I deficiencies in mitochondrial disease.
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