Identification of the human mitochondrial FAD transporter and its potential role in multiple acyl-CoA dehydrogenase deficiency

Mol Genet Metab. 2005 Dec;86(4):441-7. doi: 10.1016/j.ymgme.2005.07.014. Epub 2005 Sep 13.

Abstract

Multiple acyl-CoA dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) is most often caused by mutations in the genes encoding the alpha- or beta-subunit of electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase (ETF-DH). Since not all patients have mutations in these genes, other as yet unidentified genes are predicted to be involved as well. Because all affected mitochondrial flavoproteins in MADD have FAD as a prosthetic group, the underlying defect in these patients may be due to a thus far undisclosed disturbance in the metabolism of FAD. Since a proper mitochondrial flavin balance is maintained by a mitochondrial FAD transporter, a defect of this transporter could also cause an MADD-like phenotype. In yeast, FAD is transported across the mitochondrial inner membrane by the FLX1 protein. An FLX1-mutated Saccharomyces cerevisiae strain exhibits a decreased activity of several mitochondrial flavoproteins. In the present study, we report the identification of the human mitochondrial FAD transporter. Based on sequence similarity to FLX1, we identified two human candidate genes (MFT and N111), which were cloned and characterized by functional expression in an FLX1-mutated yeast strain. Of the two candidate genes, only the previously described mitochondrial folate transporter (MFT) was able to functionally complement the FLX1 mutant. Candidates for mutations in the MFT gene are patients with a clinical suspicion of MADD but without any mutation in the alpha- or beta-subunit of ETF or ETF-DH.

Publication types

  • Comparative Study

MeSH terms

  • Acyl-CoA Dehydrogenase / deficiency*
  • Acyl-CoA Dehydrogenase / genetics
  • Amino Acid Sequence
  • Base Sequence
  • Cloning, Molecular
  • DNA, Complementary / genetics
  • DNA, Fungal / genetics
  • Electron Transport Complex IV / metabolism
  • Flavin-Adenine Dinucleotide / metabolism*
  • Genetic Complementation Test
  • Humans
  • In Vitro Techniques
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Molecular Sequence Data
  • Mutation
  • Nucleotide Transport Proteins / genetics
  • Nucleotide Transport Proteins / metabolism*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Species Specificity
  • Succinate Dehydrogenase / metabolism

Substances

  • DNA, Complementary
  • DNA, Fungal
  • FLX1 protein, S cerevisiae
  • Membrane Transport Proteins
  • Nucleotide Transport Proteins
  • SLC25A32 protein, human
  • Saccharomyces cerevisiae Proteins
  • Flavin-Adenine Dinucleotide
  • Acyl-CoA Dehydrogenase
  • Succinate Dehydrogenase
  • Electron Transport Complex IV