IND1 / NUBPL in complex I assembly and disease

Ind1 is a mitochondrial protein found in most eukaryotes, but it is absent from baker’s yeast (Saccharomyces sp.).

The ~30-kDa P loop ATPase was first characterized in the yeast Yarrowia lipolytica, where it is involved in the assembly of respiratory complex I, NADH:ubiquinone oxidoreductase (Bych et al., 2008b)The rather specific role in complex I assembly was later confirmed in human HeLa cells (Sheftel et al., 2009) and in the model plant Arabidopsis (Wydro et al., 2013a).

It has been suggested that Ind1 inserts FeS clusters into complex I, but this has not been demonstrated to date.

Mutations in the human homologue NUBPL (NUcleotide Binding Protein-Like) cause rare cases of encephalopathy (Calvo et al 2010 Nat. Genet.; Tucker et al 2012 Hum. Mutat.; Kevelam et al 2013 Neurology). All 15 cases identified so far are compound heterozygous for a specific splice-site mutation (c.815-27T>C) in combination with a null allele.

The splice-site mutation still allows a proportion of normal NUBPL protein to be formed. The Balk lab are using the yeast Yarrowia lipolytica as a model for testing pathogenicity of mutations (Wydro et al., 2013b; Maclean, PhD thesis).