Mining yeast in silico unearths a golden nugget for mitochondrial biology

Abstract

NADH:ubiquinone oxidoreductase (complex I) of the electron transport chain is a multimeric mitochondrial enzyme of approximately 1000 kDa consisting of 46 different proteins encoded by both the mitochondrial and nuclear genomes. Little is known about the cellular mechanisms and protein chaperones that guide its assembly. In this issue of the JCI, Ogilvie et al. use genomic sequence data to compare the proteins produced by yeasts with and without complex I in order to generate a list of proteins whose human orthologs might serve as complex I assembly proteins. The gene encoding one of these candidate proteins, B17.2L, was found to harbor a nonsense mutation in one of 28 patients with a deficiency of complex I. B17.2L associated with subcomplexes that are seen when complex I assembly is incomplete. The research described here combines clever model organism genomics and bioinformatics with sophisticated human molecular and biochemical genetics to identify the first mammalian protein required for the normal assembly of complex I.

Figure 1

Schematic diagram of complexes I through IV of the electron transport chain and ATP synthase. The red line traces the path of electrons as they enter and move along the electron transport chain. Complex I is shown at the far left as an L-shaped structure with one portion extending down into the mitochondrial matrix and the other portion embedded in the inner mitochondrial membrane. Ogilvie and colleagues used bioinformatics to perform a virtual whole genome subtraction of yeasts with or without complex I to find candidate complex I assembly factors, identified the human orthologs of these proteins, and showed that one of these orthologs, B17.2L, carried a null mutation in a patient with complex I deficiency (17). The authors also demonstrate that B17.2L — the first identified mammalian protein required for the normal assembly of human complex I — associates with an immature subcomplex of complex I (shown schematically) and facilitates complex I assembly. FADH₂, reduced flavin-adenine dinucleotide; CoQ, coenzyme Q (also known as ubiquinone).