Human diseases caused by defects in oxidative phosphorylation are rare (approximately 1 per 10,000 live births) but often take the form of devastating neurological conditions (9). Symptoms can vary from fatal lactic acidosis in the neonate to mental and physical retardation with cardiomyopathy, skeletal myopathy, and hepatic failure in childhood, to acute painless loss of vision (Leber hereditary optic neuropathy) in young adults, to a form of Parkinson disease later in life. One-third of the defects in the electron transport chain that cause genetic oxidative phosphorylation diseases occur in complex I (9, 10). Only a minority of the molecular abnormalities that cause complex I deficiency are known. Laboratories that do extensive molecular diagnostic analysis for complex I deficiency report that only approximately 20–25% of such patients have homoplasmic or heteroplasmic mutations in 1 of 4 mitochondrial-encoded complex I subunit genes; another 20–25% are the result of mutations in 1 of 9 nuclear-encoded complex I structural subunit genes (9, 11-13). The molecular defects in the remaining 50–60% of patients with deficiencies in complex I, but without obvious mutations in genes encoding complex I structural subunits, still remain largely undetermined. It seems a very reasonable supposition that some of these complex I defects without structural subunit mutations are caused by defects in auxiliary proteins required for multimer assembly, as has already been demonstrated in some patients with severe encephalopathy and failure of other organ systems due to mutations in genes such as SURF1 and SCO2 that affect complex IV assembly (14) or mutations in BCS1L affecting complex III assembly (15). Of the 2 assembly proteins that have been shown to be required for N. crassa complex I assembly, 1 has a human ortholog; however, no defects in that gene have been found in patients with complex I deficiency (16). In this issue of the JCI, Ogilvie et al. report the first human protein required for assembly of human complex I (17).
Ogilvie et al. (17) report a female child, born to a normal, nonconsanguineous couple, who developed progressive neurological disease affecting many portions of her central nervous system beginning around 1 year of age and suffered relentless neurological deterioration until her death at 13.5 years of age. Her disease was associated with elevation of cerebral spinal fluid lactate levels and a deficiency of complex I enzyme activity in muscle mitochondria (approximately 38% of control complex I activity) and cultured fibroblasts (less than 20% of control complex I activity). Taking a clever bioinformatics approach in the appropriate model organisms, these researchers carried out a subtraction in silico of genes found in Y. lipolytica and another aerobic yeast with a complex I, Debaryomyces hansenii, but not in other yeasts that lack a complex I, and used the resulting protein sequences to search for human orthologs containing mitochondrial targeting sequences. Their analysis ultimately yielded 14 genes, 1 of which was B17.2L, a paralog of B17.2, which encodes a known structural subunit in the matrix arm of human complex I (18). They sequenced B17.2L in 28 patients with complex I deficiency and found 1 patient, the child described above, who appeared to be homozygous for a nonsense mutation (C182T) in exon 2 of B17.2L that caused premature termination of translation. Her mother was heterozygous for this mutation, but the mutation was not found in her father, suggesting that he was likely to be heterozygous for a deletion allele that the proband inherited from him as her paternal allele. The functional complex I deficiency and defective assembly in this patient, as determined by enzyme assay and 2D BN-PAGE, was corrected by transduction with a vector expressing B17.2L cDNA. Finally, Ogilvie et al. demonstrated that the B17.2L protein associates with a particular 830-kDa subcomplex of complex I that accumulates in a variety of patients with mutations in genes encoding structural components of complex I, but not with the normal intact complex I itself. Based on these data, the authors concluded that B17.2L is a component of the cellular machinery that is involved in the assembly of complex I without being a part of the mature complex I itself and that loss of function of this protein leads to complex I deficiency (Figure 1).
Humans stand at the opposite end of the spectrum from yeast in terms of serving as an easily manipulated genetic system. However, the study of human genetics has much to offer, not only because of the direct involvement with human disease, but also because of the depth of phenotypic richness and the locus and allelic heterogeneity that human genetic disease provides. Indeed, one of the more striking themes of modern molecular genetics has been how progress in understanding fundamental biological processes has come time and again from the marriage of model organism research with careful human genetic studies. The research reported here by Ogilvie and colleagues (17) is an excellent example of just such a successful marriage.
The author is supported by the Intramural Research Program of the National Human Genome Research Institute, NIH.
Nonstandard abbreviations used: BN-PAGE, blue native PAGE; complex I, NADH:ubiquinone oxidoreductase.
Conflict of interest: The author has declared that no conflict of interest exists.