Abstract
The majority of inherited mitochondrial disorders are due to mutations not in the mitochondrial genome (mtDNA) but rather in the nuclear genes encoding proteins targeted to this organelle. Elucidation of the molecular basis for these disorders is limited because only half1,2 of the estimated 1,500 mitochondrial proteins3 have been identified. To systematically expand this catalog, we experimentally and computationally generated eight genome-scale data sets, each designed to provide clues as to mitochondrial localization: targeting sequence prediction, protein domain enrichment, presence of cis-regulatory motifs, yeast homology, ancestry, tandem-mass spectrometry, coexpression and transcriptional induction during mitochondrial biogenesis. Through an integrated analysis we expand the collection to 1,080 genes, which includes 368 novel predictions with a 10% estimated false prediction rate. By combining this expanded inventory with genetic intervals linked to disease, we have identified candidate genes for eight mitochondrial disorders, leading to the discovery of mutations in MPV17 that result in hepatic mtDNA depletion syndrome4. The integrative approach promises to better define the role of mitochondria in both rare and common human diseases.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Andreoli, C. et al. MitoP2, an integrated database on mitochondrial proteins in yeast and man. Nucleic Acids Res. 32, D459–D462 (2004).
Cotter, D., Guda, P., Fahy, E. & Subramaniam, S. MitoProteome: mitochondrial protein sequence database and annotation system. Nucleic Acids Res. 32, D463–D467 (2004).
Lopez, M.F. et al. High-throughput profiling of the mitochondrial proteome using affinity fractionation and automation. Electrophoresis 21, 3427–3440 (2000).
Spinazzola, A. et al. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat. Genet., advance online publication 2 April 2006 (doi: 10.1038/ng1765).
Emanuelsson, O., Nielsen, H., Brunak, S. & von Heijne, G. Predicting subcellular localization of proteins based on their N-terminal amino acid sequence. J. Mol. Biol. 300, 1005–1016 (2000).
Mootha, V.K. et al. Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria. Cell 115, 629–640 (2003).
Taylor, S.W. et al. Characterization of the human heart mitochondrial proteome. Nat. Biotechnol. 21, 281–286 (2003).
Jansen, R. et al. A Bayesian networks approach for predicting protein-protein interactions from genomic data. Science 302, 449–453 (2003).
Prokisch, H. et al. Integrative analysis of the mitochondrial proteome in yeast. PLoS Biol. 2, e160 (2004).
Mootha, V.K. et al. Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc. Natl. Acad. Sci. USA 101, 6570–6575 (2004).
Andersson, S.G. et al. The genome sequence of Rickettsia prowazekii and the origin of mitochondria. Nature 396, 133–140 (1998).
Su, A.I. et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc. Natl. Acad. Sci. USA 101, 6062–6067 (2004).
Lin, J. et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418, 797–801 (2002).
Guda, C., Fahy, E. & Subramaniam, S. MITOPRED: a genome-scale method for prediction of nucleus-encoded mitochondrial proteins. Bioinformatics 20, 1785–1794 (2004).
Kopp, E. et al. ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes Dev. 13, 2059–2071 (1999).
Finsterer, J. Mitochondriopathies. Eur. J. Neurol. 11, 163–186 (2004).
Zeviani, M. Mitochondrial disorders. Suppl. Clin. Neurophysiol. 57, 304–312 (2004).
Rotig, A. & Munnich, A. Genetic features of mitochondrial respiratory chain disorders. J. Am. Soc. Nephrol. 14, 2995–3007 (2003).
Scaglia, F. et al. Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 114, 925–931 (2004).
Shoubridge, E.A. Nuclear gene defects in respiratory chain disorders. Semin. Neurol. 21, 261–267 (2001).
Thorburn, D.R. Mitochondrial disorders: prevalence, myths and advances. J. Inherit. Metab. Dis. 27, 349–362 (2004).
Zwacka, R.M. et al. The glomerulosclerosis gene Mpv17 encodes a peroxisomal protein producing reactive oxygen species. EMBO J. 13, 5129–5134 (1994).
Mootha, V.K. et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).
Steinmuller, R., Steinberger, D. & Muller, U. MEHMO (mental retardation, epileptic seizures, hypogonadism and -genitalism, microcephaly, obesity), a novel syndrome: assignment of disease locus to xp21.1-p22.13. Eur. J. Hum. Genet. 6, 201–206 (1998).
Christodoulou, K. et al. Mapping of the second Friedreich's ataxia (FRDA2) locus to chromosome 9p23-p11: evidence for further locus heterogeneity. Neurogenetics 3, 127–132 (2001).
Mariman, E.C., van Beersum, S.E., Cremers, C.W., Struycken, P.M. & Ropers, H.H. Fine mapping of a putatively imprinted gene for familial non-chromaffin paragangliomas to chromosome 11q13.1: evidence for genetic heterogeneity. Hum. Genet. 95, 56–62 (1995).
Seyda, A. et al. A novel syndrome affecting multiple mitochondrial functions, located by microcell-mediated transfer to chromosome 2p14–2p13. Am. J. Hum. Genet. 68, 386–396 (2001).
Basel-Vanagaite, L. et al. Infantile bilateral striatal necrosis maps to chromosome 19q. Neurology 62, 87–90 (2004).
Kerrison, J.B. et al. Genetic heterogeneity of dominant optic atrophy, Kjer type: Identification of a second locus on chromosome 18q12.2–12.3. Arch. Ophthalmol. 117, 805–810 (1999).
El-Shanti, H., Lidral, A.C., Jarrah, N., Druhan, L. & Ajlouni, K. Homozygosity mapping identifies an additional locus for Wolfram syndrome on chromosome 4q. Am. J. Hum. Genet. 66, 1229–1236 (2000).
Acknowledgements
We thank C. Guda for performing MitoPred analysis, J. Bunkenborg for performing Mascot searches using previously published mass spectrometry data, J. Evans of the Massachusetts Institute of Technology for assistance with microscopy and L. Gaffney for assistance with illustrations. We thank N. Patterson, L. Peshkin, B. Gewurz and E. Lander for valuable discussions and review of the manuscript. This work is funded by a grant from the United Mitochondrial Disease Foundation, a Burroughs Wellcome Fund Career Award in the Biomedical Sciences and a grant from the American Diabetes Association/Smith Family Foundation awarded to V.K.M.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Fig. 1
Maestro and MitoPred prediction overlap. (PDF 648 kb)
Supplementary Fig. 2
Mouse-to-human orthology mapping. (PDF 653 kb)
Supplementary Fig. 3
Correlation between eight data sets. (PDF 760 kb)
Supplementary Table 1
Computation of gold-standard nonmitochondrial protein T∼mito. (PDF 755 kb)
Supplementary Table 2
MS/MS validation. (XLS 20 kb)
Supplementary Table 3
Previously known nuclear genes underlying mitochondrial diseases. (XLS 22 kb)
Supplementary Table 4
Human protein predictions. (XLS 8766 kb)
Supplementary Table 5
Mouse protein predictions. (XLS 7817 kb)
Rights and permissions
About this article
Cite this article
Calvo, S., Jain, M., Xie, X. et al. Systematic identification of human mitochondrial disease genes through integrative genomics. Nat Genet 38, 576–582 (2006). https://doi.org/10.1038/ng1776
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng1776
This article is cited by
-
Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly
Nature Communications (2020)
-
ARD-PRED: an in silico tool for predicting age-related-disorder-associated proteins
Soft Computing (2019)
-
Diagnosis and Treatment of Mitochondrial Myopathies
Neurotherapeutics (2018)
-
Risikogene bei Myopathien und mitochondrialen Erkrankungen
Der Nervenarzt (2017)
-
ES1 is a mitochondrial enlarging factor contributing to form mega-mitochondria in zebrafish cones
Scientific Reports (2016)