Prediction of Mitochondrial Protein Function by Comparative Physiology and Phylogenetic Profiling

Part of the Methods in Molecular Biology book series (MIMB, volume 1264)


According to the endosymbiotic theory, mitochondria originate from a free-living alpha-proteobacteria that established an intracellular symbiosis with the ancestor of present-day eukaryotic cells. During the bacterium-to-organelle transformation, the proto-mitochondrial proteome has undergone a massive turnover, whereby less than 20 % of modern mitochondrial proteomes can be traced back to the bacterial ancestor. Moreover, mitochondrial proteomes from several eukaryotic organisms, for example, yeast and human, show a rather modest overlap, reflecting differences in mitochondrial physiology. Those differences may result from the combination of differential gain and loss of genes and retargeting processes among lineages. Therefore, an evolutionary signature, also called “phylogenetic profile”, could be generated for every mitochondrial protein. Here, we present two evolutionary biology approaches to study mitochondrial physiology: the first strategy, which we refer to as “comparative physiology,” allows the de novo identification of mitochondrial proteins involved in a physiological function; the second, known as “phylogenetic profiling,” allows to predict protein functions and functional interactions by comparing phylogenetic profiles of uncharacterized and known components.

Key words

Mitochondrial evolution Comparative genomics Comparative physiology Phylogenetic profiling Orthology 



This work was supported by Deutsche Forschungsgemeinschaft Emmy Noether Programme Grant PE 2053/1-1 and the Bavarian State Ministry of Education, Science and the Arts.


  1. 1.
    Perocchi F, Jensen LJ, Gagneur J et al (2006) Assessing systems properties of yeast mitochondria through an interaction map of the organelle. PLoS Genet 2:e170PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Pagliarini DJ, Calvo SE, Chang BA et al (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–123PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Gabaldón T (2006) Computational approaches for the prediction of protein function in the mitochondrion. Am J Physiol Cell Physiol 291:C1121–C1128PubMedCrossRefGoogle Scholar
  4. 4.
    Perocchi F, Gohil VM, Girgis HS (2010) MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature 467:291–296PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Rost B, Liu J, Nair R et al (2003) Automatic prediction of protein function. Cell Mol Life Sci 60:2637–2650PubMedCrossRefGoogle Scholar
  6. 6.
    Barrientos A (2003) Yeast models of human mitochondrial diseases. IUBMB Life 55:83–95PubMedCrossRefGoogle Scholar
  7. 7.
    Perocchi F, Mancera E, Steinmetz LM (2008) Systematic screens for human disease genes, from yeast to human and back. Mol Biosyst 4:18–29PubMedCrossRefGoogle Scholar
  8. 8.
    Prokisch H, Scharfe C, Camp DG (2004) Integrative analysis of the mitochondrial proteome in yeast. PLoS Biol 2:e160PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Gabaldón T, Huynen MA (2007) From endosymbiont to host-controlled organelle: the hijacking of mitochondrial protein synthesis and metabolism. PLoS Comput Biol 3:e219PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Kihara D (2011) Protein function prediction for omics era. Springer, New YorkCrossRefGoogle Scholar
  11. 11.
    Gabaldón T, Huynen MA (2005) Lineage-specific gene loss following mitochondrial endosymbiosis and its potential for function prediction in eukaryotes. Bioinformatics 21:144–150CrossRefGoogle Scholar
  12. 12.
    Huynen MA, Snel B, Bork P et al (2001) The phylogenetic distribution of frataxin indicates a role in iron-sulfur cluster protein assembly. Hum Mol Genet 10:2463–2468PubMedCrossRefGoogle Scholar
  13. 13.
    Gabaldón T, Rainey D, Huynen MA (2005) Tracing the evolution of a large protein complex in the eukaryotes, NADH:ubiquinone oxidoreductase (Complex I). J Mol Biol 348:857–870PubMedCrossRefGoogle Scholar
  14. 14.
    Baughman JM, Perocchi F, Girgis HS (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476:341–345PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Prokisch H, Andreoli C, Ahting U et al (2006) MitoP2: the mitochondrial proteome database—now including mouse data. Nucleic Acids Res 34:D705–D711PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Smith AC, Blackshaw JA, Robinson AJ (2012) MitoMiner: a data warehouse for mitochondrial proteomics data. Nucleic Acids Res 40:D1160–D1167PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Scharfe C, Lu HH, Neuenburg JK et al (2009) Mapping gene associations in human mitochondria using clinical disease phenotypes. PLoS Comput Biol 5:e1000374PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Sigrist CJ, de Castro E, Cerutti L et al (2013) New and continuing developments at PROSITE. Nucleic Acids Res 41:D344–D347PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Franceschini A, Szklarczyk D, Frankild S et al (2013) STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res 41:D808–D815PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Tatusov RL, Koonin EV, Lipman DJ (1997) A genomic perspective on protein families. Science 278:631–7PubMedCrossRefGoogle Scholar
  21. 21.
    Ostlund G, Schmitt T, Forslund K et al (2009) InParanoid 7: new algorithms and tools for eukaryotic orthology analysis. Nucleic Acids Res 38:D196–D203PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Datta RS, Meacham C, Samad B et al (2009) Berkeley PHOG: PhyloFacts orthology group prediction web server. Nucleic Acids Res 37:W84–W89PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Plovanich M, Bogorad RL, Sancak Y et al (2013) MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLoS One 8:e55785PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Raffaello A, De Stefani D, Sabbadin D et al (2013) The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J 32:2362–2376PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Gene CenterLudwig-Maximilians-UniversitätMunichGermany
  2. 2.Institute of Human Genetics, Helmholtz Zentrum MunichMunichGermany
  3. 3.Genzentrum/Ludwig-Maximilians-UniversitaetMunichGermany

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