Open Access Research article

Epistatic interactions modulate the evolution of mammalian mitochondrial respiratory complex components

Luísa Azevedo1*, João Carneiro12, Barbara van Asch12, Ana Moleirinho1, Filipe Pereira12 and António Amorim12

Author Affiliations

1 IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal

2 Faculty of Sciences of the University of Porto, Porto, Portugal

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BMC Genomics 2009, 10:266  doi:10.1186/1471-2164-10-266

Published: 13 June 2009



The deleterious effect of a mutation can be reverted by a second-site interacting residue. This is an epistatic compensatory process explaining why mutations that are deleterious in some species are tolerated in phylogenetically related lineages, rendering evident that those mutations are, by all means, only deleterious in the species-specific context. Although an extensive and refined theoretical framework on compensatory evolution does exist, the supporting evidence remains limited, especially for protein models. In this current study, we focused on the molecular mechanism underlying the epistatic compensatory process in mammalian mitochondrial OXPHOS proteins using a combination of in-depth structural and sequence analyses.


Modeled human structures were used in this study to predict the structural impairment and recovery of deleterious mutations alone and combined with an interacting compensatory partner, respectively. In two cases, COI and COIII, intramolecular interactions between spatially linked residues restore the folding pattern impaired by the deleterious mutation. In a third case, intermolecular contact between mitochondrial CYB and nuclear CYT1 encoded components of the cytochrome bc1 complex are likely to restore protein binding. Moreover, we observed different modes of compensatory evolution that have resulted in either a quasi-simultaneous occurrence of a mutation and corresponding compensatory partner, or in independent occurrences of mutations in distinct lineages that were always preceded by the compensatory site.


Epistatic interactions between individual replacements involving deleterious mutations seems to follow a parsimonious model of evolution in which genomes hold pre-compensating states that subsequently tolerate deleterious mutations. This phenomenon is likely to have been constraining the variability at coevolving sites and shaping the interaction between the mitochondrial and the nuclear genome.