Epistatic interactions modulate the evolution of mammalian mitochondrial respiratory complex components

Area of Science:

• Evolutionary biology
• Molecular biology
• Genomics

Background:

• Deleterious mutations can be functionally reverted by second-site interacting residues through epistatic compensation.
• This explains species-specific tolerance of mutations, though evidence in protein models is limited.
• This study investigates the molecular mechanisms of epistatic compensation in mammalian mitochondrial OXPHOS proteins.

Purpose of the Study:

• To elucidate the molecular mechanisms of epistatic compensatory processes in mammalian mitochondrial OXPHOS proteins.
• To provide supporting evidence for compensatory evolution in protein models.

Main Methods:

• In-depth structural and sequence analyses of mammalian mitochondrial OXPHOS proteins.
• Modeling of human protein structures to predict mutation effects and recovery.
• Analysis of intramolecular and intermolecular interactions restoring protein function.

Main Results:

• Modeled human structures predicted structural impairment and recovery from deleterious mutations.
• Intramolecular interactions in COI and COIII restored protein folding.
• Intermolecular contact in the cytochrome bc1 complex (mitochondrial CYB and nuclear CYT1) likely restored protein binding.
• Observed different modes of compensatory evolution: quasi-simultaneous or independent occurrences preceded by compensatory sites.

Conclusions:

• Epistatic interactions suggest genomes may hold pre-compensating states, tolerating deleterious mutations.
• This phenomenon constrains variability at coevolving sites.
• It shapes the interaction between mitochondrial and nuclear genomes.