# Adaptive evolution of cytochrome b in songbirds

## TL;DR

Songbirds evolved changes in a key mitochondrial protein to reduce harmful superoxide production, possibly increasing lifespan and brain function.

## Contribution

Identified songbird-specific cytochrome b substitutions that modulate mitochondrial superoxide production.

## Key findings

- Songbird-specific substitutions cluster around critical bc1 complex sites, including heme BH and ubiquinone reduction site Qi.
- Substitutions in the Rieske protein hinge region suggest modulation of electron transfer and superoxide generation.
- These changes are hypothesized to reduce superoxide production, enhancing songbird lifespan and cognition.

## Abstract

The mitochondrial bc1 complex catalyzes the oxidation of ubiquinol by reducing cytochrome c. Cytochrome b, the catalytic core of bc1, generates superoxide during the oxidation of ubiquinol. Excessive superoxide production is known to accelerate aging and neurodegeneration. Songbirds (oscine, Passeri) exhibit lower production of mitochondrial reactive oxygen species (ROS) and greatly accelerated evolution of cytochrome b, relative to all other modern birds, suggesting adaptive selection for lower generation of ROS. Here, we identified songbird-specific substitutions in modern bird's cytochrome b amino-acid sequences and examined the high-resolution structures of the chicken bc1 complex in an effort to predict the effect of these substitutions on the function of bc1. Many of the songbird-specific substitutions cluster around sites that are critical for the function of bc1. One cluster of substitutions interacts with heme BH. A second cluster of substitutions interacts with residues in the ubiquinone reduction site, Qi. Both groups of substitution may affect the rate of reduction of ubiquinone at the Qi site. Another cluster of cytochrome b substitutions interacts with the hinge region of the Rieske protein that transfers electron from cytochrome b to cytochrome c1. These songbird-specific substitutions appear to be selected to modulate the rate of both ubiquinol oxidation at the Qo site and ubiquinone reduction at the Qi site thereby modulating the rate of superoxide production. These findings are compatible with the hypothesis that cytochrome b evolution in songbirds was driven by selection of substitutions that reduce the rate of superoxide production thereby increasing songbird lifespan and cognitive abilities.

Summary: The accelerated evolution of the bc1 complex in songbirds resulted in clusters of songbird-specific cytochrome b substitutions of functional residues, allowing for a reduction of superoxide generation.