Mechanism of electron transfers mediated by cytochromes c and b₅ in mitochondria and endoplasmic reticulum: classical and murburn perspectives

Abstract

We explore the mechanism of electron transfers mediated by cytochrome c, a soluble protein involved in mitochondrial oxidative phosphorylation and cytochrome b₅, a microsomal membrane protein acting as a redox aide in xenobiotic metabolism. We found minimal conservation in the sequence and surface amino acid residues of cytochrome c/b₅ proteins among divergent species. Therefore, we question the evolutionary logic for electron transfer (ET) occurring through affinity binding via recognition of specific surface residues/topography. Also, analysis of putative protein-protein interactions in the crystal structures of these proteins and their redox partners did not point to any specific interaction logic. A comparison of the kinetic and thermodynamic constants of wildtype vs. mutants did not provide strong evidence to support the binding-based ET paradigm, but indicated support for diffusible reactive species (DRS)-mediated process. Topographically divergent cytochromes from one species have been substituted for reaction with proteins from other species, implying the involvement of non-specific interactions. We provide a viable alternative (murburn concept) to classical protein-protein binding-based long range ET mechanism. To account for the promiscuity of interactions and solvent-accessible hemes, we propose that the two proteins act as non- specific redox capacitors, mediating one-electron redox equilibriums involving DRS and unbound ions.

Communicated by Ramaswamy H. Sarma

Keywords:

• Cytochrome c
• cytochrome b₅
• electron transfer
• protein-protein interactions
• murburn concept
• redox metabolism

Acknowledgments

All the authors have given their consent to submit and publish this manuscript in its present form. We thank Vivian David Jacob (Bioculer) for proof-reading the manuscript.

Disclosure statement

The authors declare that there are no conflicts of interest to disclose.

Additional information

Funding

This work was powered by Satyamjayatu: The Science & Ethics Foundation.