Aerobic respiration: proof of concept for the oxygen-centric murburn perspective

Abstract

The inner mitochondrial membrane protein complexes (I–V) and prokaryotic respiratory machinery are examined for a deeper understanding of their structure–function correlations and dynamics. In silico analysis of the structure of complexes I–IV, docking studies and erstwhile literature confirm that they carry sites which are in close proximity to DROS (diffusible reactive oxygen species) generating redox centers. These findings provide supportive evidence for the newly proposed oxygen-centric chemical-coupling mechanism (murburn concept), wherein DROS catalyzes the esterification of inorganic phosphate to ADP. Further, in a reductionist system, we demonstrate that a DROS (like superoxide) can effectively esterify inorganic phosphate to ADP. The impact of these findings and the interactive dynamics of classical inhibitors (rotenone and cyanide), uncouplers (dinitrophenol and uncoupling protein) and other toxins (atractyloside and oligomycin) are briefly discussed.

Highlights

• Earlier perception: Complexes (I–IV) pump protons and Complex V make ATP (aided by protons)

• Herein: Respiratory molecular machinery is probed for new structure–function correlations

• Analyses: Quantitative arguments discount proton-centric ATP synthesis in mitochondria and bacteria

• In silico data: ADP-binding sites and O₂/ diffusible reactive oxygen species (DROS)-accessible channels are unveiled in respiratory proteins

• In vitro data: Using luminometry, ATP synthesis is demonstrated from ADP, Pi and superoxide

• Inference: Findings agree with decentralized ADP–Pi activation via oxygen-centric murburn scheme

Communicated by Ramaswamy H. Sarma

Keywords:

• Murburn concept
• respiratory complexes
• mitochondrial membrane
• heme/flavin proteins
• structure–function correlation
• ATP

Subject classification:

• Biomolecular structure and interactive dynamics

Acknowledgements

The work was powered by Satyamjayatu: The Science and Ethics Foundation. KMM dedicates this manuscript to (Late) Lowell Hager (Member, NAS-USA) and acknowledges interactions with the former senior peers of his alma mater at the University of Illinois, Urbana-Champaign: Alex Scheeline & Robert Gennis. KMM also acknowledges an input from Archita Mishra, Indian Institute of Science, Bangalore.

Disclosure statement/protocols & data availability

There are no conflicts of interests to disclose and all pertinent details of protocols/data are made available for reproduction of the works in any other labs.

Author contributions

KMM conceived the ideas, planned and executed the experiments, reasoned the findings and wrote the paper. AP carried out the dockings/cavity analyses, prepared proteins’ figures and helped in formatting the paper. VDJ traced key earlier research findings and helped with proofing the manuscript. SR carried out the luminometry experiment and reported data.