Mitochondrial oxidative phosphorylation: Debunking the concepts of electron transport chain, proton pumps, chemiosmosis and rotary ATP synthesis

  title={Mitochondrial oxidative phosphorylation: Debunking the concepts of electron transport chain, proton pumps, chemiosmosis and rotary ATP synthesis},
  author={Kelath Murali Manoj},
The prevailing half-a-century old explanation for cellular respiration solicits a synchronization of electron transfer chain (ETC) and proton pumping activity across the inner mitochondrial membrane, for generating a trans-membrane proton-electro-chemical potential. This outcome is supposedly harnessed by Complex V to synthesize ATP, working via a rotary mode. In the first part of my work (the current write-up), I highlight that a mitochondrion is a highly " proton-limited " microcosm, housing… 
The physiological role of complex V in ATP synthesis: Murzyme functioning is viable whereas rotary conformation change model is untenable.
The murburn paradigm succeeds the CRAS hypothesis for explaining the role of oxygen in mitochondrial physiologies of oxidative phosphorylation, thermogenesis, TMP and homeostasis.
The murburn precepts for aerobic respiration and redox homeostasis.
Murburn precepts for lactic‐acidosis, Cori cycle, and Warburg effect: Interactive dynamics of dehydrogenases, protons, and oxygen
The DROS‐based murburn theory explains the invariant active‐site structure of LDH isozymes and their multimeric nature and enrich the understanding of the underpinnings of “lactic acidosis” (lowering of physiological pH accompanied by lactate production), Warburg effect (increased lactateproduction at high pO2 by cancer cells) and approach for cancer therapy.
Murburn concept explains the acutely lethal effect of cyanide
The μM-level IC50 and the acutely lethal effect of CN on cellular respiration could be explained by the deleterious interaction of CN ion-radical equilibrium with DROS in matrix, disrupting mitochondrial ATP synthesis.
Interaction of membrane‐embedded cytochrome b‐complexes with quinols: Classical Q‐cycle and murburn model
It is proposed that Q‐cycle is neither necessary nor feasible at CBCs, and the classical model cannot explain the energetics, kinetics, mechanism and probabilistic considerations of bioenergetics.
Critical analysis of explanations for cellular homeostasis and electrophysiology from murburn perspective
The new entry into the field, murburn concept, builds starting from molecular considerations to macroscopic observations, and moots "effective charge separation" and intricate "molecule-ion-radical" electron transfer equilibriums as a rationale for ionic concentration differentials and TMP variation.


A Model of the Proton Translocation Mechanism of Complex I*
A mixed model combines direct and indirect coupling mechanisms to account for the pumping of the four protons and explains the observed properties of the semiquinone in the Q-binding site, the rapid superoxide production from this site during reverse electron transport, its lowsuperoxide production during forward electron transport except in the presence of inhibitory Q-analogs and high protonmotive force.
A giant molecular proton pump: structure and mechanism of respiratory complex I
  • L. Sazanov
  • Chemistry
    Nature Reviews Molecular Cell Biology
  • 2015
The crystal structure of the entire complex I was solved using a bacterial enzyme provided novel insights into the core architecture of the complex, the electron transfer and proton translocation pathways, as well as the mechanism that couples these two processes.
Electron transfer by domain movement in cytochrome bc1
X-ray crystal structures of the cytochrome bc1 complex from chicken, cow and rabbit in both the presence and absence of inhibitors of quinone oxidation, reveal two different locations for the extrinsic domain of one component of the enzyme, an iron–sulphur protein.
The Inner Mitochondrial Membrane Has Aquaporin-8 Water Channels and Is Highly Permeable to Water*
The presence of a member of the aquaporin family of water channels, AQP8, is shown and the strikingly high water permeability (Pf) characterizing the rat liver IMM is demonstrated, suggesting that AQP 8-mediated water transport may be particularly important for rapid expansions of mitochondrial volume.
Electron Transfer within Complex II
Evidence is presented that the heme, far from being a bystander in the efficient transfer of reducing equivalents from succinate to the ubiquinone via the flavin-Fe/S centers, plays a pivotal role in providing a lower energy pathway for the transfer of an electron from the high potential [3Fe-4S] center to ubiquin one.
Real-time electron transfer in respiratory complex I
The millisecond component of electron transfer in complex I from Escherichia coli is limited by a single process corresponding to dissociation of the oxidized NAD+ molecule from its binding site, where it prevents entry of the next NADH molecule.
Mössbauer Spectroscopy on Respiratory Complex I: The Iron–Sulfur Cluster Ensemble in the NADH-Reduced Enzyme Is Partially Oxidized
Mössbauer spectroscopy is used on 57Fe-labeled complex I from the mitochondria of Yarrowia lipolytica to show that the cluster ensemble is only partially reduced in the NADH-reduced enzyme, and an alternating profile of higher and lower potential clusters between the two active sites in complex I is revealed.
Architecture of Succinate Dehydrogenase and Reactive Oxygen Species Generation
The structure of Escherichia colisuccinate dehydrogenase (SQR), analogous to the mitochondrial respiratory complex II, has been determined, revealing the electron transport pathway from the electron
Oxidative phosphorylation and mitochondrial physiology: a critical review of chemiosmotic theory, and reinterpretation by the association-induction hypothesis.
Findings refute the membrane-pump theory but added powerful support for the association-induction hypothesis, on the basis of which a new mechanism of oxidative phosphorylation as well as a wide variety of mitochondrial behaviors are proposed and compared with experimental data.