Preprint

Some living beings speak up against ‘electron transport chain – chemiosmosis – rotary ATP synthesis’ bioenergetics model

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  • Satyamjayatu: The Science & Ethics Foundation
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Abstract

Since 2017, I have argued that affinity/contact-based electron transport chain (ETC) and chemiosmotic rotary ATP synthesis (CRAS) explanation fail to reason the workability or evolution of cellular bioenergetics. Cyanobacteria (Prochlorococcus) can both respire and photosynthesize. In these systems, the aqueous milieu of <0.1 femtoliter (pH 8) cannot afford any free protons to build ‘pmf’’, thereby negating chemiosmosis. The anti-parallel ETCs (NADH→H2O in respiration and H2O→NADH in photosynthesis) would lead to futile cycles, owing to the commonality of cytochromes b6f and c1. Aphids of genus Acyrthosiphon use the inbuilt carotenoid pigments to reduce NAD and synthesize ATP, without elaborate setups like Z-scheme. The classical perceptions deem archaeans to have a unique bioenergetic history, distinct from bacteria/eukarya. Although it is known that archaea lack FoF1ATP(synth)ase, the ‘molecular motor’ is otherwise believed to be conserved in bacterial/eukaryotic systems. However, the genes of Complex V are not clubbed/linked in proteobacterial Rickettsia prowazekii. Several parasitic and a free-living alveolate Tetrahymena thermophila lack essential proteins of Fo module. Complex V is completely absent in the blood-stage malarial parasite (Plasmodium berghei) and Buchnera aphidicola (a proteobacterium, endosymbiont of cedar bark aphid). Monocercomonoides (a flagellate oxymonad rodent-gut symbiont) and human erythrocytes generate ATP without mitochondria! The recently discovered cnidarian parasite Henneguya salminicola does not have respiratory Complexes I, III & IV, the purported classical proton pumps. While the ETC-CRAS model is incompatible with these facts, the newly available murburn alternative accommodates them. The principles of scientific pursuits and Ockham’s razor decide in favor of the murburn model of bioenergetics.

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... The rotary explanation for Complex V is a classical example of Michael Behe's anti-evolution argument of "irreducible complexity". We have recently compiled multitudes of evolution-based rationale for why F-A-V ATPases cannot be the original ATP-synthase for the LUCA or the earlier ancestors of life (Manoj, 2021). In fact, there are several examples living even now which do not have full or parts of Complex V. ...
... The same observation has been demonstrated in the CYP þ CPR system also, which confirms the murburn model's relevance in physiology (Manoj, 2018a;. (j) A survey of compositional and structural data of diverse life forms and experimental cells (genetically manipulated) supports murburn model's mechanism where Complex V is accorded a secondary status in ATP synthesis (Manoj, 2021). ...
Article
Complex V or FoF1-ATPase is a multimeric protein found in bioenergetic membranes of cells and organelles like mitochondria/chloroplasts. The popular perception on Complex V deems it as a reversible molecular motor, working bi-directionally (breaking or making ATP) via a conformation-change based chemiosmotic rotary ATP synthesis (CRAS) mechanism, driven by proton-gradients or trans-membrane potential (TMP). In continuance of our pursuits against the CRAS model of cellular bioenergetics, herein we demonstrate the validity of the murburn model based in diffusible reactive (oxygen) species (DRS/DROS). Supported by new in silico derived data (that there are ∼12 adenosine nucleotide binding sites on the F1 bulb and not merely 3 sites, as perceived earlier), available structural information, known experimental observations, and thermodynamic/kinetic considerations (that de-solvation of protons from hydronium ions is facile), we deduce that Complex V serves as a physiological chemostat and a murzyme (enzyme working via murburn scheme, employing DRS). That is- Complex V uses ATP (via consumption at ε or proteins of F1 module) as a Michaelis-Menten substrate to serve as a pH-stat by inletting protons via the c-ring of Fo module. Physiologically, Complex V also functions as a murzyme by presenting ADP/Pi (or their reaction intermediates) on the αβ bulb, thereby enabling greater opportunities for DRS/proton-assisted ATP formation. Thus, the murburn paradigm succeeds the CRAS hypothesis for explaining the role of oxygen in mitochondrial physiologies of oxidative phosphorylation, thermogenesis, TMP and homeostasis. Communicated by Ramaswamy H. Sarma
... (ii) inter-protein electron transfers (Gideon et al., 2012Manoj et al., 2020a), (iii) drug/xenobiotic metabolism and interactions (Manoj, Gade, et al., 2010;Parashar, Gade, et al., 2014;Venkatachalam et al., 2016), (iv) unusual physiological dose responses Manoj, 2018b;Parashar et al., 2018), 2 | C Cell ell B Biology iology I International nternational (v) aerobic respiration and its evolutionary aspects Manoj, 2017Manoj, , 2019Manoj, 2018aManoj, , 2018bManoj, Soman, et al., 2019;Manoj, 2020aManoj, , 2020bManoj, , 2020cManoj, Ramasamy, et al., 2020;Manoj et al., 2020a;Manoj, 2021), (vi) toxicity of cyanide to a bevy of physiologies in multiple organisms Manoj, Ramasamy, et al., 2020;Parashar, Venkatachalam, et al., 2014), (vii) thermogenesis (Manoj, 2017;Manoj et al., 2018;, (viii) homeostasis Manoj, Bazhin, & Tamagawa, 2021;, (ix) photoreception and the physiology of vision , (x) oxygenic photosynthesis or photophosphorylation Manoj et al., 2020a;Manoj, Bazhin, Jacob, et al., 2021;Manoj, Nikolai, et al., 2021), (xi) ATP synthesis in erythrocytes by hemoglobin , (xii) ionic differentials and electrophysiology Manoj, Bazhin, & Tamagawa, 2021;Tamagawa et al., 2021). ...
... For the first time, a murburn model for a classical acid-base catalysis like dehydrogenase mediated conversion of alpha hydroxyacids was proposed , and these aspects provide insights into Cori cycle and Warburg effect. Several examples of living beings violating the ETC-CRAS mechanism have been presented, further highlighting murburn concept as a fundamental principle of life (Manoj, 2021). Therefore, it must be seen at the outset that murburn concept is a profound idea that stands to impact our understanding of life. ...
Article
Mitochondrial membrane-embedded redox proteins are classically perceived as deterministic ‘electron transport chain’ (ETC) arrays cum proton pumps; and oxygen is seen as an ‘immobile terminal electron acceptor’. This is untenable because: (1) there are little free protons to be pumped out of the matrix; (2) proton pumping would be highly endergonic; (3) ETC-chemiosmosis-rotary ATP synthesis proposal is ‘irreducibly complex’/‘non-evolvable’ and does not fit with mitochondrial architecture or structural/distribution data of the concerned proteins/components; (4) a plethora of experimental observations do not conform to the postulates/requisites; e.g. there is little evidence for viable proton-pumps/pH-gradient in mitochondria, trans-membrane potential (TMP) is non-fluctuating/non-trappable, oxygen is seen to give copious ‘diffusible reactive (oxygen) species’ (DRS/DROS) in milieu, etc. Quite contrarily, the newly proposed murburn model’s tenets agree with known principles of energetics/kinetics, and build on established structural data and reported observations. In this purview, oxygen is needed to make DRS, the principal component of mitochondrial function. Complex V and porins respectively serve as proton-inlet and turgor-based water-exodus portals, thereby achieving organellar homeostasis. Complexes I to IV possess ADP-binding sites and their redox-centres react/interact with O2/DRS. At/around these complexes, DRS cross-react or activate/oxidize ADP/Pi via fast thermogenic one-electron reaction(s), condensing to form two-electron stabilized products (H2O2/H2O/ATP). The varied architecture and distribution of components in mitochondria validate DRS as the- (i) the coupling agent of oxidative reactions and phosphorylations, and (ii) the primary reason for manifestation of TMP in steady-state. Explorations along the new precepts stand to provide greater insights on mitochondrial function and pathophysiology. This article is protected by copyright. All rights reserved.
... Further, the insights gathered above were applied to clarify upon the more complex membrane-embedded multi-protein orchestrated phosphorylation physiologies of mitochondrial respiration/ thermogenesis and chloroplast photosynthesis . Furthermore, murburn concept addressed structure-function correlations of miscellaneous proteins and evolutionary considerations in diverse aspects of cellular (electro)physiology, homeostasis and trans-membrane flux dynamics [45][46][47][48][49][50][51][52][53]. In these works, the classical scheme of enzyme catalyzed reactions or biological electron transfers were further expanded and qualified, to explain the relevance and analogies of murburn/ murzyme concept [54,55]. ...
Article
The advent of improved structural biology protocols and bioinformatics methodologies have provided paradigm-shifting insights on metabolic or physiological processes catalyzed by homo−/hetero- proteins (super)complexes embedded in phospholipid membranes of cells/organelles. In this panoramic review, we succinctly elucidate the structural features of select redox proteins from four systems: hepatocyte/adrenal cortex endoplasmic reticulum (microsomes), inner mitochondrial membrane (cristae), thylakoid membrane (grana), and in the flattened disks of rod/cone cells (in retina). Besides catalyzing fast/crucial (photo)chemical reactions, these proteins utilize the redox-active diatomic gaseous molecule of oxygen, the elixir of aerobic life. Quite contrary to extant perceptions that invoke primarily deterministic affinity-binding or conformation-change based “proton-pump”/“serial electron-relay” type roles, we advocate murzyme functions for the membrane-embedded proteins in these systems. Murzymes are proteins that generate/stabilize/utilize diffusible reactive (oxygen) species (DRS/DROS) based activities. Herein, we present a brief compendium of the recently revealed wealth of structural information and mechanistic concepts on how the membrane proteins use DRS/DROS to aid ‘effective charge separation’ and facilitate trans-membrane dynamics of diverse species in milieu, thereby enabling the cells to function as ‘simple chemical engines’.
Preprint
Physiological redox conversion of alpha-hydroxy/keto acids is believed to be reversibly carried out by (de)hydrogenases, employing nicotinamide cofactors. With lactate dehydrogenase (LDH) as example, we point out that while the utilization of NADH for the reduction of pyruvate to lactate (the post-glycolytic reaction) can be mediated via the classical Michaelis-Menten mechanism, the oxidation of lactate to pyruvate (with or without the uphill reduction of NADH) necessitates alternative physiological approaches. This reaction could be more efficiently coupled/catalyzed with/by murzyme activities, which employ diffusible reactive (oxygen) species (DRS/DROS/ROS). Such a scheme would enable the cellular system to tide over the unfavorable energy barriers of the forward reaction (~450 kJ/mol; earlier considered to be ~25 kJ/mole!), and give kinetically viable conversions. Further, the new mechanism does not necessitate any ‘smart decision-making’ by the pertinent redox isozyme(s). For LDH, the new theory explains its multimeric nature, non-variant structure of the isozymes’ active sites and accounts for why lactate is transported to the liver for further utilization within the physiological purview of Cori cycle. The theoretical insights, in silico evidence and analyses of literature herein also enrich our understanding of ‘lactic acidosis’ (in clinical context), Warburg effect and approach for cancer therapy.
Article
In this first part of our essay on oxygenic photosynthesis, we address the various aspects of classical and murburn explanations. We had recently pointed out that the classical explanations of- trans-membrane potential (TMP)-based chemiosmotic rotary ATP synthesis, quinone-cycle at cytochrome b6f, chartered electron transport by plastocyanin, and modality of light’s interaction with chloroplast pigments- are untenable and proposed a diffusible reactive (oxygen) species (DROS)-based murburn model. In continuum, herein, we assess the operational viability of the cyclic oxygenesis and electron transport chain (ETC) explanations for oxygenic photosynthesis, in the light of updated structural/mechanistic information. Further, thermodynamically validated murburn equations of photolysis-photophosphorylation (Pl-Pp) are provided, along with the rationale for organelle-homeostasis. We propose that the photo-excitation of various pigments leads to the formation of aquated electrons (eaq) and DROS in milieu, which are stabilized by a pool of redox-active elements within chloroplasts. Subsequently, the ‘eaqþDR(O)S’ pool is utilized stochastically via disordered/parallel reactions at the stacked thylakoid membrane interface. Effective charge separation by ‘photosystem switches’ enables delocalized oxygenesis, NAD(P) reduction and ADP phosphorylation. Heat/TMP/DROS generation is also an outcome of this process. Finally, we compare the murburn and classical models of Pl-Pp and delineate agendas for their ratification /falsification.
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