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AbstractThe inefficiency of cyanide/HCN (CN) binding with heme proteins (under physiological regimes) is demonstrated with an assessment of thermodynamics, kinetics, and inhibition constants. The acute onset of toxicity and CN’s mg/Kg LD50 (μM lethal concentration) suggests that the classical hemeFe binding-based inhibition rationale is untenable to account for the toxicity of CN. In vitro mechanistic probing of CN-mediated inhibition of hemeFe reductionist systems was explored as a murburn model for mitochondrial oxidative phosphorylation (mOxPhos). The effect of CN in haloperoxidase catalyzed chlorine moiety transfer to small organics was considered as an analogous probe for phosphate group transfer in mOxPhos. Similarly, inclusion of CN in peroxidase-catalase mediated one-electron oxidation of small organics was used to explore electron transfer outcomes in mOxPhos, leading to water formation. The free energy correlations from a Hammett study and IC50/Hill slopes analyses and comparison with ligands $\left( {\text{CO}}/{{{{\text{H}}_{2}}\text{S}}/{\text{N}_{3}^{\text{-}}}\;}\; \right)$ provide insights into the involvement of diffusible radicals and proton-equilibriums, explaining analogous outcomes in mOxPhos chemistry. Further, we demonstrate that superoxide (diffusible reactive oxygen species, DROS) enables in vitro ATP synthesis from ADP+phosphate, and show that this reaction is inhibited by CN. Therefore, practically instantaneous CN ion-radical interactions with DROS in matrix catalytically disrupt mOxPhos, explaining the acute lethal effect of CN.

The physiology of thermogenesis in mitochondria (mediated by uncoupling protein, UCP) has traditionally been explained as the dissipation of proton gradient across the inner mitochondrial membrane into heat. However, there are differences of opinion ture. Recent experimental evidence suggests strong correlation of diffusible reactive oxygen species (DROS) with UCP-induced thermogenesis. Further, the mechanistic explanations of mitochondrial oxidative phosphorylation (mOxPhos) were recently revamped with murburn concept, which considers DROS as an obligatory catalytic agent in mOxPhos. Herein, we propose that of DROS. Thus, UCP facilitates DROS-reactions amongst themselves, forming water and liberating heat around the inner mitochondrial membrane. Thereby, the simple murburn scheme for biothermogenesis integrates structural information of UCP with its attributed physiological function.

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Cellular bioenergetics has been interpreted for several decades using the Keilin-Mitchell-Boyer (KMB) model of oxidative phosphorylation (OxPhos), and for understanding/managing of the pertinent mitochondrial pathophysiological states. Although decades of research had revealed many faulty chemico-physical aspects of KMB perspective, recent critical insights from our group's writings have sufficiently brought out the errors in the KMB model, rendering it obsolete/redundant. The murburn model proposed in lieu is a compelling alternative for explaining OxPhos because it reasons several facets of mitochondrial structurefunction correlations, reaction chemistry and thermodynamics. However, the mitochondrial research community appears to be recalcitrant, and continues to follow the erstwhile erroneous ideas and not take cognizance of the new insights. Hence, we deemed it opportune to make a clarion call for a jettisoning of the superseded terminologies (or keywords) and concepts routinely used by researchers in this field. First, we present a statistical perspective of the usage of these terms in the past and recent times, to support our claims and call. Then, we articulate simplified arguments why the key elements/terms of the KMB model like "electron-transfer/electron-transport/respiratory chain", "mitochondrial proton pumps", "mitochondrial membrane potential", "chemiosmosis", "proton motive force" and "rotary ATP synthase/synthesis" violate scientific/semantic logic. Finally, we conclude with summative statements projecting the importance of our claims and call.

Robert Emerson’s original observation (1957) that “oxygenesis occurs even with far-red light excitation of Photosystem I” is incompatible with the extant Kok-Joliot cycle’s foundation that “photolysis occurs only at red-light stimulated Photosystem II harboring MnComplex”. Further, the Z-scheme of electron transfer cannot account for Emerson’s observations of enhanced oxygenesis by simultaneous excitation of the two photosystems with both red and far-red light because serially connected components would surely increase systemic resistance to flow of charges, impeding the overall electron transfer process from water to NADP+. To address such discrepancies, we propose that the photo-excitation of various pigments leads to the formation of aquated electrons (eaq) and diffusible reactive oxygen species (DROS) in milieu, which are stabilized by a pool of redox-active elements within chloroplasts. Subsequently, the ‘eaq+DROS’ pool is utilized and routed via disordered and parallel reactions by the ‘photosystem switches’ for NADP reduction, O2 liberation and ADP phosphorylation. The stochastic ‘murburn’ model is thermodynamically and kinetically favorable and evidenced by the identification of multiple ADP-binding sites on PS II/Cytochrome b6f, and structure/distribution of the concerned proteins, complexes and pigments. The new model also explains the observed synergy in functioning of photosystems and plants’ photosynthetic spectral range of 400-700 nm.