Diffusible reactive (oxygen) species CANNOT be disconnected from cellular functioning or bioenergetics
Authors: Manoj Kelath Murali 
Published: January 2024

The article- “Systems-level analyses dissociate genetic regulators of reactive oxygen species (ROS) and energy production” by Bennett et al. in PNAS (Jan 11, 2024; https://doi.org/10.1073/pnas.230790412) discusses the context for disconnecting the production of diffusible reactive (oxygen) species or DR(O)S/ROS during mitochondrial ATP-synthesis. Their outlook/pursuit based in ‘Chemiosmotic Rotary ATP Synthesis’ (CRAS) is in dissonance with our group’s published iconoclastic thesis of murburn concept, which proposes DRS as the elixir of life, obligatory in acute cellular PCHEMS, i.e. Powering, Coherence, Homeostasis, Electro-Mechanics, and Sensing/response (i.e. physico-chemical stature). ‘Murburn’ is abstracted from ‘mured burning’, connoting a mild unrestricted redox catalytic scheme (a stochastic electron/moiety-transfer paradigm OR a chaotic interactive equilibrium of molecules, unbound ions and radicals). Primarily, this results from effective charge separation (ECS) at some protein redox centers, concomitantly leading to DRS production. Based on the murburn postulation, &gt;50 articles detailed novel chemico-physical explanations for the catalytic activity of heme-peroxidases/P450s, along with comprehensive models for diverse metabolic/physiological contexts, and these were recently summated in a two-part review (contrasting with the acclaimed/classical models) at an American Institute of Physics portal (1). Pre-empting the ‘problem’ addressed in the above PNAS-article, my group’s publication- “Why do cells need oxygen? Insights from mitochondrial composition and function” in Cell Biology International (2) attests that DRS directly mediates the oxidative phosphorylation “powering reaction”. Via our publications in Journal of Biomolecular Structure and Dynamics (3), we demonstrated that Complex V cannot be a physiological rotary ATP-synthase, but serves a chemostatic function. Our article presenting the thermodynamic/kinetic aspects for murburn model of cellular respiration was given cover-page credits in Progress in Biophysics and Molecular Biology (4). Our papers published in Biochemical and Biophysical Research Communications / Biochimie (5) and Toxicology / Biomolecular Concepts (6) explained the acutely debilitating effects of low doses of cyanide owing to an alteration of DRS-dynamics. Invited reviews on the predictive abilities of murburn model of cellular respiration was published in Archives of Biochemistry &amp; Biophysics (7) and structure-function correlations of membrane-embedded murburn systems was covered in Biochimica et Biophysica Acta-Biomembranes (8). A summative overview of murburn concept’s centrality in electrophysiology, roles in the origin-evolution-sustenance of life and its fundamental stature along with central dogma in cellular function was published in Journal of Cellular Physiology (9). Given that: (i) several reputed journals’ reviewers/editors have deemed murburn model to be a tangible/tenable theory for diverse routine cellular physiology (1-9), and (ii) post the publication of my exhaustive critique of CRAS model in Biochemistry Insights (10), the usage of classical “proton motive force/chemiosmosis” terminology in bioenergetics parlances is evidently declining since 2018 (Figures 6-7; https://journals.mu-varna.bg/index.php/bmr/article/view/9115/8001), a display item is presented herewith to highlight the perception-change regarding mitochondrial bioenergetics. These developments necessitate revisiting Bennett et al.’s interpretation of results and reorientation of research community’s perspectives. We first need to appreciate the Dr. Jekyll face of DRS and thereafter address the contexts of its Mr. Hyde persona. Therefore, it is mandated to probe/understand spatio-temporal DRS-dynamics as a fundamental rationale for both routine physiology and pathological outcomes!