Murburn concept and murzymes in 2023: celebrating 25th year of pursuit

Murburn concept (from “mured burning”; signifies that redox processes involving diffusible reactive species form indispensable facets of governing key metabolic/physiological facets of life) dispels the traditional/aesthetic perception that diffusible reactive species (DRS) are merely wasteful/chaotic agents and enlightens that the processes mediated by DRS are necessary for carrying out crucial/routine cellular functions. Such DRS-sponsored stochastic activities evolutionarily pre-date the deterministic affinity-driven catalysis and signal transduction cascades of classical/acclaimed protein-functions. My pursuits in this regard started in 1999 with seemingly innocuous explorations and serendipitous observations while working on a fungal heme-peroxidase in Lowell Hager’s (elected member, National Academy of Sciences, USA) lab at University of Illinois (Urbana-Champaign). Since then, murburn concept has transformed into one of the founding pillars of cell/life sciences. Biomedical Reviews played a pivotal role by serving as the first portal publishing/disseminating my articles critiquing the acclaimed bioenergetic explanations from Peter Mitchell and Paul Boyer; namely- chemiosmosis/proton motive force and rotary ATP-synthesis (recognized with Nobel Prizes in 1978 and 1997, respectively). These papers also advocated murburn concept as a viable alternative for explaining cellular powering by mitochondria, i.e. oxidative phosphorylation and thermogenesis. Herein, adopting a balanced measure of gratitude and grievances, I document the salient developments of the last few years’ progression on murburn concept and present my subjective impressions on its impact/prospects in the future

The ubiquitous biochemical logic of murburn concept

In peroxidative biotransformations, reactions occurring outside the enzyme`s `active site` were seen to yield selective and specific outcomes. These observations had inspired me then to postulate that `such a non-active site and environment-dependent mechanism could play significant roles in life-sustenance processes, besides the well-established hierarchical molecular control mechanisms at genes` and proteins` levels`. Through the decade that followed, further research on these strings culminated into the formation of murburn concept, a stochastic scheme of electron/moiety transfers and interactions among molecules, unbound ions and radicals present in reaction milieu. The new understanding explained key qualitative and quantitative aspects of heme/flavin enzymology (substrate diversity, reaction stoichiometry, etc.) and electron transfer mechanism in these enzymes` in vitro setups. Further, murburn schemes were proposed to explain xenobiotic metabolism, cellular respiration, bio-thermogenesis and maverick physiological dose-responses. This article deals with a brief summation of the development of murburn concept, its current status and potential implications/applications in biology and medicine

Iconoclasm and innovation: the inevitable and the appreciable facets of murburn concept

My cover-page credited article questioning the highly acclaimed ideas of chemiosmosis (Nobel Prize to Peter Mitchell, 1978) and rotary ATP synthesis (Nobel Prize to Paul Boyer, 1997) was first published for the dissemination of knowledge at Biomedical Reviews (2017). Thereafter, in the very same journal (in 2019), my group had called for jettisoning some redundant terminology/ ideas in bioenergetics field, as their impropriety and falsity had been established beyond reasonable doubt. PubMed surveys of leading periodicals of high impact (e.g. Cell, Nature, & Science) and some devoted bioenergetics journals (like BBA-Bioenergetics, Journal of Bioenergetics and Biomembranes, & Mitochondrion) still show some usage of classical terms like electron transport or respiratory chain, chemiosmosis, proton pump, proton motive force, mitochondrial membrane potential, rotary ATP synthesis, ATP synthase, etc. However, murburn pursuits seem to have dampened the further consolidation of the Keilin-Mitchell-Boyer paradigm. Although citations (critical or appreciative) for murburn concept are not forthcoming, some of our articles are well- read by the community. As iconoclasm and innovation are two sides of the same coin of science, it is hoped that murburn concept would soon gain traction with the bioenergetics research community. Towards this purpose, in this review, I succinctly list the salient publications that demonstrate various core aspects of murburn concept

Are adipocytes and ROS villains, or are they protagonists in the drama of life? The murburn perspective

Several questions remain unanswered regarding the roles and interactive dynamics of reactive oxygen species (ROS) and lipids/adipocytes. ROS have been conventionally associated with deleterious effects in biological systems, especially correlated with metabolic disorders exemplified by diabetes, obesity, cancer, atherogenesis, etc. Adipocytes, originally perceived as mere lipid-storing cells, were also associated with such metabolic disorders. In later times, adipose tissue was shown to have several favorable metabolic and physiological functions. Similarly, ROS were also acknowledged with favorable roles in cellular signaling. Very recently, ROS have been shown to be indispensable protagonists of key life-sustaining routines such as oxidative phosphorylation, thermogenesis and xenobiotics’ metabolism. In the light of these developments, herein, we attempt to address why different research groups derive data that project/infer contrasting correlations of ROS and lipids with good health. We advocate that rather than seeing ROS and fat deposition as deleterious to health, the modality of their generation, loci of presence and the relative amounts/distribution in milieu are the crucial factors that determine their interactions/roles (and thereby, the resulting physiology!) in miscellaneous microenvironments

2020: murburn concept heralds a new era in cellular bioenergetics

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 structure-function 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 po-tential”, “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

Murburn scheme for mitochondrial thermogenesis

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 on how thermogenesis is achieved by UCPs and the mechanistic theories have not been correlated sufficiently with UCP`s structure. 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 UCPs (aided by the large pore and positively charged amino acids of aqueous-phase loops) enable protonation and transport 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