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Thermogenesis, electro-chemical physiology (ECP), and electro-mechanical activities (EMAs) are fundamental facets of cellular functioning that are associated with powering, coherence, homeostasis, sensing, and response to stimuli. The classical Hodgkin–Huxley–Katz purview of ECP is derived from Nernst-based foundations for dilute solutions, whereas cellular milieus are mostly highly packed colloidal coacervates, with various types/levels of macromolecules (ions), interactions, and ordering of water. It has also been established that trans-membrane potential (TMP) manifestation can also be affected by adsorption of ions and effective charge separation (1e processes), necessitating the questioning and expansion of classical purviews. Further, we have demonstrated that the traditional explanation of electrogenic/stoichiometric and vitally deterministic bidirectional pumping/channeling of ions by membrane proteins (such as Na,K-ATPase) as the rationale for resting/dynamic TMP variations is untenable. In stark contrast, the murburn purview of ECP-EMAs acknowledges the complexity and discretization of the organization of water, ions, and macromolecules within the cell and does not solicit selective ion-pumping or TMP-based powering/propagation rationales. Herein, we summarize the murburn rationale for the molecular to macroscopic integration of processes such as thermogenesis, kinetic Na–K differentiation at the cell membrane, visual signal transduction and neuronal impulse relay, Complex V mediated mechano-chemostat function, flagella-based motility, etc., and discuss the alteration of cellular volume/tenor in muscle cell contraction. We assert that the membrane-embedded proteins/enzymes cannot use ATP to work against the natural laws of physics. Therefore, the classical perception of membrane-based ion pumps must be jettisoned to make way for the thermodynamics-friendly murburn purview. [ABSTRACT FROM AUTHOR]

If evolution was/is a fact, a simplified/unifying approach to explain cellular physiology is warranted. Such a perspective should agree with the thermodynamic, kinetic, structural, and operational‐probabilistic considerations; without invoking overt intelligence or determinism, and must enable a synthesis from chaos. In this regard, we first list salient theories in cellular physiology for (i) powering (generation of chemical/heat energy), (ii) coherence (interconnectivity and workability as a unit), (iii) homeostasis (metabolizing and expelling of unfamiliar/unwanted materials, maintaining concentration/volume), and (iv) cellular electrical‐mechanical activities. While doing so, we discuss the scopes and limitations of (a) the classical active‐site affinity and recognition‐based modality of lock‐key and induced‐fit enzyme‐catalytic mechanisms established by Fischer/Koshland, (b) membrane‐pump hypothesis acclaimed by biologists‐physicians and historically championed by the British Nobel‐laureates like Hodgkin–Huxley–Katz–Mitchell, and (c) association‐induction hypothesis advocated by physicists–physiologists from various parts of the world, for example, Gilbert Ling (China–USA), Gerald Pollack (USA), Ludwig Edelmann (Germany), Vladimir Matveev (Russia), and so on. We apply murburn concept (from "mured burning," capturing the thesis that one‐electron redox equilibriums involving diffusible reactive species play vital roles in maintaining life order) to amalgamate several core cellular functions and further discuss the prospects for establishing the continuum of the principles of physics in biology. [ABSTRACT FROM AUTHOR]

The redox metabolic paradigm of murburn concept advocates that diffusible reactive species (DRS, particularly oxygen‐centric radicals) are mainstays of physiology, and not mere pathological manifestations. The murburn purview of cellular function also integrates the essential principles of bioenergetics, thermogenesis, homeostasis, electrophysiology, and coherence. In this context, any enzyme that generates/ modulates/utilizes/sustains DRS functionality is called a murzyme. We have demonstrated that several water‐soluble (peroxidases, lactate dehydrogenase, hemogoblin, etc.) and membrane‐embedded (Complexes I–V in mitochondria, Photosystems I/II in chloroplasts, rhodopsin/transducin in rod cells, etc.) proteins serve as murzymes. The membrane protein of Na,K‐ATPase (NKA, also known as sodium‐potassium pump) is the focus of this article, owing to its centrality in neuro‐ cardio‐musculo electrophysiology. Herein, via a series of critical queries starting from the geometric/spatio‐temporal considerations of diffusion/mass transfer of solutes in cells to an update on structural/distributional features of NKA in diverse cellular systems, and from various mechanistic aspects of ion‐transport (thermodynamics, osmoregulation, evolutionary dictates, etc.) to assays/explanations of inhibitory principles like cardiotonic steroids (CTS), we first highlight some unresolved problems in the field. Thereafter, we propose and apply a minimalist murburn model of trans‐membrane ion‐differentiation by NKA to address the physiological inhibitory effects of trans‐dermal peptide, lithium ion, volatile anesthetics, confirmed interfacial DRS + proton modulators like nitrophenolics and unsaturated fatty acid, and the diverse classes of molecules like CTS, arginine, oximes, etc. These explanations find a pan‐systemic connectivity with the inhibitions/uncouplings of other membrane proteins in cells. [ABSTRACT FROM AUTHOR]

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; for example, 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 builds 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‐centers 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 (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. [ABSTRACT FROM AUTHOR]

The example of gelatine shows that extended proteins behave quite differently than globular ones: with water they form a gel. Historically the colloid view of protoplasm was discredited in favour of membrane-(pump)-theory (MPT), but unjustified. In his association-induction hypothesis Ling demonstrates that MPT is full of contradictions and that the colloid view has to be re-considered. In that case IDP's play a crucial role in this. What Ling calls the ‘living state’ consists of the unitary protoplasmic structure from which it was experimentally demonstrated that it can survive and keep Na + and K + concentrations without a delineating membrane. It consists of unfolded polypeptide chains whereby the repetitive backbone peptide groups orient and polarise many layers of water, in which Na + and other solutes have reduced solubility and whereby the polypeptide β- and ϒ-carboxyl-groups adsorb K + . This ‘associated’ state is the resting state: a coherent high-energy low-entropy meta-stable state. It can be kept by adsorbed ATP (NTP) eventually for years without consumption of ATP as demonstrated by Clegg on Artemia embryo's. Stimuli can transform this state into a lower-energy higher-entropy action state with dissociation of ADP and P i and newly synthesised ATP can reinstall it. Rest-to-action and action-to-rest were shown to be real phase-shifts. Ling's theory is a complete quantitative theory with corroborated equations for solute distribution, transport, cell potentials and osmotic behaviour and describing the cell's energy cycle. IDP's are involved in all this. The new view on IDP's leads to new insights on the origin of life. [ABSTRACT FROM AUTHOR]