Nikolai Mikhailovich Bazhin

Bioenergetics is the study of how life-activities are powered within the cell. This also deals with the interactive exchange of matter/radiation between cellular components and their environment, and the accompanying changes thereof. The acclaimed bioenergetics paradigm has relied on “electron transport chains” and selective/stoichiometric electrogenic “ion-pumping” mediated by vectorial protein-embedded membranes. Therein, an electrochemical gradient was deemed to be the driving force for chemical reactions leading to ATP production, physical thermogenesis by uncoupling proteins, and complex electromechanical processes like information relay along the axon. On one hand, this vitally deterministic perception requires the membrane proteins to “intelligently” manipulate ion-fluxes and generate/harness an electrochemical gradient by a gambit-type logic. At the other hand, it also seeks that the same gradient should cyclically control the membrane-proteins’ activity. Our recent pursuits have questioned such traditional perspectives and advocated the alternate explanation of murburn concept, leading to a revamping of the macroscopic treatments of overall thermodynamic, kinetic, mechanistic, and evolutionary (probability) considerations. The current review aims to consolidate the murburn paradigm of bioenergetics, wherein murzymes initiate redox processes by effective charge separation and diffusible reactive species formation, enabling cells to work as simple chemical engines. Herein, we discuss the reaction chemistry of some simple enzyme systems and also delve into protein complex arrays mediated powering routines like mitochondrial respiration-thermogenesis and chloroplast-centered photosynthesis. Furthermore, we remark that the “water–ion–molecules” phase continuum is actually discretized into dynamically fluctuating coacervates and express concern over the marginalization of sound chemico-physical ideas by the bioenergetics community.

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.

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.

Starting from the basic molecular structure and redox properties of its components, we build a macroscopic cellular electrophysiological model. We first present a murburn purview that could explain ion distribution in bulk‐milieu/membrane‐interface and support the origin of trans‐membrane potential (TMP) in cells. In particular, the discussion focuses on how cells achieve disparity in the distribution of monovalent and divalent cations within (K⁺ > Na⁺ > Mg²⁺ > Ca²⁺) and outside (Na⁺ > K⁺ > Ca²⁺ > Mg²⁺). We explore how TMP could vary for resting/graded/action potentials generation and project a model for impulse conduction in neurons. Outcomes based on murburn bioenergetic equilibriums leading to solubilization of ion‐pairs, membrane's permittivity, protein channels' fluxes, and proteins’ innate ability to bind/adsorb ions selectively are projected as the integral rationale. We also provide experimental modalities to ratify the projections.

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. In lieu, we 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 (e_aq) and DROS in milieu, which are stabilized by a pool of redox-active elements within chloroplasts. Subsequently, the ‘e_aq+DR(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. Communicated by Ramaswamy H. Sarma

The standard thermodynamic parameters of inorganic ions in an aqueous solution are based on the use of a convention on the zero values of the thermodynamic functions of protons. However, this does not allow calculating the thermodynamic parameters of reactions in which, along with ions, organic and inorganic compounds participate, the thermodynamic parameters of which are determined in the standard system of values since frames of reference are different. In this work, we calculated the standard thermodynamic parameters of inorganic ions in an aqueous solution in the same system of values that is used for organic compounds. The calculation of the standard values of the Gibbs function, enthalpy, and entropy is based on the use of reliably determined thermodynamic parameters of protons in an aqueous solution according to Tissandier et al. [ J. Phys. Chem. A, 1998, 102, 7787−7794]. The results allow one to calculate the thermodynamic parameters of reactions in aqueous media with the participation of inorganic ions and organic compounds. In this work, the thermodynamic parameters of solvation processes in aqueous solutions are determined. The standard entropy of ions in an aqueous solution was calculated by four independent methods.

This work proposes the term “hydroosmotic pressure” to define hydrostatic pressure emerging from an osmotic process during solvent diffusion through membranes. The usage of this term potentially clears the ambiguity of the term “osmotic pressure,” referring to the concentration of dissolved solids in a solution regardless of the existence of hydrostatic pressure. Hydroosmotic pressure is the difference between hydrostatic pressures on either side of the membrane; thus, the term “hydroosmotic pressure” allows for the most correct definition of many processes associated with osmotic phenomena.