Synthesis of theories on cellular powering, coherence, homeostasis and electro-mechanics: Murburn concept & evolutionary perspectives

Abstract

If evolution were to be a fact, a simplified and unifying approach to explain cellular physiology is warranted. Such a perspective should agree with the thermodynamic, kinetic, structural and the 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 Fisher/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 notable physicists-physiologists from various parts of the world, e.g. Gilbert Ling (China-USA), Gerald Pollack (USA), Ludwig Edelmann (Germany), Vladimir Matveev (Russia), Hirohisa Tamagawa (Japan), etc.]. We apply murburn concept (the thesis that 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.

The murburn explanation for redox-phosphorylative coupling by Complex I

“…This reaction furnishes an energy of only -69.5 kJ/mol, which is insufficient to meet the energetic cost of 80-88 kJ/mol (as calculated by the Mitchellian equations) for pumping out 4-protons (2)(3)(4). Most importantly, the mitochondrial matrix has only fingercountable protons at the physiological pH, rendering any significant outward proton-pumping (by thousands of Complex I molecules present in mitochondrion) infeasible (2)(3)(4)(5)(6)(7)(8). Therefore, proton-pumping cannot be justified by any sophisticated structural insights.…”

“…Even if we overlook these aspects, a purported transfer-pathway of four protons through four distinct loci in the trans-membrane foot cannot be temporally and/or spatially linked to the staggered redox relay of two electrons along the multitudes of FeS centers (of diverse spacing and redox-potentials) in the matrix-arm. Further, docking of Complexes III and IV in the respirasome-organization would definitely affect sophisticated "conformational changes", besides the systemic failure to address quinone-mobility/cycling issues (2)(3)(4)(5)(6)(7)(8). The ETC-CRAS mechanism also offers no rationale why the highly mobile/reactive oxygen cannot shunt the deterministic electron-transfers and also does not afford Complex I any independent role.…”

“…Further, presentation of NADH/O2 to mitochondria enhances DROS production, which is also positively correlated with trans-membrane potential (TMP) (3)(4)(5)(6)(7)(8). The Complex I mediated DR(O)S-assisted multi-route coupling scheme for mitochondria is an open-pot reaction (with the incoming proton underlined), as exemplified by: Redox:…”

The abundance of lysine-arginine residues in loops and channel of UCP1 supports the oxygen-centric murburn model for thermogenesis, anion-transport and uncoupling

“…Such conceptualizations necessitate a deterministic orchestration of compartmentalized proteins. The currently known structure/distribution of respiratory/uncoupling proteins, diverse mitochondrial architectures, and the non-fluctuating steady-state trans-membrane potential (TMP, ~ -200 mV) do not support the requisites of the proton-centric perception (3)(4)(5)(6)(7)(8)(9)(10). The UCP1 protein lacks any electro-magnetically active cofactor that could potentially affect/harness the TMP to generate heat.…”

“…As per the murburn model for OxPhos (4), oxygen is involved with Complexes I-IV to serve effective charge separation (ECS) and generate diffusible reactive oxygen species (DROS, like *O2 -). DROS, hitherto considered as toxic wasteful products, are in fact the essential coupling/phosphorylating agents in the OxPhos routine at the mitochondrial membrane (3,(5)(6)(7)(8)(9)(10). In this regard, the most remarkable information that Jones et al's work reveals is the precise location of 13 (K56, K67, K73, K151, K175, K249, K257, K269, and R54, R71, R140, R153, R162) and 7 (R294, K106, K107, K116, K199, K204, K293, and K298) positively charged Lys-Arg residues at the matrix and inter-membrane space (IMS) sides, respectively.…”