The murburn precepts for aerobic respiration and redox homeostasis

Self Cite

It is unresolved why lactate is transported to the liver for further utilization within the physiological purview of Cori cycle, when muscles have more lactate dehydrogenase (LDH) than liver. We point out that the answer lies in thermodynamics/equilibriums. While the utilization of NADH for the reduction of pyruvate to lactate can be mediated via the classical mechanism, the oxidation of lactate (with/without the uphill reduction of NAD+) necessitates alternative physiological approaches. The latter pathway occurs via interactive equilibriums involving the enzyme, protons and oxygen or diffusible reactive oxygen species (DROS). Since liver has high DROS, the murburn activity at LDH would enable the cellular system to tide over the unfavorable energy barriers of the forward reaction (~476 kJ/mol; earlier miscalculated as ~26 kJ/mole). Further, the new mechanism does not necessitate any “smart decision‐making” or sophisticated control by/of proteins. The DROS‐based murburn theory explains the invariant active‐site structure of LDH isozymes and their multimeric nature. The theoretical insights, in silico evidence and analyses of literature herein also enrich our understanding of the underpinnings of “lactic acidosis” (lowering of physiological pH accompanied by lactate production), Warburg effect (increased lactate production at high pO2 by cancer cells) and approach for cancer therapy.

Section: Discussionmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Approach/methodologymentioning

confidence: 99%

See 1 more Smart Citation

Murburn precepts for lactic‐acidosis, Cori cycle, and Warburg effect: Interactive dynamics of dehydrogenases, protons, and oxygen

Manoj¹,

Nirusimhan²,

Parashar³

et al. 2021

Self Cite

“…Murburn explanation for TMP: Since we have postulated that ionic homeostasis is based in murburn concept, it is natural to theorize that the origin of TMP (whether resting potential RP, graded potential GP, or action potential AP) in cells could be involved with murburn principles, as was the case in mitochondria (Manoj & Bazhin, 2021). We approach the issue of trans-phase potentials in the biological systems from a new perspective and think beyond the merely ionic origin (which we do not deny; and consider as an important contributor to TMP!).…”

Section: Figure 2: the Murburn Perspective Of Ion-differentiation At The Membrane Interface (Murzone) Resultsmentioning

confidence: 99%

The murburn precepts for cellular ionic homeostasis and electrophysiology

Manoj¹,

Bazhin

Tamagawa

2021

Self Cite

Starting from 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 transmembrane 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 + > Mg 2+ > Ca 2+ ) and outside (Na + > K + > Ca 2+ > Mg 2+ ). We explore how TMP could vary for resting/graded/action potentials generation and project a model for impulse conduction in neurons. Outcomes based in murburn bioenergetic equilibriums leading to solubilization of ionpairs, 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.

“…Using this "radical" insight (in conjunction with the data brought out by the pursuits of CMT/AIH schools), explanations that are thermodynamically, kinetically, mechanistically, and probabilistically tangible were provided for several core redox physiologies. Murburn concept connects ATP-dynamics, thermogenesis, homeostasis, and TMP (Manoj & Bazhin, 2021). Furthermore, (1) Murburn concept explains why oxygen is the elixir of life for the vast diversities of organisms.…”

Section: Analyzing the Well-known Explanationsmentioning

confidence: 99%

Critical analysis of explanations for cellular homeostasis and electrophysiology from murburn perspective

Manoj¹,

Tamagawa

2021

Self Cite

Pursuits in modern cellular electrophysiology are fraught with disagreements at a fundamental level. While the membrane theory of homeostasis deems the cell membrane and proteins embedded therein as the chief players, the associationinduction (or sorption/bulk-phase) hypothesis considers the aqueous phase of dissolved proteins (cytoplasm/protoplasm) as the key determinant of cellular composition and ionic fluxes. In the first school of thought, trans-membrane potential (TMP) and selective ion pumps/channels are deemed as key operative principles. In the latter theory, sorption-desorption dynamics and rearrangements of bulk phase determine the outcomes. In both these schools of thought, theorists believe that the macroscopic phase electroneutrality holds, TMP (whether in resting or in activated state) results solely due to ionic concentration differentials across the membrane, and the concerned proteins undergo major conformation changes to affect/effect the noted outcomes. The new entry into the field, murburn concept, builds starting from molecular considerations to macroscopic observations. It moots "effective charge separation" and intricate "molecule-ion-radical" electron transfer equilibriums as a rationale for ionic concentration differentials and TMP variation. After making an unbiased appraisal of the two classical schools of thought, the review makes a point-wise analysis of some hitherto unresolved observations/considerations and suggests the need to rethink the mechanistic perspectives.