Murburn concept explains the acutely lethal effect of cyanide

Abstract

Cyanide (CN) toxicity is traditionally understood to result from its binding of hemeFe centers, thereby disrupting mitochondrial cytochrome oxidase function and oxygen utilization by other globin proteins. Recently, a diffusible reactive oxygen species (DROS) mediated reaction mechanism called murburn concept was proposed to explain mitochondrial ATP-synthesis and heat generation. Per this purview, it was theorized that CN ion-radical equilibrium dissipates the catalytically vital DROS into futile cycles, producing water. In the current study, a comparative quantitative assessment of the above two explanations is made for: (i) lethal dosage or concentrations of CN, (ii) thermodynamics and kinetics of the binding/reaction, and (iii) correlation of CN with the binding data and reaction chemistry of H2S/CO. The quantitative findings suggest that the hemeFe binding-based toxicity explanation is untenable. CN also inhibited the experimental in vitro DROS-mediated coupling of inorganic phosphate with ADP. Further, pH-dependent inhibition profiles of heme enzyme catalyzed oxidation of a phenolic (wherein an -OH group reacts with DROS to form water, quite akin to the murburn model of ATP synthesis) indicated that- (i) multiple competitive reactions in milieu controlled outcomes and (ii) low concentrations of CN cannot disrupt activity via a coordination (binding) of cyanide at the distal hemeFe. Therefore, the μM-level IC50 and the acutely lethal effect of CN on cellular respiration could be explained by the deleterious interaction of CN ion-radical equilibrium with DROS in matrix, disrupting mitochondrial ATP synthesis. This work supports the murburn explanation for cellular respiration.

Murburn precepts for aerobic respiration and homeostasis

“…Also, our arguments (24)(25)(26)(27)(28)(29)(30)(31) against the extant paradigm of mOxPhos are corroborated by other researchers' reports demonstrating the 'dispensability' of Complex V in both prokaryotic E. coli (35) and eukaryotic Plasmodium (36) o aq f ' G ∆ systems. Disregarding such arguments and developments (24)(25)(26)(27)(28)(29)(30)(31)(32)37), the CRAS model continues to be advocated for mitochondrial physiology (10)(11)(12)(13)(14)37). Some peers vocally expressed concerns on how the murburn scheme could be 'selective', with catalytic role for diffusible radicals.…”

“…The murburn explanation invokes a ubiquitous "molecule-unbound ion-radical" interactive scheme (32) and proposes that the catalytic role of diffusible reactive (oxygen) species [DRS/DROS/ROS, hitherto deemed wasteful/toxic agents] are harnessed in some metabolic electron/moiety transfers. The murburn model of mOxPhos is strongly supported by the fact that DROS enables ATP synthesis both in vitro (27,29) and in situ [within mitochondria (33) and chloroplasts (34)]. Also, our arguments (24)(25)(26)(27)(28)(29)(30)(31) against the extant paradigm of mOxPhos are corroborated by other researchers' reports demonstrating the 'dispensability' of Complex V in both prokaryotic E. coli (35) and eukaryotic Plasmodium (36) o aq f ' G ∆ systems.…”

“…The murburn model of mOxPhos is strongly supported by the fact that DROS enables ATP synthesis both in vitro (27,29) and in situ [within mitochondria (33) and chloroplasts (34)]. Also, our arguments (24)(25)(26)(27)(28)(29)(30)(31) against the extant paradigm of mOxPhos are corroborated by other researchers' reports demonstrating the 'dispensability' of Complex V in both prokaryotic E. coli (35) and eukaryotic Plasmodium (36) o aq f ' G ∆ systems. Disregarding such arguments and developments (24)(25)(26)(27)(28)(29)(30)(31)(32)37), the CRAS model continues to be advocated for mitochondrial physiology (10)(11)(12)(13)(14)37).…”

“…Based on the founding ideas above, the extant perception is anagrammed RCPE or CRAS (chemiosmotic rotary ATP synthesis) model. In 2017, updated data on mitochondrial architecture / protein complexes' structures (7-10) were assessed in the light of insights gained from our research on simpler heme-flavin enzyme systems (15)(16)(17)(18)(19)(20)(21)(22)(23), enabling us to challenge the CRAS paradigm of mOxPhos and propose a novel explanatory model (24)(25)(26)(27)(28)(29)(30)(31) based in murburn concept. The murburn explanation invokes a ubiquitous "molecule-unbound ion-radical" interactive scheme (32) and proposes that the catalytic role of diffusible reactive (oxygen) species [DRS/DROS/ROS, hitherto deemed wasteful/toxic agents] are harnessed in some metabolic electron/moiety transfers.…”

A review on effect of air pollutants on fetal development and pregnancy outcomes

“…Exposure to the small environmental concentration of CO may form carboxyhemoglobin and compromises cellular oxygen availability and subsequent lethality. CO poisoning has been reported to develop long-term neurological effects as CO perturb the mitochondrial cytochrome-c-oxidase or Complex IV by binding to prosthetic group heme a3, resulting in shut down of oxidative phosphorylation, similarly to cyanide and nitric oxide and causing abnormal ATP synthesis rate and cell signaling [45][46][47][48][49][50].…”