Aerobic respiration: proof of concept for the oxygen-centric murburn perspective

Manoj, Kelath Murali; Parashar, Abhinav; Jacob, Vivian David; Ramasamy, Surjith

doi:10.1080/07391102.2018.1552896

Cited by 60 publications

(212 citation statements)

References 95 publications

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“…It was recently proposed that DROS are ultimately and obligatorily required as catalytic agents for metabolic activities and electron transfer (not just as molecular messengers); particularly for ATP-synthesis and heat generation in mitochondria. [3][4][5][6][7]13,32,33 Now, the thought lines that the toxicity difference must primarily lie in the reaction/interaction dynamics with DROS makes better rationale, particularly under the light of the structure-function correlations of mitochondrial proteins. For, the mitochondrial respiratory proteins (Complexes I through IV) show ADP binding sites, O 2 accessible redox centers/channels, and the ability to produce DROS.…”

Section: Explaining the Reaction Chemistry At Complex IV And The Effementioning

confidence: 99%

“…For, the mitochondrial respiratory proteins (Complexes I through IV) show ADP binding sites, O 2 accessible redox centers/channels, and the ability to produce DROS. 6 Therefore, the relevant scheme for various protagonists' interaction with Cox is projected in Figure 2. In the physiological schemes (at micromolar levels of cyanide), Cox (or other respiratory proteins) are rather unperturbed in their activity for directly interacting with O 2 /DROS.…”

Section: Explaining the Reaction Chemistry At Complex IV And The Effementioning

confidence: 99%

“…In the new murburn explanation, low levels of CN (radical) can effectively serve as a CATALYTIC INHIBITOR, which does not get consumed. 6 At low levels (≤ 10 -6 M), via fast reactions occurring in the matrix, "cyanide anion-cyanyl radical" equilibrium effectively dissipates the functional DROS. With latency and at higher cyanide levels, clinical cyanosis could result.…”

Section: Explaining the Reaction Chemistry At Complex IV And The Effementioning

confidence: 99%

“…We have also shown that DROS-modulating species can have potentially high impact in heme/flavin-enzyme systems' reaction outcomes and that these effects are mediated via one-electron (radical) chemistry. [3][4][5][6][7]12,13,[19][20][21][31][32][33][34][38][39][40][41] The following experiments are suggested to further ratify the proposals/deductions of the current work on the impact of cyanide on cellular respiration and toxicity.…”

Section: Predictability and Verifiability Of The Hypothesesmentioning

confidence: 99%

“…[1][2] Recently, an oxygen-centric mechanism called murburn (from 'mured burning') concept was proposed to explain the physiology of xenobiotic metabolism and cellular respiration. [3][4][5][6][7] The new proposal states that diffusible reactive oxygen species (DROS) generated at the mitochondrial complexes directly serve as the coupling agents of oxidative phosphorylation. It was proposed that cyanide ion-radical mediated catalysis, and not cyanide binding to heme (as currently held), is the primary rationale for cyanide lethality.…”

Section: Introductionmentioning

confidence: 99%

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Murburn concept explains the acutely lethal effect of cyanide

Manoj¹

2019

Preprint

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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.

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Section: Explaining the Reaction Chemistry At Complex IV And The Effementioning

confidence: 99%

Section: Explaining the Reaction Chemistry At Complex IV And The Effementioning

confidence: 99%

Section: Explaining the Reaction Chemistry At Complex IV And The Effementioning

confidence: 99%

Section: Predictability and Verifiability Of The Hypothesesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Murburn concept explains the acutely lethal effect of cyanide

Manoj¹

2019

Preprint

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Interaction of membrane‐embedded cytochrome b‐complexes with quinols: Classical Q‐cycle and murburn model

Manoj¹,

Gideon²,

Jaeken

2022

Cell Biochemistry & Function

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We recently proposed a diffusible reactive (oxygen) species (DRS/DROS) based function for cytochrome b complexes (CBC) and quinones (Q)/quinols (QH2) in the murburn model of bioenergetics. This proposal is in direct conflict with the classical purview of Q‐cycle. Via extensive analyses of the structure‐function correlations of membrane‐quinones/quinols and proteins, we present qualitative and quantitative arguments to infer that the classical model cannot explain the energetics, kinetics, mechanism and probabilistic considerations. Therefore, it is proposed that Q‐cycle is neither necessary nor feasible at CBCs. In contrast, we substantiate that the murburn model explains: (a) crucial structural data of CBCs, (b) why quinones/quinols are utilized in bioenergetic membranes, (c) how trans‐membrane potential is generated owing to effective charge separation at CBCs, (d) mobility data of O2, DRS, Q/QH2, and (e) utility of other reaction/membrane components. Further, the murburn model also accommodates the absence of quinones in anaerobic Archaea, wherein methanophenazines are prevalent. The work mandates that the textbooks and research agendas are refreshed to reflect the new perception. Significance The current article must be seen as a critical and detailed analysis of the role and working mechanism of quinone (Q) /quinols (QH2) in bioenergetic membranes. In the classical model, QH2 are perceived as highly mobile electron‐transport agents that bind and donate electrons to cytochrome b complexes (CBCs), using sophisticated electronic circuitries, in order to recycle Q and pump protons. The classical perception sees radicals (such as Q*‐, O2*‐, etc., also called diffusible reactive species, DRS) as wasteful or toxic (patho) physiological manifestations. It is highlighted herein that QH2 has low mobility and matrix has little protons to pump. New insights from the structural analyses of diverse CBCs and quinols, in conjunction with murburn reaction thermodynamics suggest that the electrons from substrates/quinols are effectively utilized via DRS. This perception fits into a much broader analysis of 1 and 2 electron transfers in overall redox metabolism, as recently brought out by the murburn model, wherein DRS are considered obligatory ingredients of physiology. Thus, the findings mandate a reorientation in the pertinent research field.

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Why do cells need oxygen? Insights from mitochondrial composition and function

Manoj¹,

Gideon²,

Jaeken

2021

Cell Biology International

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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.

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Aerobic respiration: proof of concept for the oxygen-centric murburn perspective

Cited by 60 publications

References 95 publications

Murburn concept explains the acutely lethal effect of cyanide

Murburn concept explains the acutely lethal effect of cyanide

Interaction of membrane‐embedded cytochrome b‐complexes with quinols: Classical Q‐cycle and murburn model

Why do cells need oxygen? Insights from mitochondrial composition and function

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