Chen 2022 Am J Physiol Cell Physiol

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Chen CL, Zhang L, Jin Z, Kasumov T, Chen YR (2022) Mitochondrial redox regulation and myocardial ischemia-reperfusion injury. Am J Physiol Cell Physiol 322:C12-23. https://doi.org/10.1152/ajpcell.00131.2021

Β» PMID: 34757853 Open Access

Chen CL, Zhang L, Jin Z, Kasumov T, Chen YR (2022) Am J Physiol Cell Physiol

Abstract: Mitochondrial reactive oxygen species (ROS) have emerged as an important mechanism of disease and redox signaling in the cellular system. Under basal or pathological conditions, electron leakage for ROS production is primarily mediated by complexes I and III of the electron transport chain (ETC) and by the proton motive force (PMF), consisting of a membrane potential (ΔΨ) and a proton gradient (Ξ”pH). Several factors control redox status in mitochondria, including ROS, the PMF, oxidative posttranslational modifications (OPTM) of the ETC subunits, SOD2, and cytochrome c heme lyase (HCCS). In the mitochondrial PMF, increased Ξ”pH-supported backpressure due to diminishing electron transport and chemiosmosis promotes a more reductive mitochondrial physiological setting. OPTM by protein cysteine sulfonation in complex I and complex III has been shown to affect enzymatic catalysis, the proton gradient, redox status, and enzyme-mediated ROS production. Pathological conditions associated with oxidative or nitrosative stress, such as myocardial ischemia and reperfusion (I/R), increase mitochondrial ROS production and redox dysfunction via oxidative injury to complexes I and III, intensely enhancing protein cysteine sulfonation and impairing heme integrity. The physiological conditions of reductive stress induced by gains in SOD2 function normalize I/R-mediated ROS overproduction and redox dysfunction. Further insight into the cellular mechanisms by which HCCS, biogenesis of c-type cytochrome, and OPTM regulate PMF and ROS production in mitochondria will enrich our understanding of redox signal transduction and identify new therapeutic targets for cardiovascular diseases in which oxidative stress perturbs normal redox signaling.

Chen 2022 Am J Physiol Cell Physiol CORRECTION.png

Correction: FADH2 and Complex II

Ambiguity alert.png
FADH2 is shown as the substrate feeding electrons into Complex II (CII). This is wrong and requires correction - for details see Gnaiger (2024).
Gnaiger E (2024) Complex II ambiguities ― FADH2 in the electron transfer system. J Biol Chem 300:105470. https://doi.org/10.1016/j.jbc.2023.105470 - Β»Bioblast linkΒ«

Hydrogen ion ambiguities in the electron transfer system

Communicated by Gnaiger E (2023-10-08) last update 2023-11-10
Electron (e-) transfer linked to hydrogen ion (hydron; H+) transfer is a fundamental concept in the field of bioenergetics, critical for understanding redox-coupled energy transformations.
Ambiguity alert H+.png
However, the current literature contains inconsistencies regarding H+ formation on the negative side of bioenergetic membranes, such as the matrix side of the mitochondrial inner membrane, when NADH is oxidized during oxidative phosphorylation (OXPHOS). Ambiguities arise when examining the oxidation of NADH by respiratory Complex I or succinate by Complex II.
Ambiguity alert e-.png
Oxidation of NADH or succinate involves a two-electron transfer of 2{H++e-} to FMN or FAD, respectively. Figures indicating a single electron e- transferred from NADH or succinate lack accuracy.
Ambiguity alert NAD.png
The oxidized NAD+ is distinguished from NAD indicating nicotinamide adenine dinucleotide independent of oxidation state.
NADH + H+ β†’ NAD+ +2{H++e-} is the oxidation half-reaction in this H+-linked electron transfer represented as 2{H++e-} (Gnaiger 2023). Putative H+ formation shown as NADH β†’ NAD+ + H+ conflicts with chemiosmotic coupling stoichiometries between H+ translocation across the coupling membrane and electron transfer to oxygen. Ensuring clarity in this complex field is imperative to tackle the apparent ambiguity crisis and prevent confusion, particularly in light of the increasing number of interdisciplinary publications on bioenergetics concerning diagnostic and clinical applications of OXPHOS analysis.
Figure legend from Chen CL et al (2022) Am J Physiol Cell Physiol: Schematic picture explaining the mechanism of oxygen free radical(s) generation mediated by electron transport chain, the electrochemical gradient (Ξ”p), or the proton motive force (PMF) in mitochondria. In the presence of ADP, PMF provides the driving force for reentry of H+ to matrix by chemiosmosis, resulting in ATP synthesis. Blue arrows indicate the path of forward electron transport from NADH or FADH2 to O2, and red arrow specifies reverse electron flow from FADH2-linked succinate to complex I. Brown arrows indicate the sites mediating β€’O2βˆ’ generation in mitochondria. As electrons pass through the chain, protons are pumped from the mitochondrial matrix to the intermembrane space (IMS), thereby establishing an electrochemical potential gradient, also called proton motive force, across the inner membrane. The positive and negative charges on the membrane denote the membrane potential (ΔΨ). The proton gradient, denoted by Ξ”pH for the difference of pH across the membrane. Ξ”p- or Ξ”pH-supported backpressure can contribute to β€’O2βˆ’ generation when electron transport is slowed down under the physiological conditions of low ADP or low Po2. The common inhibitors used for studying the ETC components, Ξ”pH, and ΔΨ are indicated in brick red. ETC, mitochondrial electron transport chain.
Chen 2014 Circ Res CORRECTION.png
Comparison with Figure 1 and Figure legend from Chen YR, Zweier (2014) Circ Res: Schematic representation illustrating the mechanism of oxygen free radical(s) generation mediated by electron transport chain, the proton motive force (PMF, Ξ”p), and the aconitase of Krebs cycle in mitochondria. Blue arrows show the path of electron transport from NADH or FADH2 to O2, or reverse electron flow from FADH2-linked succinate to complex I. Brown dashed arrows indicate the sites mediating β€’O2βˆ’ generation in mitochondria. As electrons pass through the chain, protons are pumped from the mitochondrial matrix to the inter-membrane space, thereby establishing an electrochemical potential gradient or called proton motive force (Ξ”p) across the inner membrane. The positive and negative charges on the membrane denote the membrane potential (ΔΨ). A proton gradient is denoted by Ξ”pH for the difference of pH across the membrane. Ξ”p can contribute to β€’O2βˆ’ generation in the respiratory conditions of state 2 and state 4. Black circles show aconitase of the Krebs Cycle that generates NADH and FADH2 as the substrates of the ETC that are the source of hydroxyl radical production induced by β€’O2βˆ’. The common inhibitors used for studying the ETC components, Ξ”pH, and ΔΨ are indicated in brick red italics.


Labels:

Stress:Ischemia-reperfusion, Oxidative stress;RONS 

Tissue;cell: Heart 


Regulation: Redox state 




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