Gnaiger 2023 MitoFit CII

Gnaiger E (2023) Complex II ambiguities ― FADH₂ in the electron transfer system. MitoFit Preprints 2023.3.v2. https://doi.org/10.26124/mitofit:2023-0003.v2

» MitoFit Preprints 2023.3.v2.

Complex II ambiguities ― FADH₂ in the electron transfer system

Gnaiger Erich (2023) MitoFit Prep

Abstract:

Version 2 (v2) 2023-04-04 10.26124/mitofit:2023-0003.v2

Version 1 (v1) 2023-03-247 10.26124/mitofit:2023-0003 - »Link to all versions«

The current narrative that the reduced coenzymes NADH and FADH₂ feed electrons from the tricarboxylic acid cycle into the mitochondrial electron transfer system creates ambiguities around respiratory Complex II (CII). The succinate dehydrogenase subunit SDHA of CII oxidizes succinate and reduces covalently bound FAD to FADH₂ in the canonical forward tricarboxylic acid cycle. However, several graphical representations of the membrane-bound electron transfer system (ETS) depict FADH₂ in the mitochondrial matrix to be oxidized by CII. This leads to the false conclusion that FADH₂ feeds electrons into the ETS through CII, including FADH₂ from the tricarboxylic acid cycle, the β-oxidation cycle in fatty acid oxidation, and the glycerophosphate shuttle. In reality, FAD and succinate are the substrates of SDHA at the ETS-entry into CII. The reduced flavin groups FADH₂ and FMNH₂ are products downstream within CII and CI, respectively. Further electron transfer converges at the coenzyme Q-junction. Similarly, electron transferring flavoprotein and mitochondrial glycerophosphate dehydrogenase feed electrons into the Q-junction but not through CII. The ambiguities surrounding Complex II in the literature and educational tools call for quality control, to secure scientific standards in current communications on bioenergetics and ultimately support adequate clinical applications.
• Keywords: coenzyme Q junction; Complex CII; electron transfer system; fatty acid oxidation; flavin adenine dinucleotide;succinate dehydrogenase; tricarboxylic acid cycle

• O2k-Network Lab: AT Innsbruck Oroboros

Labels:

Enzyme: Complex II;succinate dehydrogenase

FAT4BRAIN, Publication:FAT4BRAIN

Figure 1. Complex II bridges electron transfer from the TCA cycle to the mitochondrial inner membrane. Graphical representations of the electron transfer system ETS with successive emphasis on pathway architecture and concomitant loss of detail. CII is integrated in the TCA cycle (matrix-ETS) and the membrane-bound electron transfer system (membrane-ETS in the mt-inner membrane mtIM). Joint half-circular arrows indicate electron transfer 2{H⁺+e^-}, distinguished from hydrogen ion H⁺ transport across the mtIM. (a) In the soluble domain of CII, the flavoprotein SDHA catalyzes the oxidation succinate → fumarate+2{H⁺+e^-} and reduction FAD+2{H⁺+e^-} → FADH₂. The iron–sulfur protein SDHB transfers electrons through Fe-S clusters to the mtIM domain where ubiquinone UQ is reduced with 2{H⁺+e^-} to ubiquinol UQH₂ in SDHC and SDHD. (b) NADH and succinate are substrates of redox reactions in CI and CII, respectively, with FMNH₂ and FADH₂ as the corresponding products. Succinate and fumarate indicate the chemical entities irrespective of ionization, whereas the charges are shown in NADH, NAD⁺, and H⁺. (c) Electron flow catalyzed by dehydrognases localized in the mitochondrial (mt) matrix converges at the N-junction, reducing NAD⁺ to NADH. Electron flow from NADH and succinate S to molecular oxygen, 2{H⁺+e^-}+0.5 O₂ ⇢ H₂O, converges through CI and CII at the Q-junction. CIII passes electrons to cytochrome c and in CIV to O₂.

ORCID: Gnaiger Erich, Oroboros Instruments, Innsbruck, Austria

Acknowledgements: I thank Luiza H. Cardoso and Sabine Schmitt for stimulating discussions, and Paolo Cocco for expert help on the graphical abstract and Figures 1b and c. Contribution to the European Union’s Horizon 2020 research and innovation program Grant 857394 (FAT4BRAIN).

Updates to Supplement Figure S1

Last update 2023-04-15

Figure S1. Complex II ambiguities in graphical representations on FADH₂ as a substrate of Complex II in the canonical forward electron transfer. Chronological sequence of publications from 2001 to 2023.

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While CI functions as a proton pump, CII does not. Depicting CII as a proton pump would be analogous to falsely portraying FADH₂ as the substrate of CII, as if it were a copy of CI, which functions as a proton pump with NADH as its substrate.

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While CI functions as a proton pump, CII does not. Depicting CII as a proton pump would be analogous to falsely portraying FADH₂ as the substrate of CII, as if it were a copy of CI, which functions as a proton pump with NADH as its substrate.

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NADH is shown as the product of the reaction catalyzed by CI in respiration. This error is rare in the literature, but comparable to the error frequenty encountered when FADH₂ is shown as the substrate of CII.

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Supplement Figure S1 (v2)

Figure S1. Complex II ambiguities in graphical representations on FADH₂ as a substrate of Complex II in the canonical forward electron transfer. Chronological sequence of publications from 2001 to 2023.

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Supplement Figure S2 (v2)

Figure S2. Complex II ambiguities in graphical representations on FADH₂ as a substrate of Complex II in the canonical forward electron transfer (retrieved 2023-03-21 to 2023-04-04)

Website 1: OpenStax Biology - Fig. 7.10 Oxidative phosphorylation (CC BY 3.0). - OpenStax Biology got it wrong in figures and text. The error is copied without quality assessment and propagated in several links.

Website 2: Concepts of Biology - 1st Canadian Edition by Charles Molnar and Jane Gair - Fig. 4.19a

Website 3: LibreTexts Biology Oxidative Phosphorylation - Electron Transport Chain - Figure 7.11.1

Website 4: lumen Biology for Majors I - Fig. 1

Website 5: Pharmaguideline

Website 37: Texas Gateway - Figure 7.11

Website 38: Concepts of Biology - Charles Molnar and Jane Gair. 4.3 Citric Acid Cycle and Oxidative Phosphorylation. Concepts of Biology - 1st Canadian Edition, BCcampus

Website 39: -CUNY

Website 40: - Brain Brooder

Website 6: Khan Academy - Image modified from "Oxidative phosphorylation: Figure 1", by OpenStax College, Biology (CC BY 3.0). Figure and text underscore the FADH₂-error: "FADH₂ .. feeds them (electrons) into the transport chain through complex II."

Website 7: Saylor Academy