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Gnaiger 2023 MitoFit CII

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Gnaiger E (2023) Complex II ambiguities ― FADH2 in the electron transfer system. MitoFit Preprints 2023.3.v6. - Published 2023-11-22 J Biol Chem (2024)

» MitoFit Preprints 2023.3.v6.

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Complex II ambiguities ― FADH2 in the electron transfer system

Gnaiger Erich (2023) MitoFit Prep


CII-ambiguities Graphical abstract.png
Gnaiger E (2024) Complex II ambiguities ― FADH2 in the electron transfer system. J Biol Chem 300:105470.
Version 6 (v6) 2023-06-21
Version 5 (v5) 2023-05-31, (v4) 2023-05-12, (v3) 2023-05-04, (v2) 2023-04-04, (v1) 2023-03-24 - »Link to all versions«

The prevailing notion that reduced cofactors NADH and FADH2 transfer electrons from the tricarboxylic acid cycle to the mitochondrial electron transfer system creates ambiguities regarding respiratory Complex II (CII). The succinate dehydrogenase subunit SDHA of CII oxidizes succinate and reduces the covalently bound prosthetic group FAD to FADH2 in the canonical forward tricarboxylic acid cycle. However, several graphical representations of the electron transfer system depict FADH2 in the mitochondrial matrix as a substrate to be oxidized by CII. This leads to the false conclusion that FADH2 from the β-oxidation cycle in fatty acid oxidation feeds electrons into CII. In reality, dehydrogenases of fatty acid oxidation channel electrons to the coenzyme Q-junction but not through CII. The ambiguities surrounding Complex II in the literature and educational resources call for quality control, to secure scientific standards in current communications of bioenergetics, and ultimately support adequate clinical applications. This review aims to raise awareness of the inherent ambiguity crisis, complementing efforts to address the well-acknowledged issues of credibility and reproducibility.
Keywords: coenzyme; cofactor; prosthetic group; coenzyme Q junction, Q-junction; Complex II, CII; H+-linked electron transfer; electron transfer system, ETS; matrix-ETS; membrane-ETS; fatty acid oxidation, FAO; flavin adenine dinucleotide, FAD/FADH2; nicotinamide adenine dinucleotide, NAD+/NADH; succinate dehydrogenase, SDH; tricarboxylic acid cycle, TCA; substrate; Gibbs force

O2k-Network Lab: AT Innsbruck Oroboros

» Links: Ambiguity crisis, Complex II ambiguities, Complex I and hydrogen ion ambiguities in the electron transfer system
Acknowledgements: I thank Luiza H.D. Cardoso, Sabine Schmitt, and Chris Donnelly for stimulating discussions, and Paolo Cocco for expert help on the graphical abstract and Figures 1d and e. The constructive comments of an anonymous reviewer (J Biol Chem) are explicitly acknowledged. Contribution to the European Union’s Horizon 2020 research and innovation program Grant 857394 (FAT4BRAIN).

Additions to 312 references on CII-ambiguities after publication of JBC 2024

Last update 2023-12-19
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Supplement: FADH2 or FADH as substrate of CII in websites

Complex II ambiguities in graphical representations on FADH2 as a substrate of Complex II in the canonical forward electron transfer. FADH → FAD+H (g), FADH2 → FAD+2H+ (a’, c, h-n), and FADH2 → FAD (a, b, d-f, o-θ) should be corrected to FADH2 → FAD (Eq. 3b). NADH → NAD+ is frequently written in graphs without showing the H+ on the left side of the arrow, except for (p-r). NADH → NAD++H+ (a-g, m), NADH → NAD++2H+ (h-l), NADH+H+ → NAD++2H+ (j, k), and NADH → NAD (ι) should be corrected to NADH+H+ → NAD+ (Eq. 3a). (Retrieved 2023-03-21 to 2023-05-04).
OpenStax Biology.png
Website 1 (a,b): 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 (a,b): Concepts of Biology - 1st Canadian Edition by Charles Molnar and Jane Gair - Fig. 4.19a
Website 3 (a,b): Pharmaguideline
Website 4 (a,b): Texas Gateway - Figure 7.11
Website 5 (a,b): - CUNY
Website 6 (a,b): lumen Biology for Majors I - Fig. 1
Website 7 (a): LibreTexts Biology Oxidative Phosphorylation - Electron Transport Chain - Figure 7.11.1
Website 8 (a): - Brain Brooder
Khan Academy modified from OpenStax CORRECTION.png
Website 9 (a’,b,v): 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 10 (a’,b,v): Saylor Academy
Expii OpenStax CORRECTION.png
Website 1 (a,b): OpenStax Biology - Fig. 7.12
Website 2 (a,b): Concepts of Biology - 1st Canadian Edition by Charles Molnar and Jane Gair - Fig. 4.19c
Website 3 (a,b): Pharmaguideline
Website 4 (a,b): Texas Gateway - Figure 7.13
Website 5 (a,b): - CUNY
Website 6 (a,b): lumen Biology for Majors I - Fig. 3
Website 9 (a’,b,v): Khan Academy - Image modified from "Oxidative phosphorylation: Figure 3," by Openstax College, Biology (CC BY 3.0)
Website 10 (a’,b,v): Saylor Academy
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Website 38 (x): UrbanPro
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Website 39 (y): Quizlet CORRECTION.png
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Stillway LW CORRECTION.png
xx Stillway L William (2017) CHAPTER 9 Bioenergetics and Oxidative Metabolism. In: Medical Biochemistry

from FAO and CII ambiguitiy to CII as a H+ in websites

xx CHM333 LECTURES 37 & 38: 4/27 – 29/13 SPRING 2013 Professor Christine Hrycyna

(retrieved 2023-03-21 to 2023-05-02)
Website 49: Conduct Science: "In Complex II, the enzyme succinate dehydrogenase in the inner mitochondrial membrane reduce FADH2 to FAD+. Simultaneously, succinate, an intermediate in the Krebs cycle, is oxidized to fumarate." - Comments: FAD does not have a postive charge. FADH2 is the reduced form, it is not reduced. And again: In CII, FAD is reduced to FADH2.
Website 50: The Medical Biochemistry Page: ‘In addition to transferring electrons from the FADH2 generated by SDH, complex II also accepts electrons from the FADH2 generated during fatty acid oxidation via the fatty acyl-CoA dehydrogenases and from mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) of the glycerol phosphate shuttle’ (Figure 8d).
Website 51: CHM333 LECTURES 37 & 38: 4/27 – 29/13 SPRING 2013 Professor Christine Hrycyna: Acyl-CoA dehydrogenase is listed under 'Electron transfer in Complex II'.

Expii-Gabi Slizewska CORRECTION.png
xx: expii expii - Image source: By Gabi Slizewska: ‘FADH2 from glycolysis and Krebs cycle is oxidized to FAD by Complex II. It also releases H+ ions into the intermembrane space and passes off electrons’ (retrieved 2023-05-04).
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xx: BioNinja (retrieved 2023-05-04).


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» Gnaiger E (2023) Complex II ambiguities ― FADH2 in the electron transfer system. MitoFit Preprints 2023.3.v6.

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Enzyme: Complex II;succinate dehydrogenase 

Ambiguity crisis, FAT4BRAIN, Publication:FAT4BRAIN