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

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 2023-04-10

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)

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