Gnaiger 2023 MitoFit CII

Gnaiger E (2023) Complex II ambiguities ― FADH2 in the electron transfer system. MitoFit Preprints 2023.3.v5. https://doi.org/10.26124/mitofit:2023-0003.v5

» MitoFit Preprints 2023.3.v5.

Complex II ambiguities ― FADH₂ in the electron transfer system

Gnaiger Erich (2023) MitoFit Prep

Abstract:

Version 5 (v5) 2023-05-31 10.26124/mitofit:2023-0003.v5

Version 4 (v4) 2023-05-12

Version 3 (v3) 2023-05-04

Version 2 (v2) 2023-04-04

Version 1 (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 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 Q junction, Q-junction; Complex II, CII; electron transfer system, ETS; fatty acid oxidation, FAO; flavin adenine dinucleotide, FAD/FADH₂; nicotinamide adenine dinucleotide, NAD⁺/NADH; succinate dehydrogenase, SDH; tricarboxylic acid cycle, TCA

• O2k-Network Lab: AT Innsbruck Oroboros

ORCID: Gnaiger Erich, Oroboros Instruments, Innsbruck, Austria

Figure 1. Complex II (SDH) bridges H+-linked electron transfer from the TCA cycle (matrix-ETS) to the electron transfer system (membrane-ETS) of the mt-inner membrane (mtIM). (a) NADH+H⁺ and (b) succinate are substrates of 2{H⁺+e^-} transfer to CI and CII, respectively, with prosthetic groups FMN and FAD as the corresponding electron acceptors. (c) Symbolic representation of ETS pathway architecture. Electron flow converges at the N-junction (NAD⁺ → NADH+H⁺). Electron flow from NADH and succinate S converges through CI and CII at the Q-junction. CIII passes electrons to cytochrome c and in CIV to molecular O₂, 2{H⁺+e^-}+0.5 O₂ ⇢ H₂O. (d) NADH+H⁺ and NAD⁺ cycle between matrix-dehydrogenases and CI, whereas FAD and FADH₂ cycle permanently bound within the same enzyme CII. Succinate and fumarate indicate the chemical entities irrespective of ionization, but charges are shown in NADH, NAD⁺, and H⁺. Joint pairs of half-circular arrows distinguish electron transfer 2{H⁺+e­^-} to CI and CII from vectorial H⁺ translocation across the mtIM (H⁺_neg → H⁺_pos). CI and CIII pump hydrogen ions from the negatively (neg) to the positively charged compartment (pos). (e) Iconic representation of SDH subunits. SDHA catalyzes the oxidation succinate → fumarate + 2{H⁺+e^-} and reduction FAD + 2{H⁺+e^-} → FADH₂ in the soluble domain of CII. The iron–sulfur protein SDHB transfers electrons through Fe-S clusters to the mtIM domain where ubiquinone UQ is reduced to ubiquinol UQH₂ in SDHC and SDHD.

Figure 4. Fatty acid oxidation through the β-oxidation cycle (β-ox), the multi-enzyme electron transferring flavoprotein Complex (CETF, ETF:ETFDH; see text), and Complex I (CI) with convergent electron transfer into the Q-junction.

Acknowledgements: I thank Luiza H. Cardoso and Sabine Schmitt 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).

Supplement 1. Footnotes on terminology

• Coenzyme:

A coenzyme or cosubstrate is a cofactor that is attached loosely and transiently to an enzyme (IUPAC definition).

• Cofactor:

A cofactor is 'an organic molecule or ion (usually a metal ion) that is required by an enzyme for its activity. It may be attached either loosely (coenzyme) or tightly (prosthetic group)' (IUPAC definition).

• Electron transfer system ETS:

The convergent architecture of the electron transfer system is emphasized in contrast to linear electron transfer chains ETCs within segments of the ETS.

• Electron transfer:

A distinction is necessary between electron transfer in redox reactions and electron transport (translocation) in the diffusion of charged ionic species within or between cellular compartments. The symbol 2{H⁺+e⁻} is introduced to indicate H⁺-linked electron transfer of two hydrogen ions and two electrons in a redox reaction.

• H⁺-linked electron transfer:

The term H⁺-coupled electron transfer (Hsu et al 2022) is replaced by H⁺-linked electron transfer, to avoid confusion with coupled H⁺ translocation.

• Matrix-ETS:

Electron transfer and corresponding OXPHOS capacities are classically studied in mitochondrial preparations as oxygen consumption supported by various fuel substrates undergoing partial oxidation in the mt-matrix, such as pyruvate, malate, succinate, and others. Therefore, the matrix component of ETS (matrix-ETS) is distinguished from the ETS bound to the mt-inner membrane (membrane-ETS; Gnaiger et al 2020).

• Membrane-ETS:

Electron transfer is frequently considered as the segment of redox reactions linked to the mtIM. However, the membrane-ETS is only part of the total ETS, which includes the upstream matrix-ETS.

• Misinformation:

Misinformation is the mistaken sharing of the same content (Wardle 2023).

• Prosthetic group:

A prosthetic group is cofactor that is attached permanently and tightly or even covalently to an enzyme and that is regenerated in each enzymatic turnover.

• Substrate:

A substrate in a chemical reaction has a negative stoichiometric number since it is consumed, whereas a product has a positive stoichiometric number since it is produced. The general definition of a substrate in an enzyme-catalized reaction relies on the definition of the chemical reaction, without restriction to the nature of the substrate, i.e. independent of the substrate being a chemical entity in solution or a loosely bound cosubstrate (coenzyme) or even a tightly bound prosthetic group. The latter may be explicitly distinguished as a bound (internal) substrate from a free (external) substrate. Even different substrate pools may coexist (CoQ).

• 2{H⁺+e^-}

The symbol [2 H] is frequently used to indicate redox equivalents in the transfer from hydrogen donors to hydrogen acceptors. However, 2[H] does not explicitly express that it applies to both electron and hydrogen ion transfer. Brackets are avoided to exclude the confusion with their frequent application to indicate amount-of-substance concentrations. Two-electron transfer 2{H⁺+e^-} is distinguished from single-electron transfer {H⁺}+{e^-}.

Supplement 2. FAD a substrate of SDH and FADH₂ a substrate of CII

Figure S2. Complex II ambiguities in graphical representations on FADH₂ as a substrate of Complex II in the canonical forward electron transfer. The TCA cycle reduces FAD to FADH₂ - in several cases shown to be catalyzed by SDH. Then FADH₂ is erroneously shown to feed electrons into CII. Alphabetical sequence of publications from 2001 to 2023.

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Supplement 3. FADH₂ a substrate of CII

Figure S3. Complex II ambiguities in graphical representations on FADH₂ as a substrate of Complex II in the canonical forward electron transfer. Alphabetical sequence of publications from 2001 to 2023.

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Supplement 4. FADH₂ as substrate of CII and FAD + 2H⁺ as products

Figure S4. Complex II ambiguities: FADH₂ as substrate of CII and FAD + 2H⁺ as products. Alphabetical sequence of publications from 2001 to 2023.

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Supplement 5. FADH₂ as substrate of CII and FAD⁺ as product

Figure S5. Complex II ambiguities: FADH₂ as substrate of CII and FAD+ as products. Alphabetical 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.

g Sullivan LB, Chandel NS (2014) Mitochondrial metabolism in TCA cycle mutant cancer cells. Cell Cycle 13:347-8. - »Bioblast link«

Supplement 6. FADH₂ or FADH as substrate of CII and FADH, FADH⁺, or FAD⁺ as product

Figure S6. Complex II ambiguities: FADH₂ as substrate of CII and FADH or FADH⁺ as product. Sequence of publications from 2001 to 2023 according to (4) to (9).

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b Kezic A, Spasojevic I, Lezaic V, Bajcetic M (2016) Mitochondria-targeted antioxidants: future perspectives in kidney ischemia reperfusion injury. Oxid Med Cell Longev 2016:2950503. - »Bioblast link«

c Li X, Fang P, Mai J, Choi ET, Wang H, Yang XF (2013) Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol 6:19. - »Bioblast link«

d Yang L, Youngblood H, Wu C, Zhang Q (2020) Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation. Transl Neurodegener 9:19. - »Bioblast link«

e Torres MJ, Kew KA, Ryan TE, Pennington ER, Lin CT, Buddo KA, Fix AM, Smith CA, Gilliam LA, Karvinen S, Lowe DA, Spangenburg EE, Zeczycki TN, Shaikh SR, Neufer PD (2018) 17β-estradiol directly lowers mitochondrial membrane microviscosity and improves bioenergetic function in skeletal muscle. Cell Metab 27:167-79. - »Bioblast link«

f Johnson X, Alric J (2013) Central carbon metabolism and electron transport in Chlamydomonas reinhardtii: metabolic constraints for carbon partitioning between oil and starch. Eukaryot Cell 12:776-93. - »Bioblast link«

g Middleton P, Vergis N (2021) Mitochondrial dysfunction and liver disease: role, relevance, and potential for therapeutic modulation. Therap Adv Gastroenterol 14:17562848211031394. - »Bioblast link«

h Puntel RL, Roos DH, Seeger RL, Rocha JB (2013) Mitochondrial electron transfer chain complexes inhibition by different organochalcogens. Toxicol In Vitro 27:59-70. - »Bioblast link«

i Xing Yunxie (2022) Is genome instability a significant cause of aging? A review. Atlantis Press. - »Bioblast link«

Supplement 7. FADH₂ or FADH as substrate of CII in websites

Figure S7. 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).

(a)

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

(a’)

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

(b)

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

Website 11 (b,c,n,w,β): expii - Image source: By CNX OpenStax

(c)

Website 11 (b,c,n,w,β): expii - Image source: By CNX OpenStax

Website 12 (c,t): ThoughtCo - extender01 / iStock / Getty Images Plus

Website 13 (c): wikimedia 30148497 - Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, 2013-06-19

Website 14 (c): biologydictionary.net 2018-08-21

Website 15 (c): Quora

Website 16 (c): TeachMePhysiology - Fig. 1. 2023-03-13

Website 17 (c): toppr

(d)

Website 18 (d): Labxchange - Figure 8.15 credit: modification of work by Klaus Hoffmeier

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Website 19 (e): Jack Westin MCAT Courses

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Website 20 (f): videodelivery

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Website 21 (g): - SparkNotes

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Website 22 (h,t): researchtweet

Website 23 (h): Microbe Notes

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Website 24 (i): FlexBooks - CK-12 Biology for High School- 2.28 Electron Transport, Figure 2

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Website 25 (j): Labster Theory

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Website 26 (k): nau.edu

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Website 27 (l): ScienceFacts

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Website 28 (m): cK-12

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Website 11 (b,c,n,w,β): expii - Image source: By CNX OpenStax

Website 29 (n): Wikimedia

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Website 30 (o): creative-biolabs

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Website 31 (p): dreamstime

Website 32 (p): VectorMine

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Website 33: YouTube Dirty Medicine Biochemistry - Uploaded 2019-07-18

(r)

Website 34 (r): DBriers

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Website 35 (s): SNC1D - BIOLOGY LESSON PLAN BLOG

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Website 12 (c,t): ThoughtCo - extender01 / iStock / Getty Images Plus

Website 22 (h,t): researchtweet

Website 36 (t): dreamstime

(u)

Website 37 (u): hyperphysics

(v)

Website 9 (a’,b,v): Khan Academy

Website 10 (a’,b,v): Saylor Academy

(w)

Website 11 (b,c,n,w,β): expii - Whitney, Rolfes 2002

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Website 38 (x): UrbanPro

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Website 39 (y): Quizlet

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Website 40 (z): unm.edu

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Website 41 (α): YouTube sciencemusicvideos - Uploaded 2014-08-19

(β)

Website 11 (b,c,n,w,β): expii expii - Image source: By Gabi Slizewska

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Website 42 (γ): BiochemDen.com

(δ)

Website 43 (δ): hopes, Huntington’s outreach project for education, at Stanford

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Website 44 (ε): [ https://www.studocu.com/en-gb/document/university-college-london/mammalian-physiology/electron-transport-chain/38063777 studocu, University College London]

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Website 45 (ζ): ScienceDirect

(η)

Website 46 (η): BBC BITESIZE cK-12

(θ)

Website 47 (θ): freepik

(ι)

Website 48 (ι): - LibreTexts Chemistry - The Citric Acid Cycle and Electron Transport – Fig. 12.4.3

Supplement 8. Weblinks on FAO and CII

(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'.

Supplement 9. CII as a proton pump

Figure S9. Complex II as a proton pump

a Cronshaw M, Parker S, Arany P (2019) Feeling the heat: evolutionary and microbial basis for the analgesic mechanisms of photobiomodulation therapy. Photobiomodul Photomed Laser Surg 37:517-26. - »Bioblast link«

b Jian C, Fu J, Cheng X, Shen LJ, Ji YX, Wang X, Pan S, Tian H, Tian S, Liao R, Song K, Wang HP, Zhang X, Wang Y, Huang Z, She ZG, Zhang XJ, Zhu L, Li H (2020) Low-dose sorafenib acts as a mitochondrial uncoupler and ameliorates nonalcoholic steatohepatitis. Cell Metab 31:892-908. - »Bioblast link«

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.

c Shirakawa R, Nakajima T, Yoshimura A, Kawahara Y, Orito C, Yamane M, Handa H, Takada S, Furihata T, Fukushima A, Ishimori N, Nakagawa M, Yokota I, Sabe H, Hashino S, Kinugawa S, Yokota T (2023) Enhanced mitochondrial oxidative metabolism in peripheral blood mononuclear cells is associated with fatty liver in obese young adults. Sci Rep 13:5203. - »Bioblast link«

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.

d: 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).

e,f: BioNinja (retrieved 2023-05-04).

Beyond preprint

Last update: 2023-05-21

1 Grandoch M, Flögel U, Virtue S, Maier JK, Jelenik T, Kohlmorgen C, Feldmann K, Ostendorf Y, Castañeda TR, Zhou Z, Yamaguchi Y, Nascimento EBM, Sunkari VG, Goy C, Kinzig M, Sörgel F, Bollyky PL, Schrauwen P, Al-Hasani H, Roden M, Keipert S, Vidal-Puig A, Jastroch M5, Haendeler J, Fischer JW (2019) 4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue. Nat Metab 1:546-59. - »Bioblast link«

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.

2 Beier UH, Angelin A, Akimova T, Wang L, Liu Y, Xiao H, Koike MA, Hancock SA, Bhatti TR, Han R, Jiao J, Veasey SC, Sims CA, Baur JA, Wallace DC, Hancock WW (2015) Essential role of mitochondrial energy metabolism in Foxp3⁺ T-regulatory cell function and allograft survival. FASEB J 29:2315-26. - »Bioblast link«

3 Lancaster CR (2002) Succinate:quinone oxidoreductases: an overview. Biochim Biophys Acta 1553:1-6. - »Bioblast link«

fumarate + 2H⁺ shown besides NADH + H⁺ is ambiguous.

3 Lancaster CR (2001) Succinate:quinone oxidoreductases--what can we learn from Wolinella succinogenes quinol:fumarate reductase?. FEBS Lett 504:133-41. - »Bioblast link«

Bioblast links: Substrates and cofactors - >>>>>>> - Click on [Expand] or [Collapse] - >>>>>>>

Substrate

» Substrate

» Product

» Substrates as electron donors

» Cellular substrates

» MitoPedia: Substrates and metabolites

» Substrate-uncoupler-inhibitor titration

Cofactor

» Cofactor

» Coenzyme, cosubstrate

» Nicotinamide adenine dinucleotide

» Coenzyme Q2

» Prosthetic group

» Flavin adenine dinucleotide

Referennces

» Gnaiger E (2023) Complex II ambiguities ― FADH2 in the electron transfer system. MitoFit Preprints 2023.3.v6. https://doi.org/10.26124/mitofit:2023-0003.v6

Labels:

Enzyme: Complex II;succinate dehydrogenase 

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