Gnaiger 2023 MitoFit CII

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 - Published 2023-11-22 J Biol Chem (2024)

» MitoFit Preprints 2023.3.v6.

Complex II ambiguities ― FADH₂ in the electron transfer system

Gnaiger Erich (2023) MitoFit Prep

Abstract:

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

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

1 Bektas A, Schurman SH, Gonzalez-Freire M, Dunn CA, Singh AK, Macian F, Cuervo AM, Sen R, Ferrucci L (2019) Age-associated changes in human CD4+ T cells point to mitochondrial dysfunction consequent to impaired autophagy. Aging (Albany NY) 11:9234-63. - »Bioblast link«

2 Ben-Shachar D (2009) The interplay between mitochondrial complex I, dopamine and Sp1 in schizophrenia. J Neural Transm (Vienna) 116:1383-96. - »Bioblast link«

3 Bon E, Maksimovich NY, Dremza IK (2022) Alendronate-induced nephropathy. J Clin Case Rep Stud 3. - »Bioblast link«

4 Elsaeed EM, Hamad A, Erfan OS, Elshahat M, Ebrahim F (2021) Role played by hippocampal apoptosis, autophagy and necroptosis in pathogenesis of diabetic cognitive dysfunction: a review of literature. Medicine Updates 6:41-63. - »Bioblast link«

5 Facucho-Oliveira JM, St John JC (2009) The relationship between pluripotency and mitochondrial DNA proliferation during early embryo development and embryonic stem cell differentiation. Stem Cell Rev Rep 5:140-58. - »Bioblast link«

6 Iqbal T, Welsby PJ, Howarth FC, Bidasee K, Adeghate E, Singh J (2014) Effects of diabetes-induced hyperglycemia in the heart: biochemical and structural slterations. In: Turan B, Dhalla N (eds) Diabetic cardiomyopathy. Advances in biochemistry in health and disease 9. Springer, New York. - »Bioblast link«

7 Keogh MJ, Chinnery PF (2015) Mitochondrial DNA mutations in neurodegeneration. Biochim Biophys Acta 1847:1401-11. - »Bioblast link«

8 Kunst C, Schmid S, Michalski M, Tümen D, Buttenschön J, Müller M, Gülow K (2023) The influence of gut microbiota on oxidative stress and the immune system. Biomedicines 11:1388. - »Bioblast link«

9 Lal MA (2018) Respiration. In: Bhatla SC, Lal MA (eds) Plant physiology, development and metabolism. Springer, Singapore:253-314. - »Bioblast link«

10 Lane RH, Tsirka AE, Gruetzmacher EM (2000) Uteroplacental insufficiency alters cerebral mitochondrial gene expression and DNA in fetal and juvenile rats. Pediatr Res 47:792-7. - »Bioblast link«

11 Palma FR, Gantner BN, Sakiyama MJ, Kayzuka C, Shukla S, Lacchini R, Cunniff B, Bonini MG (2023) ROS production by mitochondria: function or dysfunction? Oncogene. - »Bioblast link«

12 Quintard H, Fontaine E, Ichai C (2018) Energy metabolism: from the organ to the cell. In: Ichai, C., Quintard, H., Orban, JC. (eds) Metabolic Disorders and Critically Ill Patients. Springer, Cham. - »Bioblast link«

13 Reiss AB, Ahmed S, Dayaramani C, Glass AD, Gomolin IH, Pinkhasov A, Stecker MM, Wisniewski T, De Leon J (2022) The role of mitochondrial dysfunction in Alzheimer's disease: A potential pathway to treatment. Exp Gerontol 164:111828. - »Bioblast link«

14 Saghiv MS, Sagiv MS (2020) Metabolism. In: Basic Exercise Physiology. Springer, Cham. - »Bioblast link«

15 SiouNing AS, Seong TS, Kondo H, Bhassu S (2023) MicroRNA regulation in infectious diseases and its potential as a biosensor in future aquaculture industry: a review. Molecules 28:4357. - »Bioblast link«

16 St John JC (2012) Transmission, inheritance and replication of mitochondrial DNA in mammals: implications for reproductive processes and infertility. Cell Tissue Res 349:795-808. - »Bioblast link«

17 Su J, Ye D, Gao C, Huang Q, Gui D (2020) Mechanism of progression of diabetic kidney disease mediated by podocyte mitochondrial injury. Mol Biol Rep 47:8023-35. - »Bioblast link«

18 Thorgersen MP, Schut GJ, Poole FL 2nd, Haja DK, Putumbaka S, Mycroft HI, de Vries WJ, Adams MWW (2022) Obligately aerobic human gut microbe expresses an oxygen resistant tungsten-containing oxidoreductase for detoxifying gut aldehydes. Front Microbiol 13:965625. - »Bioblast link«

19 Venkatachalam K (2022) Regulation of aging and longevity by ion channels and transporters. Cells 11:1180. - »Bioblast link«

20 Wall JA, Wei J, Ly M, Belmont P, Martindale JJ, Tran D, Sun J, Chen WJ, Yu W, Oeller P, Briggs S, Gustafsson AB, Sayen MR, Gottlieb RA, Glembotski CC (2006) Alterations in oxidative phosphorylation complex proteins in the hearts of transgenic mice that overexpress the p38 MAP kinase activator, MAP kinase kinase 6. Am J Physiol Heart Circ Physiol 291:H2462-72. - »Bioblast link«

21 Wang T, Zhang M, Jiang Z, Seli E (2017) Mitochondrial dysfunction and ovarian aging. Am J Reprod Immunol 77. - »Bioblast link«

22 Wider JM, Gruley E, Morse PT, Wan J, Lee I, Anzell AR, Fogo GM, Mathieu J, Hish G, O’Neil B, Neumar RW, Przyklenk K, Hüttemann M, Sanderson TH (2023) Modulation of mitochondrial function with near-infrared light reduces brain injury in a translational model of cardiac arrest. Crit Care 27:491. - »Bioblast link«

23 Wu Y, Liu X, Wang Q, Han D, Lin S (2022) Fe3O4-fused magnetic air stone prepared from wasted iron slag enhances denitrification in a biofilm reactor by increasing electron transfer flow. Front Chem 10:948453. - »Bioblast link«

24 Zapico SC, Ubelaker DH (2013) mtDNA mutations and their role in aging, diseases and forensic sciences. Aging Dis 4:364-80. - »Bioblast link«

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).

(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

(e)

Website 19 (e): Jack Westin MCAT Courses

(f)

Website 20 (f): videodelivery

(g)

Website 21 (g): - SparkNotes

(h)

Website 22 (h,t): researchtweet

Website 23 (h): Microbe Notes

(i)

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

(j)

Website 25 (j): Labster Theory

(k)

Website 26 (k): nau.edu

(l)

Website 27 (l): ScienceFacts

(m)

Website 28 (m): cK-12

(n)

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

Website 29 (n): Wikimedia

(o)

Website 30 (o): creative-biolabs

(p)

Website 31 (p): dreamstime

Website 32 (p): VectorMine

(q)

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

(r)

Website 34 (r): DBriers

(s)

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

(t)

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

(x)

Website 38 (x): UrbanPro

(y)

Website 39 (y): Quizlet

(z)

Website 40 (z): unm.edu

(α)

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

(β)

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

(γ)

Website 42 (γ): BiochemDen.com

(δ)

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

(ε)

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

(ζ)

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

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'.

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).

xx: BioNinja (retrieved 2023-05-04).

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: MiParea: Patients, mt-Awareness 

Enzyme: Complex II;succinate dehydrogenase 

Ambiguity crisis, FAT4BRAIN, Publication:FAT4BRAIN