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

» MitoFit Preprints 2023.3.v6.

Complex II ambiguities ― FADH₂ in the electron transfer system

Gnaiger Erich (2023) MitoFit Prep

Abstract:

Version 6 (v6) 2023-06-21 10.26124/mitofit:2023-0003.v6

Version 5 (v5) 2023-05-31

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 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 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

» Links: Ambiguity crisis, Complex II ambiguities, Complex I and hydrogen ion ambiguities in the electron transfer system

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.

Acknowledgements: I thank Luiza H.D. Cardoso, Sabine Schmitt, and Donnelly Chris 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:

‘The dissociable, low-relative-molecular-mass active group of an enzyme which transfers chemical groups, hydrogen, or electrons. A coenzyme binds with its associated protein (apoenzyme) to form the active enzyme (holoenzyme) (Burtis, Geary 1994). ‘A low-molecular-weight, non-protein organic compound participating in enzymatic reactions as dissociable acceptor or donor of chemical groups or electrons’ - https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:23354 (CHEBI:23354, retrieved 2023-06-21). A coenzyme or cosubstrate is a cofactor that is attached loosely and transiently to an enzyme. NADH is listed as a coenzyme, which should be regarded as a substrate of pyridine-linked dehydrogenases (Lehninger 1975).

• 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)' - https://www.ebi.ac.uk/chebi/searchId.do?chebiId=23357 (CHEBI:23357, retrieved 2023-06-21).

• 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.

• Gibbs force:

In contrast to the extensive quantity Gibbs energy [J], Gibbs force [J·mol^-1] is an intensive quantity expressed as the partial derivative of Gibbs energy [J] per advancement of a reaction [mol] (Gnaiger 1993; 2020).

• 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 a cofactor that is ‘a tightly bound, specific nonpolypeptide unit in a protein determining and involved in its biological activity’ - https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:26348 (CHEBI:26348, retrieved 2023-06-21). A prosthetic group is attached permanently and tightly or even covalently to an enzyme and that is regenerated in each enzymatic turnover. FAD is the prosthetic group of flavin-linked dehydrogenases, covalently bound to CII.

• 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^-}

In H⁺-linked two-electron transfer, 2H⁺ + 2e^-, ‘the terms reducing equivalents or electron equivalents are used to refer to electrons and/or hydrogen atoms participating in oxidoreductions’ (Lehninger 1975). The symbol 2[H] is frequently used to distinguish reducing equivalents in the transfer from hydrogen donors to hydrogen acceptors from aqueous H⁺. Acid-base reactions obtain equilibrium fast without catalyst, whereas the slow oxidation-reduction reactions require an enzyme to proceed. 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 amount-of-substance concentrations frequently indicated by brackets. H⁺-linked two-electron transfer 2{H⁺+e^-} is distinguished from single-electron transfer {H⁺}+{e^-}.

Beyond version 6

Last update: 2023-11-20

SDH: FAD ⟶ FADH₂; CII: FADH₂ ⟶ FAD

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FADH₂ ⟶ FAD

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FADH₂ ⟶

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FADH₂ ⟶ FAD + H⁺

4a.1 Cowan K, Anichtchik O, Luo S (2019) Mitochondrial integrity in neurodegeneration. CNS Neurosci Ther 25:825-36. - »Bioblast link«

FADH₂ ⟶ FAD + 2H⁺

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4b.15 Hidalgo-Gutiérrez A, González-García P, Díaz-Casado ME, Barriocanal-Casado E, López-Herrador S, Quinzii CM, López LC (2021) Metabolic targets of coenzyme Q10 in mitochondria. Antioxidants (Basel) 10:520. - »Bioblast link«

4b.16 Ignatieva E, Smolina N, Kostareva A, Dmitrieva R (2021) Skeletal muscle mitochondria dysfunction in genetic neuromuscular disorders with cardiac phenotype. Int J Mol Sci 22:7349. - »Bioblast link«

4b.17 Joshi A, Ito T, Picard D, Neckers L (2022) The mitochondrial HSP90 paralog TRAP1: structural dynamics, interactome, role in metabolic regulation, and inhibitors. Biomolecules 12:880. - »Bioblast link«

4b.18 Kalainayakan SP, FitzGerald KE, Konduri PC, Vidal C, Zhang L (2018) Essential roles of mitochondrial and heme function in lung cancer bioenergetics and tumorigenesis. Cell Biosci 8:56. - »Bioblast link«

4b.19 Koene S, Willems PH, Roestenberg P, Koopman WJ, Smeitink JA (2011) Mouse models for nuclear DNA-encoded mitochondrial complex I deficiency. J Inherit Metab Dis 34:293-307. - »Bioblast link«

4b.20 Lee WE, Genetzakis E, Figtree GA (2023) Novel strategies in the early detection and treatment of endothelial cell-specific mitochondrial dysfunction in coronary artery disease. Antioxidants (Basel) 12:1359. - »Bioblast link«

4b.21 Lu F (2023) Hypothetical hydrogenase activity of human mitochondrial Complex I and its role in preventing cancer transformation. Explor Res Hypothesis Med 8:280-5. - »Bioblast link«

4b.22 Manickam DS (2022) Delivery of mitochondria via extracellular vesicles - a new horizon in drug delivery. J Control Release 343:400-7. - »Bioblast link«

4b.23 Martell E, Kuzmychova H, Kaul E, Senthil H, Chowdhury SR, Morrison LC, Fresnoza A, Zagozewski J, Venugopal C, Anderson CM, Singh SK, Banerji V, Werbowetski-Ogilvie TE, Sharif T (2023) Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma. Nat Commun 14:2502. - »Bioblast link«

4b.24 Mejia-Vergara AJ, Seleme N, Sadun AA, Karanjia R (2020) Pathophysiology of conversion to symptomatic leber hereditary optic neuropathy and therapeutic implications: a review. Curr Neurol Neurosci Rep 20:11. - »Bioblast link«

4b.25 Musicco C, Signorile A, Pesce V, Loguercio Polosa P, Cormio A (2023) Mitochondria deregulations in cancer offer several potential targets of therapeutic interventions. Int J Mol Sci 24:10420. - »Bioblast link«

4b.26 Nguyen TT, Nguyen DK, Ou YY (2021) Addressing data imbalance problems in ligand-binding site prediction using a variational autoencoder and a convolutional neural network. Brief Bioinform 22:bbab277. - »Bioblast link«

4b.27 Payen VL, Zampieri LX, Porporato PE, Sonveaux P (2019) Pro- and antitumor effects of mitochondrial reactive oxygen species. Cancer Metastasis Rev 38:189-203. - »Bioblast link«

4b.28 Prasuhn J, Davis RL, Kumar KR (2021) Targeting mitochondrial impairment in Parkinson's disease: challenges and opportunities. Front Cell Dev Biol 8:615461. - »Bioblast link«

4b.29 Sainero-Alcolado L, Liaño-Pons J, Ruiz-Pérez MV, Arsenian-Henriksson M (2022) Targeting mitochondrial metabolism for precision medicine in cancer. Cell Death Differ 29:1304-17. - »Bioblast link«

4b.30 Schniertshauer D, Wespel S, Bergemann J (2023) Natural mitochondria targeting substances and their effect on cellular antioxidant system as a potential benefit in mitochondrial medicine for prevention and remediation of mitochondrial dysfunctions. Curr Issues Mol Biol 45:3911-32. - »Bioblast link«

4b.31 Shields HJ, Traa A, Van Raamsdonk JM (2021) Beneficial and detrimental effects of reactive oxygen species on lifespan: a comprehensive review of comparative and experimental studies. Front Cell Dev Biol 9:628157. - »Bioblast link«

4b.32 Solhaug A, Gjessing M, Sandvik M, Eriksen GS (2023) The gill epithelial cell lines RTgill-W1, from Rainbow trout and ASG-10, from Atlantic salmon, exert different toxicity profiles towards rotenone. Cytotechnology 75:63-75. - »Bioblast link«

4b.33 Tseng W-W, Wei A-C (2022) Kinetic mathematical modeling of oxidative phosphorylation in cardiomyocyte mitochondria. Cells 11:4020. - »Bioblast link«

4b.34 Turton N, Bowers N, Khajeh S, Hargreaves IP, Heaton RA (2021) Coenzyme Q10 and the exclusive club of diseases that show a limited response to treatment. Expert Opinion Orphan Drugs 9:151-60. - »Bioblast link«

4b.35 Vargas-Mendoza N, Angeles-Valencia M, Morales-González Á, Madrigal-Santillán EO, Morales-Martínez M, Madrigal-Bujaidar E, Álvarez-González I, Gutiérrez-Salinas J, Esquivel-Chirino C, Chamorro-Cevallos G, Cristóbal-Luna JM, Morales-González JA (2021) Oxidative stress, mitochondrial function and adaptation to exercise: new perspectives in nutrition. Life (Basel) 11:1269. - »Bioblast link«

4b.36 Vesga LC, Silva AMP, Bernal CC, Mendez-Sánchez SC, Bohórquez ARR (2021) Tetrahydroquinoline/4,5-dihydroisoxazole hybrids with a remarkable effect over mitochondrial bioenergetic metabolism on melanoma cell line B16F10. Med Chem Res 30:2127–43. - »Bioblast link«

4b.37 Wu Z, Ho WS, Lu R (2022) Targeting mitochondrial oxidative phosphorylation in glioblastoma therapy. Neuromolecular Med 24:18-22. - »Bioblast link«

4b.38 Yang Y, Zhang X, Hu X, Zhao J, Chen X, Wei X, Yu X (2022) Analysis of the differential metabolic pathway of cultured Chlorococcum humicola with hydroquinone toxic sludge extract. J Cleaner Production 370:133486. - »Bioblast link«

4b.39 Yin M, O'Neill LAJ (2021) The role of the electron transport chain in immunity. FASEB J 35:e21974. - »Bioblast link«

FADH₂ ⟶ FAD⁺ (+H⁺ or +2H⁺)

FADH₂ ⟶ FAD⁺

5a.1 Area-Gomez E, Guardia-Laguarta C, Schon EA, Przedborski S (2019) Mitochondria, OxPhos, and neurodegeneration: cells are not just running out of gas. J Clin Invest 129:34-45. - »Bioblast link«

5a.2 Bennett CF, Latorre-Muro P, Puigserver P (2022) Mechanisms of mitochondrial respiratory adaptation. Nat Rev Mol Cell Biol 23:817-35. - »Bioblast link«

5a.3 Bennett MJ, Sheng F, Saada A (2020) Biochemical assays of TCA cycle and β-oxidation metabolites. Methods Cell Biol 155:83-120. - »Bioblast link«

5a.4 Carriere A, Casteilla L (2019) Role of mitochondria in adipose tissues metabolism and plasticity. Academic Press In: Mitochondria in obesity and type 2 diabetes. Morio B, Pénicaud L, Rigoulet M (eds) Academic Press. - »Bioblast link«

5a.5 Che X, Zhang T, Li H, Li Y, Zhang L, Liu J (2023) Nighttime hypoxia effects on ATP availability for photosynthesis in seagrass. Plant Cell Environ 46:2841-50. - »Bioblast link«

5a.6 Chi SC, Cheng HC, Wang AG (2022) Leber hereditary optic neuropathy: molecular pathophysiology and updates on gene therapy. Biomedicines 10:1930. - »Bioblast link«

5a.7 Duan J, Chen Z, Wu Y, Zhu B, Yang L, Yang C (2019) Metabolic remodeling induced by mitokines in heart failure. Aging (Albany NY) 11:7307-27. - »Bioblast link«

5a.8, 51.9 Fisher-Wellman KH, Neufer PD (2012) Linking mitochondrial bioenergetics to insulin resistance via redox biology. Trends Endocrinol Metab 23:142-53. - »Bioblast link«

5a.10 Flønes IH, Tzoulis C (2022) Mitochondrial respiratory chain dysfunction-a hallmark pathology of idiopathic Parkinson's disease? Front Cell Dev Biol 10:874596. - »Bioblast link«

5a.11 Gero D (2023) Hyperglycemia-induced endothelial dysfunction. IntechOpen Chapter 8. - »Bioblast link«

5a.12 Kikusato M, Furukawa K, Kamizono, Hakamata Y, Toyomizu M (2016) Roles of mitochondrial oxidative phosphorylation and reactive oxygen species generation in the metabolic modification of avian skeletal muscle. Proc Jpn Soc Anim Nutr Metab 60:57-68. - »Bioblast link«

5a.13 Knott AB, Bossy-Wetzel E (2009) Nitric oxide in health and disease of the nervous system. Antioxid Redox Signal 11:541-54. - »Bioblast link«

5a.14 Kraegen EW, Cooney GJ, Turner N (2008) Muscle insulin resistance: a case of fat overconsumption, not mitochondrial dysfunction. Proc Natl Acad Sci U S A 105:7627-8. - »Bioblast link«

5a.15 Lettieri-Barbato D (2019) Redox control of non-shivering thermogenesis. Mol Metab 25:11-9. - »Bioblast link«

5a.16 Loussouarn C, Pers YM, Bony C, Jorgensen C, Noël D (2021) Mesenchymal stromal cell-derived extracellular vesicles regulate the mitochondrial metabolism via transfer of miRNAs. Front Immunol 12:623973. - »Bioblast link«

5a.17 Mracek T, Drahota Z, Houstek J (2013) The function and the role of the mitochondrial glycerol-3-phosphate dehydrogenase in mammalian tissues. Biochim Biophys Acta 1827:401-10. - »Bioblast link«

5a.18 Onukwufor JO, Dirksen RT, Wojtovich AP (2022) Iron dysregulation in mitochondrial dysfunction and Alzheimer's disease. Antioxidants (Basel) 11:692. - »Bioblast link«

5a.19 Perouansky M, Johnson-Schlitz D, Sedensky MM, Morgan PG (2023) A primordial target: Mitochondria mediate both primary and collateral anesthetic effects of volatile anesthetics. Exp Biol Med (Maywood) 248:545-52. - »Bioblast link«

5a.20 Rinaldo P, Matern D, Bennett MJ (2002) Fatty acid oxidation disorders. Annu Rev Physiol 64:477-502. - »Bioblast link«

Copied: Bennett MJ, Sheng F, Saada A (2020) Biochemical assays of TCA cycle and β-oxidation metabolites. Methods Cell Biol 155:83-120. - »Bioblast link«

5a.21 Sacchetto C, Sequeira V, Bertero E, Dudek J, Maack C, Calore M (2019) Metabolic alterations in inherited cardiomyopathies. J Clin Med 8:2195. - »Bioblast link«

5a.22 Schinagl CW, Vrabl P, Burgstaller W (2016) Adapting high-resolution respirometry to glucose-limited steady state mycelium of the filamentous fungus Penicillium ochrochloron: method development and standardisation. PLoS One 11:e0146878. - »Bioblast link«

5a.23 Schottlender N, Gottfried I, Ashery U (2021) Hyperbaric oxygen treatment: effects on mitochondrial function and oxidative stress. Biomolecules 11:1827. - »Bioblast link«

5a.24 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.

5a.25 Sullivan LB, Chandel NS (2014) Mitochondrial metabolism in TCA cycle mutant cancer cells. Cell Cycle 13:347-8. - »Bioblast link«

5a.26 Tanaka M, Szabó Á, Spekker E, Polyák H, Tóth F, Vécsei L (2022) Mitochondrial impairment: a common motif in neuropsychiatric presentation? The link to the tryptophan-kynurenine metabolic system. Cells 11:2607. - »Bioblast link«

5a.27 Valle-Mendiola A, Soto-Cruz I (2020) Energy metabolism in cancer: The roles of STAT3 and STAT5 in the regulation of metabolism-related genes. Cancers (Basel) 12:124. - »Bioblast link«

5a.28 Vartak R, Porras CA, Bai Y (2013) Respiratory supercomplexes: structure, function and assembly. Protein Cell 4:582-90. - »Bioblast link«

5a.29 Wang K, Jiang J, Lei Y, Zhou S, Wei Y, Huang C (2019) Targeting metabolic-redox circuits for cancer therapy. Trends Biochem Sci 44:401-14. - »Bioblast link«

5a.30 Wang R, Liang L, Matsumoto M, Iwata K, Umemura A, He F (2023) Reactive oxygen species and NRF2 signaling, friends or foes in cancer? Biomolecules 13:353. - »Bioblast link«

5a.31 Zhao H, Swanson KD, Zheng B (2021) Therapeutic repurposing of biguanides in cancer. Trends Cancer 7:714-30. - »Bioblast link«

FADH₂ ⟶ FAD⁺ + H⁺

5b.1 Lima A, Lubatti G, Burgstaller J, Hu D, Green AP, Di Gregorio A, Zawadzki T, Pernaute B, Mahammadov E, Perez-Montero S, Dore M, Sanchez JM, Bowling S, Sancho M, Kolbe T, Karimi MM, Carling D, Jones N, Srinivas S, Scialdone A, Rodriguez TA (2021) Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development. Nat Metab 3:1091-108. - »Bioblast link«

5b.2 Liu R, Jagannathan R, Sun L, Li F, Yang P, Lee J, Negi V, Perez-Garcia EM, Shiva S, Yechoor VK, Moulik M (2020) Tead1 is essential for mitochondrial function in cardiomyocytes. Am J Physiol Heart Circ Physiol 319:H89-99. - »Bioblast link«

FADH₂ ⟶ FAD⁺ + 2H⁺

5c.1 Bratic A, Larsson NG (2013) The role of mitochondria in aging. J Clin Invest 123:951-7. - »Bioblast link«

5c.2 Brischigliaro M, Zeviani M (2021) Cytochrome c oxidase deficiency. Biochim Biophys Acta Bioenerg 1862:148335. - »Bioblast link«

5c.3 Cerqua C, Buson L, Trevisson E (2021) Mutations in assembly dactors required for the biogenesis of mitochondrial respiratory chain. Springer, Cham In: Navas P, Salviati L (eds) Mitochondrial diseases. - »Bioblast link«

5c.4 DeBalsi KL, Hoff KE, Copeland WC (2017) Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases. Ageing Res Rev 33:89-104. - »Bioblast link«

5c.5 Gallinat A, Vilahur G, Padró T, Badimon L (2022) Network-assisted systems biology analysis of the mitochondrial proteome in a pre-clinical model of ischemia, revascularization and post-conditioning. Int J Mol Sci 23:2087. - »Bioblast link«

5c.6 Głombik K, Detka J, Budziszewska B (2021) Hormonal regulation of oxidative phosphorylation in the brain in health and disease. Cells 10:2937. - »Bioblast link«

5c.7 Keidar N, Peretz NK, Yaniv Y (2023) Ca²⁺ pushes and pulls energetics to maintain ATP balance in atrial cells: computational insights. Front Physiol 14:1231259. - »Bioblast link«

FADH₂ ⟶ FAD²⁺

5d.1 Yan LJ (2014) Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress. J Diabetes Res 2014:137919. - »Bioblast link«

FADH₂ ⟶ FADH or FADH⁺

FADH₂ ⟶ FADH

6a.1 Cadonic C, Sabbir MG, Albensi BC (2016) Mechanisms of mitochondrial dysfunction in Alzheimer's disease. Mol Neurobiol 53:6078-90. - »Bioblast link«

6a.2 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«

6a.3 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«

6a.4 Liskova A, Samec M, Koklesova L, Kudela E, Kubatka P, Golubnitschaja O (2021) Mitochondriopathies as a clue to systemic disorders-analytical tools and mitigating measures in context of predictive, preventive, and personalized (3P) medicine. Int J Mol Sci 22:2007. - »Bioblast link«

6a.5 Sander WJ, Fourie C, Sabiu S, O'Neill FH, Pohl CH, O'Neill HG (2022) Reactive oxygen species as potential antiviral targets. Rev Med Virol 32:e2240. - »Bioblast link«

6a.6 Steiner JL, Lang CH (2017) Etiology of alcoholic cardiomyopathy: Mitochondria, oxidative stress and apoptosis. Int J Biochem Cell Biol 89:125-35. - »Bioblast link«

6a.7 Tabassum N, Kheya IS, Ibn Asaduzzaman SA, Maniha SM, Fayz AH, Zakaria A, Fayz AH, Zakaria A, Noor R (2020) A review on the possible leakage of electrons through the electron transport chain within mitochondria. J Biomed Res Environ Sci 1:105-13. - »Bioblast link«

6a.8 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«

6a.9 Yu T, Wang L, Zhang L, Deuster PA (2023) Mitochondrial fission as a therapeutic target for metabolic diseases: insights into antioxidant strategies. Antioxidants (Basel) 12:1163. - »Bioblast link«

FADH₂ ⟶ FADH +H⁺

6b.1 Burgin HJ, McKenzie M (2020) Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency. FEBS Lett 594:590-610. - »Bioblast link«

FADH₂ ⟶ FADH⁺

6c.1 Achreja A, Yu T, Mittal A, Choppara S, Animasahun O, Nenwani M, Wuchu F, Meurs N, Mohan A, Jeon JH, Sarangi I, Jayaraman A, Owen S, Kulkarni R, Cusato M, Weinberg F, Kweon HK, Subramanian C, Wicha MS, Merajver SD, Nagrath S, Cho KR, DiFeo A, Lu X, Nagrath D (2022) Metabolic collateral lethal target identification reveals MTHFD2 paralogue dependency in ovarian cancer. Nat Metab 4:1119-37. - »Bioblast link«

6c.2 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«

FADH or FADH⁺ ⟶

7a.1 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«

7a.2 Kuznetsov AV, Margreiter R, Ausserlechner MJ, Hagenbuchner J (2022) The complex interplay between mitochondria, ROS and entire cellular metabolism. Antioxidants (Basel) 11:1995. - »Bioblast link«

FADH ⟶ FAD

7b.1 Diaz EC, Adams SH, Weber JL, Cotter M, Børsheim E (2023) Elevated LDL-C, high blood pressure, and low peak V˙O2 associate with platelet mitochondria function in children-The Arkansas Active Kids Study. Front Mol Biosci 10:1136975. - »Bioblast link«

7b.2 Ježek P, Jabůrek M, Holendová B, Engstová H, Dlasková A (2023) Mitochondrial cristae morphology reflecting metabolism, superoxide formation, redox homeostasis, and pathology. Antioxid Redox Signal. https://doi.org/10.1089/ars.2022.0173 - »Bioblast link«

FADH ⟶ FAD⁺

7c.1 Grasso D, Zampieri LX, Capelôa T, Van de Velde JA, Sonveaux P (2020) Mitochondria in cancer. Cell Stress 4:114-46. - »Bioblast link«

7c.2 Middleton P, Vergis N (2021) Mitochondrial dysfunction and liver disease: role, relevance, and potential for therapeutic modulation. Therap Adv Gastroenterol 14:17562848211031394. - »Bioblast link«

7c.3 Moudgil R, Michelakis ED, Archer SL (2005) Hypoxic pulmonary vasoconstriction. J Appl Physiol (1985) 98:390-403. - »Bioblast link«

FADH ⟶ FAD⁺ +H⁺

7d.1 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«

FADH ⟶ FAD +2H⁺

7e.1 Xing Yunxie (2022) Is genome instability a significant cause of aging? A review. Atlantis Press. - »Bioblast link«

FADH⁺ ⟶ FAD

7f.1 Catania A, Iuso A, Bouchereau J, Kremer LS, Paviolo M, Terrile C, Bénit P, Rasmusson AG, Schwarzmayr T, Tiranti V, Rustin P, Rak M, Prokisch H, Schiff M (2019) Arabidopsis thaliana alternative dehydrogenases: a potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls. Orphanet J Rare Dis 14:236. - »Bioblast link«

FAD or FAD⁺ ⟶ or other

FAD ⟶

8a.1 Ahmad G, Almasry M, Dhillon AS, Abuayyash MM, Kothandaraman N, Cakar Z (2017) Overview and sources of reactive oxygen species (ROS) in the reproductive system. In: Agarwal A, et al (eds) Oxidative stress in human reproduction. Springer, Cham. - »Bioblast link«

8a.2 Irazabal MV, Torres VE (2020) Reactive oxygen species and redox signaling in chronic kidney disease. Cells 9:1342. - »Bioblast link«

8a.3 LaMoia TE, Butrico GM, Kalpage HA, Goedeke L, Hubbard BT, Vatner DF, Gaspar RC, Zhang XM, Cline GW, Nakahara K, Woo S, Shimada A, Hüttemann M, Shulman GI (2022) Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis. Proc Natl Acad Sci U S A 119:e2122287119. - »Bioblast link«

FAD⁺ ⟶ FADH₂

8b.1 Chinopoulos C (2013) Which way does the citric acid cycle turn during hypoxia? The critical role of α-ketoglutarate dehydrogenase complex. J Neurosci Res 91:1030-43. - »Bioblast link«

FADH2+ Succinate ⟶ Fumarate +2H+

8c.1 Andrieux P, Chevillard C, Cunha-Neto E, Nunes JPS (2021) Mitochondria as a cellular hub in infection and inflammation. Int J Mol Sci 22:11338. - »Bioblast link«

FADH2 ⟶ CI ⟶ CII

8d.1 Huss JM, Kelly DP (2005) Mitochondrial energy metabolism in heart failure: a question of balance. J Clin Invest 115:547-55. - »Bioblast link«

ETF ⟶ CII

8e.1 Bugarski M, Martins JR, Haenni D, Hall AM (2018) Multiphoton imaging reveals axial differences in metabolic autofluorescence signals along the kidney proximal tubule. Am J Physiol Renal Physiol 315:F1613-25. - »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

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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

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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

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Website 37 (u): hyperphysics

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Website 9 (a’,b,v): Khan Academy

Website 10 (a’,b,v): Saylor Academy

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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

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Website 42 (γ): BiochemDen.com

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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 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

FAO and CII ambiguitiy

1.4 Balasubramaniam S, Yaplito-Lee J (2020) Riboflavin metabolism: role in mitochondrial function. J Transl Genet Genom 4:285-306. - »Bioblast link«

xx Bertero E, Maack C (2018) Metabolic remodelling in heart failure. Nat Rev Cardiol 15:457-70. - »Bioblast link«

xx Bugarski M, Martins JR, Haenni D, Hall AM (2018) Multiphoton imaging reveals axial differences in metabolic autofluorescence signals along the kidney proximal tubule. Am J Physiol Renal Physiol 315:F1613-25. - »Bioblast link«

xx Cortassa S, Aon MA, Sollott SJ (2019) Control and regulation of substrate selection in cytoplasmic and mitochondrial catabolic networks. A systems biology analysis. Front Physiol 10:201. - »Bioblast link«

xx DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348:2656-68. - »Bioblast link«

xx Esparza-Moltó PB, Cuezva JM (2020) Reprogramming oxidative phosphorylation in cancer: a role for RNA-binding proteins. Antioxid Redox Signal 33:927-45. - »Bioblast link«

xx Frangos SM, DesOrmeaux GJ, Holloway GP (2023) Acidosis attenuates CPT-I supported bioenergetics as a potential mechanism limiting lipid oxidation. J Biol Chem 299:105079. - »Bioblast link«

xx Hinder LM, Sas KM, O'Brien PD, Backus C, Kayampilly P, Hayes JM, Lin CM, Zhang H, Shanmugam S, Rumora AE, Abcouwer SF, Brosius FC 3rd, Pennathur S, Feldman EL (2019) Mitochondrial uncoupling has no effect on microvascular complications in type 2 diabetes. Sci Rep 9:881. - »Bioblast link«

xx Huss JM, Kelly DP (2005) Mitochondrial energy metabolism in heart failure: a question of balance. J Clin Invest 115:547-55. - »Bioblast link«

xx Kikusato M, Furukawa K, Kamizono T, Hakamata Y, Toyomizu M (2016) Roles of mitochondrial oxidative phosphorylation and reactive oxygen species generation in the metabolic modification of avian skeletal muscle. Proc Jpn Soc Anim Nutr Metab 60:57-68. - »Bioblast link«

xx Kraegen EW, Cooney GJ, Turner N (2008) Muscle insulin resistance: a case of fat overconsumption, not mitochondrial dysfunction. Proc Natl Acad Sci U S A 105:7627-8. - »Bioblast link«

xx Loussouarn C, Pers YM, Bony C, Jorgensen C, Noël D (2021) Mesenchymal stromal cell-derived extracellular vesicles regulate the mitochondrial metabolism via transfer of miRNAs. Front Immunol 12:623973. - »Bioblast link«

xx Ma Y, Temkin SM, Hawkridge AM, Guo C, Wang W, Wang XY, Fang X (2018) Fatty acid oxidation: an emerging facet of metabolic transformation in cancer. Cancer Lett 435:92-100. - »Bioblast link«

xx Ma Y, Wang W, Devarakonda T, Zhou H, Wang XY, Salloum FN, Spiegel S, Fang X (2020) Functional analysis of molecular and pharmacological modulators of mitochondrial fatty acid oxidation. Sci Rep 10:1450. - »Bioblast link«

xx Massart J, Begriche K, Buron N, Porceddu M, Borgne-Sanchez A, Fromenty B (2013) Drug-induced inhibition of mitochondrial fatty acid oxidation and steatosis. Curr Pathobiol Rep 1:147–57. - »Bioblast link«

xx Merritt JL 2nd, MacLeod E, Jurecka A, Hainline B (2020) Clinical manifestations and management of fatty acid oxidation disorders. Rev Endocr Metab Disord 21:479-93. - »Bioblast link«

xx Murray AJ (2009) Metabolic adaptation of skeletal muscle to high altitude hypoxia: how new technologies could resolve the controversies. Genome Med 1:117. - »Bioblast link«

xx Picard M, Jung B, Liang F, Azuelos I, Hussain S, Goldberg P, Godin R, Danialou G, Chaturvedi R, Rygiel K, Matecki S, Jaber S, Des Rosiers C, Karpati G, Ferri L, Burelle Y, Turnbull DM, Taivassalo T, Petrof BJ (2012) Mitochondrial dysfunction and lipid accumulation in the human diaphragm during mechanical ventilation. Am J Respir Crit Care Med 186:1140-9. - »Bioblast link«

xx Picard M, McEwen BS (2018) Psychological stress and mitochondria: a systematic review. Psychosom Med 80:141-53. - »Bioblast link«

xx Copied by: Picard M, Prather AA, Puterman E, Cuillerier A, Coccia M, Aschbacher K, Burelle Y, Epel ES (2018) A mitochondrial health index sensitive to mood and caregiving stress. Biol Psychiatry 84:9-17. - »Bioblast link«

xx Copied by: Karan KR, Trumpff C, McGill MA, Thomas JE, Sturm G, Lauriola V, Sloan RP, Rohleder N, Kaufman BA, Marsland AL, Picard M (2020) Mitochondrial respiratory capacity modulates LPS-induced inflammatory signatures in human blood. Brain Behav Immun Health 5:100080. - »Bioblast link«

xx Copied by: Bindra S, McGill MA, Triplett MK, Tyagi A, Thaker PH, Dahmoush L, Goodheart MJ, Ogden RT, Owusu-Ansah E, R Karan K, Cole S, Sood AK, Lutgendorf SK, Picard M (2021) Mitochondria in epithelial ovarian carcinoma exhibit abnormal phenotypes and blunted associations with biobehavioral factors. Sci Rep 11:11595. - »Bioblast link«

xx Copied by: Rausser S, Trumpff C, McGill MA, Junker A, Wang W, Ho SH, Mitchell A, Karan KR, Monk C, Segerstrom SC, Reed RG, Picard M (2021) Mitochondrial phenotypes in purified human immune cell subtypes and cell mixtures. Elife 10:e70899. - »Bioblast link«

xx Prasun P (2020) Role of mitochondria in pathogenesis of type 2 diabetes mellitus. J Diabetes Metab Disord 19:2017-22. - »Bioblast link«

xx Rinaldo P, Matern D, Bennett MJ (2002) Fatty acid oxidation disorders. Annu Rev Physiol 64:477-502. - »Bioblast link«

xx Bennett MJ, Sheng F, Saada A (2020) Biochemical assays of TCA cycle and β-oxidation metabolites. Methods Cell Biol 155:83-120. - »Bioblast link«

xx Toleikis A, Trumbeckaite S, Liobikas J, Pauziene N, Kursvietiene L, Kopustinskiene DM (2020) Fatty acid oxidation and mitochondrial morphology changes as key modulators of the affinity for ADP in rat heart mitochondria. Cells 9:340. - »Bioblast link«

xx Vockley J (2021) Inborn errors of fatty acid oxidation. In: Suchy FS, Sokol RJ, Balistreri WF (eds) Liver disease in children. Cambridge Univ Press:611-27. https://doi.org/10.1017/9781108918978.034 - »Bioblast link«

xx Zhang X, Tomar N, Kandel SM, Audi SH, Cowley AW Jr, Dash RK (2021) Substrate- and calcium-dependent differential regulation of mitochondrial oxidative phosphorylation and energy production in the heart and kidney. Cells 11:131. - »Bioblast link«

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'.

From CGpDH and other pathways to FADH₂ to CII?

/// /// ///

Comment (Cardoso Luiza, Gnaiger Erich, 2023-08-06):

Fig. 9.19 from Blanco, Blanco (2017), Fig. 1 from Willson et al (2022), and Fig. 1 from Rai et al (2022) show FADH₂ (1) to be formed in the mitochondrial matrix from GPDH, GPD2, or GPO1 (all indicating CGpDH) and from the TCA cycle (Fig. 1 Rai et al (2022)), then (2) feeding electrons further 'To respiratory chain', the 'ETC', or 'Electron Transport Chain' (ETS). Combined with FADH₂ shown (1) to be formed in the mt-matrix from the TCA cycle and (2) feeding into CII (Fig. 1 from Koopman et al (2016); among >120 examples discussed as CII-ambiguities), one may arrive at the erroneous conclusion on a direct role of CII in the oxidation of glycerophosphate, analogous to false representations of CII involved in fatty acid oxidation.

xx Blanco A, Blanco G (2017) Chapter 9 - Biological oxidations: bioenergetics. In Blanco A, Blanco G, eds, Medical biochemistry. Academic Press:177-204. - »Bioblast link«

xx Covarrubias AJ, Perrone R, Grozio A, Verdin E (2021) NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol 22:119-41. - »Bioblast link«

xx Hashimoto T, Hussien R, Brooks GA (2006) Colocalization of MCT1, CD147, and LDH in mitochondrial inner membrane of L6 muscle cells: evidence of a mitochondrial lactate oxidation complex. Am J Physiol Endocrinol Metab 290:E1237-44. - »Bioblast link«

xx LaMoia TE, Butrico GM, Kalpage HA, Goedeke L, Hubbard BT, Vatner DF, Gaspar RC, Zhang XM, Cline GW, Nakahara K, Woo S, Shimada A, Hüttemann M, Shulman GI (2022) Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis. Proc Natl Acad Sci U S A 119:e2122287119. - »Bioblast link«

xx Lautrup S, Sinclair DA, Mattson MP, Fang EF (2019) NAD⁺ in brain aging and neurodegenerative disorders. Cell Metab 30:630-55. - »Bioblast link«

xx Willson JA, Arienti S, Sadiku P, Reyes L, Coelho P, Morrison T, Rinaldi G, Dockrell DH, Whyte MKB, Walmsley SR (2022) Neutrophil HIF-1α stabilization is augmented by mitochondrial ROS produced via the glycerol 3-phosphate shuttle. Blood 139:281-6. - »Bioblast link«

xx Xiao W, Wang RS, Handy DE, Loscalzo J (2018) NAD(H) and NADP(H) redox couples and cellular energy metabolism. Antioxid Redox Signal 28:251–72. - »Bioblast link«

xx Cogliati S, Cabrera-Alarcón JL, Enriquez JA (2021) Regulation and functional role of the electron transport chain supercomplexes. Biochem Soc Trans 49:2655-68. - »Bioblast link«

xx Mosegaard S, Dipace G, Bross P, Carlsen J, Gregersen N, Olsen RKJ (2020) Riboflavin deficiency-implications for general human health and inborn errors of metabolism. Int J Mol Sci 21:3847. - »Bioblast link«

CII as a H⁺ pump

xx 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«

xx Dumollard R, Ward Z, Carroll J, Duchen MR (2007) Regulation of redox metabolism in the mouse oocyte and embryo. Development 134:455-65. - »Bioblast link«

xx 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.

xx 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.

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

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).

Beyond preprint

xx 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.

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

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

xx 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 

Ambiguity crisis, FAT4BRAIN, Publication:FAT4BRAIN