Gnaiger 2024 J Biol Chem

Gnaiger E (2023) Complex II ambiguities ― FADH2 in the electron transfer system. J Biol Chem. https://doi.org/10.1016/j.jbc.2023.105470

» J Biol Chem Open Access

Gnaiger E (2023) J Biol Chem

Abstract:

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). CII is the only membrane-bound enzyme in the tricarboxylic acid cycle and is part of the electron transfer system of the mitochondrial inner membrane feeding electrons into the coenzyme Q-junction. 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 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

ORCID: Gnaiger Erich, Oroboros Instruments, Innsbruck, Austria

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

References grouped in Table 2

SDH: FAD ⟶ FADH₂; CII: FADH₂ ⟶ FAD

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FADH₂ ⟶

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FADH₂ ⟶ FAD + H⁺

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FADH₂ ⟶ FAD + 2H⁺

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4b.32. Ref 274 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. Ref 275 Tseng W-W, Wei A-C (2022) Kinetic mathematical modeling of oxidative phosphorylation in cardiomyocyte mitochondria. Cells 11:4020. - »Bioblast link«

4b.34. Ref 276 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. Ref 277 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. Ref 278 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. Ref 279 Wu Z, Ho WS, Lu R (2022) Targeting mitochondrial oxidative phosphorylation in glioblastoma therapy. Neuromolecular Med 24:18-22. - »Bioblast link«

4b.38. Ref 280 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. Ref 281 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. Ref 282 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. Ref 283 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. Ref 284 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. Ref 285 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. Ref 286 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. Ref 287 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. Ref 288 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. Ref 289 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. Ref 290 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. Ref 291 Gero D (2023) Hyperglycemia-induced endothelial dysfunction. IntechOpen Chapter 8. - »Bioblast link«

5a.12. Ref 292 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. Ref 293 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. Ref 294 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. Ref 295 Lettieri-Barbato D (2019) Redox control of non-shivering thermogenesis. Mol Metab 25:11-9. - »Bioblast link«

5a.16. Ref 296 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. Ref 297 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. Ref 298 Onukwufor JO, Dirksen RT, Wojtovich AP (2022) Iron dysregulation in mitochondrial dysfunction and Alzheimer's disease. Antioxidants (Basel) 11:692. - »Bioblast link«

5a.19. Ref 299 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. Ref 300 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. Ref 301 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. Ref 302 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. Ref 303 Schottlender N, Gottfried I, Ashery U (2021) Hyperbaric oxygen treatment: effects on mitochondrial function and oxidative stress. Biomolecules 11:1827. - »Bioblast link«

5a.24. Ref 304 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. Ref 305 Sullivan LB, Chandel NS (2014) Mitochondrial metabolism in TCA cycle mutant cancer cells. Cell Cycle 13:347-8. - »Bioblast link«

5a.26. Ref 306 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. Ref 307 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. Ref 308 Vartak R, Porras CA, Bai Y (2013) Respiratory supercomplexes: structure, function and assembly. Protein Cell 4:582-90. - »Bioblast link«

5a.29. Ref 309 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. Ref 310 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. Ref 311 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. Ref 312 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. Ref 313 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. Ref 314 Bratic A, Larsson NG (2013) The role of mitochondria in aging. J Clin Invest 123:951-7. - »Bioblast link«

5c.2. Ref 315 Brischigliaro M, Zeviani M (2021) Cytochrome c oxidase deficiency. Biochim Biophys Acta Bioenerg 1862:148335. - »Bioblast link«

5c.3. Ref 316 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. Ref 317 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. Ref 318 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. Ref 319 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. Ref 320 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. Ref 321 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. Ref 322 Cadonic C, Sabbir MG, Albensi BC (2016) Mechanisms of mitochondrial dysfunction in Alzheimer's disease. Mol Neurobiol 53:6078-90. - »Bioblast link«

6a.2. Ref 323 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. Ref 324 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. Ref 325 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. Ref 326 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. Ref 327 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. Ref 328 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. Ref 329 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. Ref 330 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. Ref 331 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. Ref 332 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. Ref 333 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. Ref 334 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. Ref 335 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. Ref 336 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. Ref 337 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. Ref 338 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. Ref 339 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. Ref 340 Moudgil R, Michelakis ED, Archer SL (2005) Hypoxic pulmonary vasoconstriction. J Appl Physiol (1985) 98:390-403. - »Bioblast link«

FADH ⟶ FAD⁺ +H⁺

7d.1. Ref 341 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. Ref 342 Xing Yunxie (2022) Is genome instability a significant cause of aging? A review. Atlantis Press. - »Bioblast link«

FADH⁺ ⟶ FAD

7f.1. Ref 343 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. Ref 344 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. Ref 345 Irazabal MV, Torres VE (2020) Reactive oxygen species and redox signaling in chronic kidney disease. Cells 9:1342. - »Bioblast link«

8a.3. Ref 346 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. Ref 347 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. Ref 348 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. Ref 349 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. Ref 350 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«

8e.2. Ref 351 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«

8e.3. Ref 352 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«

8e.4. Ref 353 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«

8e.5. Ref 354 Picard M, McEwen BS (2018) Psychological stress and mitochondria: a systematic review. Psychosom Med 80:141-53. - »Bioblast link«

8e.6. Ref 355 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«

8e.7. Ref 356 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«

FAO and CII ambiguitiy

Ref 50 Balasubramaniam S, Yaplito-Lee J (2020) Riboflavin metabolism: role in mitochondrial function. J Transl Genet Genom 4:285-306. - »Bioblast link«

Ref 192 Bertero E, Maack C (2018) Metabolic remodelling in heart failure. Nat Rev Cardiol 15:457-70. - »Bioblast link«

Ref 351 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«

Ref 352 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«

Ref 202 DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348:2656-68. - »Bioblast link«

Ref 62 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«

Ref 205 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«

Ref 71 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«

Ref 349 Huss JM, Kelly DP (2005) Mitochondrial energy metabolism in heart failure: a question of balance. J Clin Invest 115:547-55. - »Bioblast link«

Ref 292 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«

Ref 294 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«

Ref 296 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«

Ref 291 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«

Ref 292 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«

Ref 81 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«

Ref 291 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«

Ref 221 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«

Ref 226 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«

Ref 354 Picard M, McEwen BS (2018) Psychological stress and mitochondria: a systematic review. Psychosom Med 80:141-53. - »Bioblast link«

Ref 355 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«

Ref 353 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«

Ref 350 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«

Ref 356 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«

Ref 228 Prasun P (2020) Role of mitochondria in pathogenesis of type 2 diabetes mellitus. J Diabetes Metab Disord 19:2017-22. - »Bioblast link«

Ref 300 Rinaldo P, Matern D, Bennett MJ (2002) Fatty acid oxidation disorders. Annu Rev Physiol 64:477-502. - »Bioblast link«

Ref 284 Bennett MJ, Sheng F, Saada A (2020) Biochemical assays of TCA cycle and β-oxidation metabolites. Methods Cell Biol 155:83-120. - »Bioblast link«

Ref 97 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«

Ref 237 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«

Ref 240 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«

From CGpDH and other pathways to FADH₂ to CII?

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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«

MitoFit Preprint

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

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Cofactor

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» Coenzyme, cosubstrate

» Nicotinamide adenine dinucleotide

» Coenzyme Q2

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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

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Enzyme: Complex II;succinate dehydrogenase 

Ambiguity crisis, FAT4BRAIN, Publication:FAT4BRAIN