Category:Ambiguidity crisis - NAD and H+: Difference between revisions

Hydrogen ion ambiguities in the electron transfer system

Communicated by Gnaiger E (2023-10-08) last update 2023-11-10

Electron (e^-) transfer linked to hydrogen ion (hydron; H⁺) transfer is a fundamental concept in the field of bioenergetics, critical for understanding redox-coupled energy transformations.

However, the current literature contains inconsistencies regarding H⁺ formation on the negative side of bioenergetic membranes, such as the matrix side of the mitochondrial inner membrane, when NADH is oxidized during oxidative phosphorylation (OXPHOS). Ambiguities arise when examining the oxidation of NADH by respiratory Complex I or succinate by Complex II.

Oxidation of NADH or succinate involves a two-electron transfer of 2{H⁺+e^-} to FMN or FAD, respectively. Figures indicating a single electron e^- transferred from NADH or succinate lack accuracy.

The oxidized NAD⁺ is distinguished from NAD indicating nicotinamide adenine dinucleotide independent of oxidation state.

NADH + H⁺ → NAD⁺ +2{H⁺+e^-} is the oxidation half-reaction in this H⁺-linked electron transfer represented as 2{H⁺+e^-} (Gnaiger 2023). Putative H⁺ formation shown as NADH → NAD⁺ + H⁺ conflicts with chemiosmotic coupling stoichiometries between H⁺ translocation across the coupling membrane and electron transfer to oxygen. Ensuring clarity in this complex field is imperative to tackle the apparent ambiguity crisis and prevent confusion, particularly in light of the increasing number of interdisciplinary publications on bioenergetics concerning diagnostic and clinical applications of OXPHOS analysis.

CI substrates

xx Bottje WG (2019) Oxidative metabolism and efficiency: the delicate balancing act of mitochondria. Poult Sci 98:4223-30. - »Bioblast link«

Electron transfer from CI ⟶ CII ⟶ CIII

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

NADH ⟶ NAD⁺ + H⁺

xx Ahmad M, Wolberg A, Kahwaji CI (2022) Biochemistry, electron transport chain. StatPearls Publishing StatPearls [Internet]. Treasure Island (FL) - »Bioblast link«

xx Anoar S, Woodling NS, Niccoli T (2021) Mitochondria dysfunction in frontotemporal dementia/amyotrophic lateral sclerosis: lessons from Drosophila models. Front Neurosci 15:786076. - »Bioblast link«

xx Bajeli S, Baid N, Kaur M, Pawar GP, Chaudhari VD, Kumar A (2020) Terminal respiratory oxidases: a targetables vulnerability of mycobacterial bioenergetics?. Front Cell Infect Microbiol 10:589318. - »Bioblast link«

xx Bennekou SH, van der Stel W, Carta G, Eakins J, Delp J, Forsby A, Kamp H, Gardner I, Zdradil B, Pastor M, Gomes JC, White A, Steger-Hartman T, Danen EHJ, Leist M, Walker P, Jennings P, van de Water B (2020) Case stuy on the use of integrated approaches to testing and assessment for mitochondrial Complex-III-mediated neurotoxicity of azoxystrobin - read-across to other strobilurins. OECD Environment, Health and Safety Publications Series on Testing and Assessment No. 327. ENV/JM/MONO(2020)23. - »Bioblast link«

xx Bețiu AM, Noveanu L, Hâncu IM, Lascu A, Petrescu L, Maack C, Elmér E, Muntean DM (2022) Mitochondrial effects of common cardiovascular medications: the good, the bad and the mixed. Int J Mol Sci 23:13653. - »Bioblast link«

xx Biner O, Schick T, Ganguin AA, von Ballmoos C (2018) Towards a synthetic mitochondrion. Chimia (Aarau) 72:291-6. - »Bioblast link«

xx Black PA, Warren RM, Louw GE, van Helden PD, Victor TC, Kana BD (2014) Energy metabolism and drug efflux in Mycobacterium tuberculosis. Antimicrob Agents Chemother 58:2491-503. - »Bioblast link«

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

xx Brzezinski P, Moe A, Ädelroth P (2021) Structure and mechanism of respiratory III-IV supercomplexes in bioenergetic membranes. Chem Rev 121:9644-73. - »Bioblast link«

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

xx 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«

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

xx Curtabbi A, Enríquez JA (2022) The ins and outs of the flavin mononucleotide cofactor of respiratory complex I. IUBMB Life 74:629-44. - »Bioblast link«

xx Esterházy D, King MS, Yakovlev G, Hirst J (2008) Production of reactive oxygen species by complex I (NADH:ubiquinone oxidoreductase) from Escherichia coli and comparison to the enzyme from mitochondria. Biochemistry 47:3964-71. - »Bioblast link«

xx Friedman J, Mourokh L, Vittadello M (2021) Mechanism of proton pumping in Complex I of the mitochondrial respiratory chain. Quantum Reports 3:425-34. - »Bioblast link«

xx Gasmi A, Peana M, Arshad M, Butnariu M, Menzel A, Bjørklund G (2021) Krebs cycle: activators, inhibitors and their roles in the modulation of carcinogenesis. Arch Toxicol 95:1161-78. - »Bioblast link«

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

xx Hummer G, Wikström M (2016) Molecular simulation and modeling of complex I. Biochim Biophys Acta 1857:915-21. - »Bioblast link«

xx Iqbal IK, Bajeli S, Akela AK, Kumar A (2018) Bioenergetics of Mycobacterium: an emerging landscape for drug discovery. Pathogens 7:24. - »Bioblast link«

xx 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«

xx Kim J, Cheong JH (2020) Role of mitochondria-cytoskeleton interactions in the regulation of mitochondrial structure and function in cancer stem cells. Cells 9:1691. - »Bioblast link«

xx 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«

xx 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«

xx 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«

xx 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«

xx Ľupták M, Fišar Z, Hroudová J (2023) Different effects of SSRIs, Bupropion, and Trazodone on mitochondrial functions and monoamine oxidase isoform activity. Antioxidants (Basel) 12:1208. - »Bioblast link«

xx Maldonado M, Abe KM, Letts JA (2022) A structural perspective on the RNA editing of plant respiratory Complexes. Int J Mol Sci 23:684. - »Bioblast link«

xx Martin DR, Matyushov DV (2017) Electron-transfer chain in respiratory complex I. Sci Rep 7:5495. - »Bioblast link«

xx 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«

xx Peña-Corona SI, Hernández-Parra H, Bernal-Chávez SA, Mendoza-Muñoz N, Romero-Montero A, Del Prado-Audelo ML, Cortés H, Ateşşahin DA, Habtemariam S, Almarhoon ZM, Abdull Razis AF, Modu B, Sharifi-Rad J, Leyva-Gómez G (2023) Neopeltolide and its synthetic derivatives: a promising new class of anticancer agents. Front Pharmacol 14:1206334. - »Bioblast link«

xx 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«

xx Risiglione P, Leggio L, Cubisino SAM, Reina S, Paternò G, Marchetti B, Magrì A, Iraci N, Messina A (2020) High-resolution respirometry reveals MPP+ mitochondrial toxicity mechanism in a cellular model of parkinson's disease. Int J Mol Sci 21:E7809. - »Bioblast link«

xx Sazanov LA (2015) A giant molecular proton pump: structure and mechanism of respiratory complex I. Nat Rev Mol Cell Biol 16:375-88. - »Bioblast link«

xx Schon EA (2018) Bioenergetics through thick and thin. Science 362:1114-5. - »Bioblast link«

xx Sharpley MS, Hirst J (2006) The inhibition of mitochondrial complex I (NADH:ubiquinone oxidoreductase) by Zn²⁺. J Biol Chem 281:34803-9. - »Bioblast link«

ο Srivastava S (2016) Emerging therapeutic roles for NAD(+) metabolism in mitochondrial and age-related disorders. Clin Transl Med 5:25. - »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 Tseng W-W, Wei A-C (2022) Kinetic mathematical modeling of oxidative phosphorylation in cardiomyocyte mitochondria. Cells 11:4020. - »Bioblast link«

xx Wang G, Feng H, Gao A, Hao Q, Jin W, Peng X, Li W, Wu G, Chu PK (2016) Extracellular electron transfer from aerobic bacteria to Au-loaded TiO2 semiconductor without light: a new bacteria-killing mechanism other than localized surface plasmon resonance or microbial fuel cells. ACS Appl Mater Interfaces 8:24509-16. - »Bioblast link«

xx Wikström M, Hummer G (2012) Stoichiometry of proton translocation by respiratory complex I and its mechanistic implications. Proc Natl Acad Sci U S A 109:4431-6. - »Bioblast link«

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

xx Yakovlev G, Hirst J (2007) Transhydrogenation reactions catalyzed by mitochondrial NADH-ubiquinone oxidoreductase (Complex I). Biochemistry 46:14250-8. - »Bioblast link«

xx Yusoff AAM (2015) Role of mitochondrial DNA mutations in brain tumors: A mini-review. J Cancer Res Ther 11:535-44. - »Bioblast link«

xx Yusoff AAM, Ahmad F, Idris Z, Jaafar H, Abdullah JM (2015) Understanding mitochondrial DNA in brain tumorigenesis. In: Lichtor T, ed. Molecular considerations and evolving surgical management issues in the treatment of patients with a brain tumor. InTech: http://dx.doi.org/10.5772/58965 - »Bioblast link«

NADH ⟶ NAD + H⁺

xx Alston CL, Rocha MC, Lax NZ, Turnbull DM, Taylor RW (2017) The genetics and pathology of mitochondrial disease. J Pathol 241:236-50. - »Bioblast link«

xx Branca JJV, Pacini A, Gulisano M, Taddei N, Fiorillo C, Becatti M (2020) Cadmium-induced cytotoxicity: effects on mitochondrial electron transport chain. Front Cell Dev Biol 8:604377. - »Bioblast link«

xx Chen TH, Koh KY, Lin KM, Chou CK (2022) Mitochondrial dysfunction as an underlying cause of skeletal muscle disorders. Int J Mol Sci 23:12926. - »Bioblast link«

xx 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«

xx Distelmaier F, Koopman WJ, van den Heuvel LP, Rodenburg RJ, Mayatepek E, Willems PH, Smeitink JA (2009) Mitochondrial complex I deficiency: from organelle dysfunction to clinical disease. Brain 132:833-42. - »Bioblast link«

xx 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«

NADH ⟶ NAD⁺ + 2H⁺

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

xx Chavda V, Lu B (2023) Reverse electron transport at mitochondrial Complex I in ischemic stroke, aging, and age-related diseases. Antioxidants (Basel) 12:895. - »Bioblast link«

xx Cojocaru KA, Luchian I, Goriuc A, Antoci LM, Ciobanu CG, Popescu R, Vlad CE, Blaj M, Foia LG (2023) Mitochondrial dysfunction, oxidative stress, and therapeutic strategies in diabetes, obesity, and cardiovascular disease. Antioxidants (Basel) 12:658. - »Bioblast link«

xx Egan B, Sharples AP (2023) Molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise training. Physiol Rev 103:2057-2170. - »Bioblast link«

xx El-Gammal Z, Nasr MA, Elmehrath AO, Salah RA, Saad SM, El-Badri N (2022) Regulation of mitochondrial temperature in health and disease. Pflugers Arch 474:1043-51. - »Bioblast link«

xx Faria R, Boisguérin P, Sousa Â, Costa D (2023) Delivery systems for mitochondrial gene therapy: a review. Pharmaceutics 15:572. - »Bioblast link«

xx Foo J, Bellot G, Pervaiz S, Alonso S (2022) Mitochondria-mediated oxidative stress during viral infection. Trends Microbiol 30:679-92. - »Bioblast link«

xx 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«

xx 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«

xx 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«

xx 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«

xx 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«

xx 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«

xx Mathur D, Riffo-Campos AL, Castillo J, Haines JD, Vidaurre OG, Zhang F, Coret-Ferrer F, Casaccia P, Casanova B, Lopez-Rodas G (2017) Bioenergetic failure in rat oligodendrocyte progenitor cells treated with cerebrospinal fluid derived from multiple sclerosis poatients. Front Cell Neurosci 11:209. - »Bioblast link«

xx 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«

xx 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«

xx 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«

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

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

xx Yu-Wai-Man P, Griffiths PG, Chinnery PF (2011) Mitochondrial optic neuropathies - disease mechanisms and therapeutic strategies. Prog Retin Eye Res 30:81-114. - »Bioblast link«

NADH ⟶ NAD

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

xx Geng Y, Hu Y, Zhang F, Tuo Y, Ge R, Bai Z (2023) Mitochondria in hypoxic pulmonary hypertension, roles and the potential targets. Front Physiol 14:1239643. - »Bioblast link«

xx Simon L, Molina PE (2022) Cellular bioenergetics: experimental evidence for alcohol-induced adaptations. Function (Oxf) 3:zqac039. - »Bioblast link«

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

xx Tirichen H, Yaigoub H, Xu W, Wu C, Li R, Li Y (2021) Mitochondrial reactive oxygen species and their contribution in chronic kidney disease progression through oxidative stress. Front Physiol 12:627837. - »Bioblast link«

xx Yang J, Guo Q, Feng X, Liu Y, Zhou Y (2022) Mitochondrial dysfunction in cardiovascular diseases: potential targets for treatment. Front Cell Dev Biol 10:841523. - »Bioblast link«

NADH + H ⟶ NADH⁺

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

NADH + H⁺ ⟶ NADH

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

NAD⁺ + H⁺ ⟶ NADH

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.

2 NADH₂ ⟶ 2 NAD⁺

xx Papa S, Petruzzella V, Scacco S (2007) Electron transport. Structure, redox-coupled protonmotive activity, and pathological disorders of respiratory chain Complexes. Springer, Boston, MA. In: Lajtha A, Gibson GE, Dienel GA (eds) Handbook of neurochemistry and molecular neurobiology:93–118. - »Bioblast link«

NADP ⟶

xx Zhao H, Li Y (2021) Cancer metabolism and intervention therapy. Mol Biomed 2:5. - »Bioblast link«

NADP⁺ + 2H⁺ ⟶ NADPH + H⁺

xx Michelet L, Zaffagnini M, Morisse S, Sparla F, Pérez-Pérez ME, Francia F, Danon A, Marchand CH, Fermani S, Trost P, Lemaire SD (2013) Redox regulation of the Calvin-Benson cycle: something old, something new. Front Plant Sci 4:470. - »Bioblast link«

NADH + H+ ⟶ for TCA cycle DH, but NADH ⟶ for CI

xx DiMauro S, Rustin P (2009) A critical approach to the therapy of mitochondrial respiratory chain and oxidative phosphorylation diseases. Biochim Biophys Acta 1792:1159-67. - »Bioblast link«