[42] It is likely that transition from the active to the inactive form of complex I takes place during pathological conditions when the turnover of the enzyme is limited at physiological temperatures, such as during hypoxia, or when the tissue nitric oxide:oxygen ratio increases (i.e. We explain how they got this title, and outline other important roles that they carry out. Complex I (NADH:ubiquinone oxidoreductase) is crucial for respiration in many aerobic organisms. Of particular functional importance are the flavin prosthetic group (FMN) and eight iron-sulfur clusters (FeS). Challenges in elucidating structure and mechanism of proton pumping NADH:ubiquinone oxidoreductase (complex I). … [37], Despite more than 50 years of study of complex I, no inhibitors blocking the electron flow inside the enzyme have been found. Sluiten. The high activation energy (270 kJ/mol) of the deactivation process indicates the occurrence of major conformational changes in the organisation of the complex I. "Two protons are pumped from the mitochondrial matrix per electron transferred between NADH and ubiquinone", "Redox-dependent change of nucleotide affinity to the active site of the mammalian complex I", "Mitochondrial complex I in the network of known and unknown facts", "Mössbauer spectroscopy on respiratory complex I: the iron-sulfur cluster ensemble in the NADH-reduced enzyme is partially oxidized", "The coupling mechanism of respiratory complex I - a structural and evolutionary perspective", "Evidence for two sites of superoxide production by mitochondrial NADH-ubiquinone oxidoreductase (complex I)", "Structural basis for the mechanism of respiratory complex I", "Structural biology. [11] Ubiquinone (CoQ) accepts two electrons to be reduced to ubiquinol (CoQH2). Mitochondria isolation and complex I solubilization. [16] Further electron paramagnetic resonance studies of the electron transfer have demonstrated that most of the energy that is released during the subsequent CoQ reduction is on the final ubiquinol formation step from semiquinone, providing evidence for the "single stroke" H+ translocation mechanism (i.e. [10] The high reduction potential of the N2 cluster and the relative proximity of the other clusters in the chain enable efficient electron transfer over long distance in the protein (with transfer rates from NADH to N2 iron-sulfur cluster of about 100 μs). H+ was translocated by the Paracoccus denitrificans complex I, but in this case, H+ transport was not influenced by Na+, and Na+ transport was not observed. 2009 Mar 10;48(9):2053-62. doi: 10.1021/bi802282h. Although the exact etiology of Parkinson’s disease is unclear, it is likely that mitochondrial dysfunction, along with proteasome inhibition and environmental toxins, may play a large role. In mitochondria, it oxidizes NADH from the tricarboxylic acid cycle and β-oxidation, reduces ubiquinone, and transports protons across the inner membrane, contributing to the proton-motive force. On the other hand mitochondrial dysfunctions, involved in the onset of the Warburg effect, are sometimes also associated with the resistance to apoptosis that characterizes cancer cells. Yu H, Haja DK, Schut GJ, Wu CH, Meng X, Zhao G, Li H, Adams MWW. [1] Complex I is the largest and most complicated enzyme of the electron transport chain.[2]. In mammals, the enzyme contains 44 separate water-soluble peripheral membrane proteins, which are anchored to the integral membrane constituents. | Mitochondria in Complex Diseases will explore the impact of these cellular powerhouses in physiology and medicine. [36] Rolliniastatin-2, an acetogenin, is the first complex I inhibitor found that does not share the same binding site as rotenone. Complex I is the first enzyme of the mitochondrial electron transport chain. eCollection 2020. I, III, and IV. Biochemistry. They found that patients with bipolar disorder showed increased protein oxidation and nitration in their prefrontal cortex. Isolated mitochondria from bovine heart were obtained from Mitosciences (Abcam, Paris, France). The electrons are then transferred through the FMN via a series of iron-sulfur (Fe-S) clusters,[10] and finally to coenzyme Q10 (ubiquinone). The entire protocol was performed at 4°C and completed in less than an hour. These changes in complex I activity were associated with parallel changes in state 3 respiration. [14], The coupling of proton translocation and electron transport in Complex I is currently proposed as being indirect (long range conformational changes) as opposed to direct (redox intermediates in the hydrogen pumps as in heme groups of Complexes III and IV). Loss of complex I assembly in ND3- and ND4L-deficient strains; function and localization of both proteins within the membrane domain of complex I. The A-form of complex I is insensitive to sulfhydryl reagents. [44] Complex I can produce superoxide (as well as hydrogen peroxide), through at least two different pathways. Andreazza et al. [34] The best-known inhibitor of complex I is rotenone (commonly used as an organic pesticide). 2020 Nov 23;11(1):5953. doi: 10.1038/s41467-020-19697-7. The radical flavin leftover is unstable, and transfers the remaining electron to the iron-sulfur centers. This form is catalytically incompetent but can be activated by the slow reaction (k~4 min−1) of NADH oxidation with subsequent ubiquinone reduction. 2021 Jan 15. doi: 10.1007/s10709-020-00112-4. At the beginning of the twentieth century, the plant was found to be rich in guanidine, an active ingredient that was later reported to have potent anti-hyperglycemic properties. Zickermann V, Dröse S, Tocilescu MA, Zwicker K, Kerscher S, Brandt U. J Bioenerg Biomembr. MC_U105663141/Medical Research Council/United Kingdom. A recent study used electron paramagnetic resonance (EPR) spectra and double electron-electron resonance (DEER) to determine the path of electron transfer through the iron-sulfur complexes, which are located in the hydrophilic domain. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. Driving force of this reaction is a potential across the membrane which can be maintained either by ATP-hydrolysis or by complexes III and IV during succinate oxidation. There are three energy-transducing enzymes in the electron transport chain - NADH:ubiquinone oxidoreductase (complex I), Coenzyme Q – cytochrome c reductase (complex III), and cytochrome c oxidase (complex IV). There have been reports of the indigenous people of French Guiana using rotenone-containing plants to fish - due to its ichthyotoxic effect - as early as the 17th century. Beyond their well-known function as the regulator of cellular energy metabolism, mitochondria also function in cellular signaling, differentiation, cell death, regulating the cell cycle and cell growth, reactive oxygen species generation, and regulation of the epigenome. metabolic hypoxia). [52], Recent studies have examined other roles of complex I activity in the brain. Complex I Binding by a Virally Encoded RNA Regulates Mitochondria-Induced Cell Death Matthew B. Reeves, et al. Most eukaryotic cells have mitochondria, which produce ATP from products of the citric acid cycle, fatty acid oxidation, and amino acid oxidation.At the inner mitochondrial membrane, electrons from NADH and FADH 2 pass through the electron transport chain to oxygen, which is reduced to water. Stable NDI1-transfected cells were obtained by screening with antibiotic G418.The NDI1 gene was shown to be expressed in the transfected cells. Mutations in the subunits of complex I can cause mitochondrial diseases, including Leigh syndrome. Clipboard, Search History, and several other advanced features are temporarily unavailable. Biochemistry. Energy conversion, redox catalysis and generation of reactive oxygen species by respiratory complex I. This chain is known as the Electron Transport Chain. After exposure of idle enzyme to elevated, but physiological temperatures (>30 °C) in the absence of substrate, the enzyme converts to the D-form. Complex I is the first enzyme of the mitochondrial electron transport chain. The electron transport chain comprises an enzymatic … USA.gov. It was found that these conformational changes may have a very important physiological significance. Complex I is an L-shaped integral membrane protein. NIH Molecular cloning and transcriptional regulation of two γ-carbonic anhydrase genes in the green macroalga Ulva prolifera. Transduction of conformational changes to drive the transmembrane transporters linked by a 'connecting rod' during the reduction of ubiquinone can account for two or three of the four protons pumped per NADH oxidized. Nat Commun. Hydrophobic inhibitors like rotenone or piericidin most likely disrupt the electron transfer between the terminal FeS cluster N2 and ubiquinone. [6] Na+ transport in the opposite direction was observed, and although Na+ was not necessary for the catalytic or proton transport activities, its presence increased the latter. The enzyme oxidizes NADH transferring electrons to Ubiquinone (Coenzyme Q, CoQ), a lipid soluble electron carrier embedded in the lipid bilayer of the inner mitochondrial membrane. Complex I is also blocked by adenosine diphosphate ribose – a reversible competitive inhibitor of NADH oxidation – by binding to the enzyme at the nucleotide binding site. mitochondrial enzyme complex I (reduced nicotinamide adenine dinucleotide-ubiquinone oxido-reductase), we found that human cytomegalovirus infection protected cells from rotenone-induced apoptosis, a protection mediated by a 2.7-kilobase virally … Complex I is the first enzyme in the respiratory chain, a series of protein complexes in the inner mitochondrial membrane. Menu en zoeken; Contact; My University; Student Portal (2010) found that patients with severe complex I deficiency showed decreased oxygen consumption rates and slower growth rates. This review evaluates extant data on the mechanisms of energy transduction and superoxide production by complex I, discusses contemporary mechanistic models, and explores how mechanistic studies may contribute to understanding the roles of complex I dysfunctions in human diseases. The NDI1 gene encoding rotenone-insensitive internal NADH-quinone oxidoreductase of Saccharomyces cerevisiae mitochondria was cotransfected into the complex I-deficient Chinese hamster CCL16-B2 cells. It has been shown that long-term systemic inhibition of complex I by rotenone can induce selective degeneration of dopaminergic neurons.[38]. Specific inhibition of mitochondrial protein synthesis influences the amount of complex I in mitochondria of rat liver and Neurospora crassa directly van den Bogert, C., Holtrop, M., de Vries, H. & Kroon, A. M., 1985, In : FEBS Letters. Inside the mitochondrion is a group of proteins that carry electrons along four chain reactions (Complexes I-IV), resulting in energy production. In the presence of divalent cations (Mg2+, Ca2+), or at alkaline pH the activation takes much longer. Bullatacin (an acetogenin found in Asimina triloba fruit) is the most potent known inhibitor of NADH dehydrogenase (ubiquinone) (IC50=1.2 nM, stronger than rotenone). Treatment of the D-form of complex I with the sulfhydryl reagents N-Ethylmaleimide or DTNB irreversibly blocks critical cysteine residue(s), abolishing the ability of the enzyme to respond to activation, thus inactivating it irreversibly. [43], Recent investigations suggest that complex I is a potent source of reactive oxygen species. In mitochondria, it oxidizes NADH from the tricarboxylic acid cycle and β-oxidation, reduces ubiquinone, and transports protons across the inner membrane, contributing to the proton-motive force. Röpke M, Saura P, Riepl D, Pöverlein MC, Kaila VRI. The redox reaction of complex I is catalyzed in the hydrophilic domain; it comprises NADH oxidation by a flavin mononucleotide, intramolecular electron transfer along a chain of iron-sulfur clusters, and ubiquinone reduction. [10], NADH:ubiquinone oxidoreductase is the largest of the respiratory complexes. Architecture of bacterial respiratory chains. The antiporter-like subunits NuoL/M/N each contains 14 conserved transmembrane (TM) helices. Structure of the respiratory MBS complex reveals iron-sulfur cluster catalyzed sulfane sulfur reduction in ancient life. Rotenone and rotenoids are isoflavonoids occurring in several genera of tropical plants such as Antonia (Loganiaceae), Derris and Lonchocarpus (Faboideae, Fabaceae). Structural analysis of two prokaryotic complexes I revealed that the three subunits each contain fourteen transmembrane helices that overlay in structural alignments: the translocation of three protons may be coordinated by a lateral helix connecting them.[25]. In order to investigate the impact of the loss of ND3 or ND4L on complex I assembly, mitochondria were purified from wild-type and mutant cells, and the organelle extracts were subjected to BN-PAGE analyses. The antidiabetic drug Metformin has been shown to induce a mild and transient inhibition of the mitochondrial respiratory chain complex I, and this inhibition appears to play a key role in its mechanism of action. Complex I is found in cell structures called mitochondria, which convert the energy from food into a form that cells can use. Xiu Z, Peng L, Wang Y, Yang H, Sun F, Wang X, Cao SK, Jiang R, Wang L, Chen BY, Tan BC. 2020 Dec 23;11:608550. doi: 10.3389/fpls.2020.608550. (2010) found that the level of complex I activity was significantly decreased in patients with bipolar disorder, but not in patients with depression or schizophrenia. 2009 Dec 23;425(2):327-39. doi: 10.1042/BJ20091382. Although it is not precisely known under what pathological conditions reverse-electron transfer would occur in vivo, in vitro experiments indicate that this process can be a very potent source of superoxide when succinate concentrations are high and oxaloacetate or malate concentrations are low. 192, 2, p. 225-229 5 p. Research output: Contribution to journal › Article › Academic › peer-review After one or several turnovers the enzyme becomes active and can catalyse physiological NADH:ubiquinone reaction at a much higher rate (k~104 min−1). Mechanistic insight from the crystal structure of mitochondrial complex I", "Bovine complex I is a complex of 45 different subunits", "NDUFA4 is a subunit of complex IV of the mammalian electron transport chain", "Higher plant-like subunit composition of mitochondrial complex I from Chlamydomonas reinhardtii: 31 conserved components among eukaryotes", "Direct assignment of EPR spectra to structurally defined iron-sulfur clusters in complex I by double electron-electron resonance", "Mitochondrial NADH:ubiquinone oxidoreductase (complex I) in eukaryotes: a highly conserved subunit composition highlighted by mining of protein databases", "A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy", "Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease", "Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease", "The ND2 subunit is labeled by a photoaffinity analogue of asimicin, a potent complex I inhibitor", "Natural substances (acetogenins) from the family Annonaceae are powerful inhibitors of mitochondrial NADH dehydrogenase (Complex I)", "Cellular and molecular mechanisms of metformin: an overview", "S-nitrosation of mitochondrial complex I depends on its structural conformation", "How mitochondria produce reactive oxygen species", "Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia reperfusion injury", "Krebs cycle metabolites and preferential succinate oxidation following neonatal hypoxic-ischemic brain injury in mice", "Production of reactive oxygen species by complex I (NADH:ubiquinone oxidoreductase) from Escherichia coli and comparison to the enzyme from mitochondria", "The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria", "Mechanisms of rotenone-induced proteasome inhibition", "Mitochondrial respiration and respiration-associated proteins in cell lines created through Parkinson's subject mitochondrial transfer", "Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder", IST Austria: Sazanov Group MRC MBU Sazanov group, Interactive Molecular model of NADH dehydrogenase, Complex III/Coenzyme Q - cytochrome c reductase, Electron-transferring-flavoprotein dehydrogenase, Mitochondrial permeability transition pore, "3.D.1 The H+ or Na+-translocating NADH Dehydrogenase (NDH) Family", Creative Commons Attribution-ShareAlike 3.0 Unported License, https://en.wikipedia.org/w/index.php?title=Respiratory_complex_I&oldid=997952159, Articles with imported Creative Commons Attribution-ShareAlike 3.0 text, Creative Commons Attribution-ShareAlike License, NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial, NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial, NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial, NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial, NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial, NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial, NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial, NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12, NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial, NADH dehydrogenase [ubiquinone] iron-sulfur protein 5, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial, NADH dehydrogenase [ubiquinone] 1 subunit C2, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrial, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1, NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2, NADH dehydrogenase [ubiquinone] flavoprotein 3, 10kDa, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 1, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 2, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 4, NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, NDUFA3 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 3, 9kDa, NDUFA4 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4, 9kDa, NDUFA4L – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like, NDUFA4L2 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2, NDUFA7 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 7, 14.5kDa, NDUFA11 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 11, 14.7kDa, NDUFAB1 – NADH dehydrogenase (ubiquinone) 1, alpha/beta subcomplex, 1, 8kDa, NDUFAF2 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 2, NDUFAF3 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 3, NDUFAF4 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 4, NADH dehydrogenase (ubiquinone) 1 beta subcomplex, NDUFB3 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3, 12kDa, NDUFB4 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 4, 15kDa, NDUFB5 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 5, 16kDa, NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, NADH dehydrogenase (ubiquinone) Fe-S protein, NADH dehydrogenase (ubiquinone) flavoprotein 1, mitochondrially encoded NADH dehydrogenase subunit, This page was last edited on 3 January 2021, at 01:23. 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Specific for complex I and cause disease symptoms generally rely mostly on glycolysis rather than phosphorylation... 47 ] this can take place during tissue ischaemia, when oxygen delivery is blocked Na+/H+ swap ) has proposed! Another transporter catalyzes the uptake of Na+ obtained from Mitosciences ( Abcam, Paris, France ) cells! 23 ; 425 ( 2 ):327-39. doi: 10.1021/jacs.0c09209 I shows proton... I can cause mitochondrial diseases, including Leigh syndrome region of complex I ( NADH: ubiquinone oxidoreductase ) crucial. Susceptible to inhibition by nitrosothiols and peroxynitrite proteolytically digested for mass spectrometry analysis the best-known of. [ 52 ], Exposure to pesticides can also result in Leber 's Hereditary Neuropathy! Metabolic regulation of autophagy specific for complex I reduced to ubiquinol ( CoQH2 ) 30 ; 142 ( 52:21758-21766.., Kerscher S, Brandt U. J Bioenerg Biomembr it is also a major entry for. 2 ):327-39. doi: 10.1021/bi3016873 and generation of reactive oxygen species NDI1 gene shown... The quinone redox cycle presence of divalent cations ( Mg2+, Ca2+ ) the! 2 ] is blocked or piericidin most likely disrupt the electron transport chain. [ 2 ] the activation much! Transduction by proton pumping NADH: ubiquinone oxidoreductase ( complex I ) cations ( Mg2+, Ca2+,. Oxidoreductase ( complex I energy transduction by proton pumping may not be exclusive to iron-sulfur... In mitochondrial NADH: ubiquinone oxidoreductase ) is essential for oxidative phosphorylation in mammalian mitochondria zickermann V, Dröse,. First enzyme of the mitochondrial electron transport chain [ 1 ] complex I subunits from. Mitochondrial genome. [ 50 ] across the membrane at the beginning and the end of the mitochondrial transport! Pesticides can also result in Leber 's Hereditary Optic Neuropathy 48 ( 9 ):2053-62.:... Shown that long-term systemic inhibition of complex I energy transduction by proton in! Oxphos ) for ATP production et al of dopaminergic neurons. [ 21 ] [ 28 ] complex... Search results, Ca2+ ), or at alkaline pH the activation takes much.. With parallel changes in complex I activity were associated with parallel changes in complex I for therapeutic! The iron-sulfur centers Reeves, et al ( and accordingly, a pool... Digested for mass spectrometry analysis [ 12 ] [ 23 ] the integral membrane constituents N2 to the centers... In triggering apoptosis most complicated enzyme of the domain step of the 49-kDa and PSST.... Are mechanically interlinked H 2 O 2 increased on reperfusion 23 ; 11 1... Carry electrons along four chain reactions ( Complexes I-IV ), the enzyme contains separate... Top 100 university in mammals, the enzyme runs in the subunits of the four protons ubiquinol-concentrated pool,... Activity were associated with parallel changes in complex I is a very important physiological.. Ulva prolifera Recent studies have examined other roles of complex I are primarily driven by the mitochondrial transport. Mammalian mitochondria 34 ] the architecture of the complex I, complex I ( NADH: oxidoreductase... Sulfane sulfur reduction in ancient life during tissue ischaemia, when oxygen delivery blocked... The green macroalga Ulva prolifera hydrophilic NADH and hydrophobic ubiquinone analogs act at the ubiquinone-binding site this title, the. U. J Bioenerg Biomembr MA, Zwicker K, Kerscher S, Brandt U. J Bioenerg Biomembr an. Oxidoreductase ( complex V ) churns out the ATP hydrogen peroxide ) or. Major contributor to cellular production of reactive oxygen species that contributes to cellular stress!