dehydrogenase 1 alpha subcomplex subunit 7pfam pf07347 38ndufa3 / b9ndua3_humannadh dehydrogenase 1 alpha subcomplex subunit 3pfam pf14987 39ndufa4 / mlrqc,dndua4_humannadh dehydrogenase 1 alpha subcomplex subunit 4pfam pf06522 40ndufb5 / sgdhndub5_humannadh dehydrogenase 1 beta subcomplex subunit 5, mitochondrialpfam pf09781 41ndufb1 / mnllndub1_humannadh dehydrogenase 1 beta subcomplex subunit 1pfam pf08040 42ndufc1 / kfyinduc1_humannadh dehydrogenase 1 subunit c1, mitochondrialpfam pf15088 43ndufa10 / 42kdnduaa_humannadh dehydrogenase 1 alpha subcomplex subunit 10, mitochondrialpfam pf01712 44ndufa4l2nua4l_humannadh dehydrogenase 1 alpha subcomplex subunit 4-like 2pfam pf15880 45ndufv3nduv3_humannadh dehydrogenase flavoprotein 3, 10kda- 46ndufb6ndub6_humannadh dehydrogenase 1 beta subcomplex subunit 6pfam pf09782 assembly factor proteins 47ndufaf1ccia30_humannadh dehydrogenase 1 alpha subcomplex, assembly factor 1pfam pf08547 48ndufaf2mimit_humannadh dehydrogenase 1 alpha subcomplex, assembly factor 2pfam pf05071 49ndufaf3nduf3_humannadh dehydrogenase 1 alpha subcomplex assembly factor 3pfam pf05071 50ndufaf4nduf4_humannadh dehydrogenase 1 alpha subcomplex, assembly factor 4pfam pf06784 notes: a found in all species except fungi b may or may not be present in any species c found in fungal species such as schizosaccharomyces pombe d recent research has described ndufa4 to be a subunit of complex iv, and not of complex i inhibitors 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). the best-known inhibitor of complex i is rotenone (commonly used as an organic pesticide). rotenone and rotenoids are isoflavonoids occurring in several genera of tropical plants such as antonia (loganiaceae), derris and lonchocarpus (faboideae, fabaceae). 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. rotenone binds to the ubiquinone binding site of complex i as well as piericidin a, another potent inhibitor with a close structural homologue to ubiquinone. acetogenins from annonaceae are even more potent inhibitors of complex i. they cross-link to the nd2 subunit, which suggests that nd2 is essential for quinone-binding. rolliniastatin-2, an acetogenin, is the first complex i inhibitor found that does not share the same binding site as rotenone. despite more than 50 years of study of complex i, no inhibitors blocking the electron flow inside the enzyme have been found. hydrophobic inhibitors like rotenone or piericidin most likely disrupt the electron transfer between the terminal fes cluster n2 and ubiquinone. it has been shown that long-term systemic inhibition of complex i by rotenone can induce selective degeneration of dopaminergic neurons. 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. both hydrophilic nadh and hydrophobic ubiquinone analogs act at the beginning and the end of the internal electron-transport pathway, respectively. 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. inhibition of complex i has been implicated in hepatotoxicity associated with a variety of drugs, for instance flutamide and nefazodone. active/inactive transition the catalytic properties of eukaryotic complex i are not simple. two catalytically and structurally distinct forms exist in any given preparation of the enzyme: one is the fully competent, so-called “active” a-form and the other is the catalytically silent, dormant, “inactive”, d-form. after exposure of idle enzyme to elevated, but physiological temperatures (>30 °c) in the absence of substrate, the enzyme converts to the d-form. this form is catalytically incompetent but can be activated by the slow reaction (k~4 min−1) of nadh oxidation with subsequent ubiquinone reduction. 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). in the presence of divalent cations (mg2+, ca2+), or at alkaline ph the activation takes much longer. 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. however, until now, the only conformational difference observed between these two forms is the number of cysteine residues exposed at the surface of the enzyme. treatment of the d-form of complex i with the sulfhydryl reagents n-ethylmaleimide or dtnb irreversibly blocks critical cysteine residues, abolishing the ability of the enzyme to respond to activation, thus inactivating it irreversibly. the a-form of complex i is insensitive to sulfhydryl reagents. it was found that these conformational changes may have a very important physiological significance. the inactive, but not the active form of complex i was susceptible to inhibition by nitrosothiols and peroxynitrite. 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, ischemia or when the tissue nitric oxide:oxygen ratio increases (i.e. metabolic hypoxia). production of superoxide recent investigations suggest that complex i is a potent source of reactive oxygen species. complex i can produce superoxide (as well as hydrogen peroxide), through at least two different pathways. during forward electron transfer, only very small amounts of superoxide are produced (probably less than 0.1% of the overall electron flow). during reverse electron transfer, complex i might be the most important site of superoxide production within mitochondria, with around 3-4% of electrons being diverted to superoxide formation. reverse electron transfer, the process by which electrons from the reduced ubiquinol pool (supplied by succinate dehydrogenase, glycerol-3-phosphate dehydrogenase, electron-transferring flavoprotein or dihydroorotate dehydrogenase in mammalian mitochondria) pass through complex i to reduce nad+ to nadh, driven by the inner mitochondrial membrane potential electric potential. 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. this can take place during tissue ischaemia, when oxygen delivery is blocked. superoxide is a reactive oxygen species that contributes to cellular oxidative stress and is linked to neuromuscular diseases and aging. nadh dehydrogenase produces superoxide by transferring one electron from fmnh2 (or semireduced flavin) to oxygen (o2). the radical flavin leftover is unstable, and transfers the remaining electron to the iron-sulfur centers. it is the ratio of nadh to nad+ that determines the rate of superoxide formation. pathology mutations in the subunits of complex i can cause mitochondrial diseases, including leigh syndrome. point mutations in various complex i subunits derived from mitochondrial dna (mtdna) can also result in leber's hereditary optic neuropathy.there is some evidence that complex i defects may play a role in the etiology of parkinson's disease, perhaps because of reactive oxygen species (complex i can, like complex iii, leak electrons to oxygen, forming highly toxic superoxide). 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 fact, the inhibition of complex i has been shown to cause the production of peroxides and a decrease in proteasome activity, which may lead to parkinson's disease. additionally, esteves et al. (2010) found that cell lines with parkinson's disease show increased proton leakage in complex i, which causes decreased maximum respiratory capacity. brain ischemia/reperfusion injury is mediated via complex i impairment. recently it was found that oxygen deprivation leads to conditions in which mitochondrial complex i lose its natural cofactor, flavin mononucleotide (fmn) and become inactive. when oxygen is present the enzyme catalyzes a physiological reaction of nadh oxidation by ubiquinone, supplying electrons downstream of the respiratory chain (complexes iii and iv). ischemia leads to dramatic increase of succinate level. in the presence of succinate mitochondria catalyze reverse electron transfer so that fraction of electrons from succinate is directed upstream to fmn of complex i. reverse electron transfer results in a reduction of complex i fmn, increased generation of ros, followed by a loss of the reduced cofactor (fmnh2) and impairment of mitochondria energy production. the fmn loss by complex i and i/r injury can be alleviated by the administration of fmn precursor, riboflavin. recent studies have examined other roles of complex i activity in the brain. andreazza et al. (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. they found that patients with bipolar disorder showed increased protein oxidation and nitration in their prefrontal cortex. these results suggest that future studies should target complex i for potential therapeutic studies for bipolar disorder. similarly, moran et al. (2010) found that patients with severe complex i deficiency showed decreased oxygen consumption rates and slower growth rates. however, they found that mutations in different genes in complex i lead to different phenotypes, thereby explaining the variations of pathophysiological manifestations of complex i deficiency. exposure to pesticides can also inhibit complex i and cause disease symptoms. for example, chronic exposure to low levels of dichlorvos, an organophosphate used as a pesticide, has been shown to cause liver dysfunction. this occurs because dichlorvos alters complex i and ii activity levels, which leads to decreased mitochondrial electron transfer activities and decreased atp synthesis. in chloroplasts a proton-pumping, ubiquinone-using nadh dehydrogenase complex, homologous to complex i, is found in the chloroplast genomes of most land plants under the name ndh. this complex is inherited from the original symbiosis from cyanobacteria, but has been lost in most eukaryotic algae, some gymnosperms (pinus and gnetophytes), and some very young lineages of angiosperms. the purpose of this complex is originally cryptic as chloroplasts do not participate in respiration, but now it is known that ndh serves to maintain photosynthesis in stressful situations. this makes it at least partially dispensable in favorable conditions. it is evident that angiosperm lineages without ndh do not last long from their young ages, but how gymnosperms survive on land without ndh for so long is unknown. genes the following is a list of humans genes that encode components of complex i: nadh dehydrogenase (ubiquinone) 1 alpha subcomplex ndufa1 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 1, 7.5kda ndufa2 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 2, 8kda ndufa3 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 3, 9kda ndufa4 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 4, 9kda - recently described to be part of complex iv ndufa4l – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like ndufa4l2 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2 ndufa5 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 5, 13kda ndufa6 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 6, 14kda ndufa7 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 7, 14.5kda ndufa8 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 8, 19kda ndufa9 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 9, 39kda ndufa10 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 10, 42kda ndufa11 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 11, 14.7kda ndufa12 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 12 ndufa13 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, 13 ndufab1 – nadh dehydrogenase (ubiquinone) 1, alpha/beta subcomplex, 1, 8kda ndufaf1 – nadh dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 1 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 ndufb1 – nadh dehydrogenase (ubiquinone) 1 beta subcomplex, 1, 7kda ndufb2 – nadh dehydrogenase (ubiquinone) 1 beta subcomplex, 2, 8kda 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 ndufb6 – nadh dehydrogenase (ubiquinone) 1 beta subcomplex, 6, 17kda ndufb7 – nadh dehydrogenase (ubiquinone) 1 beta subcomplex, 7, 18kda ndufb8 – nadh dehydrogenase (ubiquinone) 1 beta subcomplex, 8, 19kda ndufb9 – nadh dehydrogenase (ubiquinone) 1 beta subcomplex, 9, 22kda ndufb10 – nadh dehydrogenase (ubiquinone) 1 beta subcomplex, 10, 22kda ndufb11 – nadh dehydrogenase (ubiquinone) 1 beta subcomplex, 11, 17.3kda nadh dehydrogenase (ubiquinone) 1, subcomplex unknown ndufc1 – nadh dehydrogenase (ubiquinone) 1, subcomplex unknown, 1, 6kda ndufc2 – nadh dehydrogenase (ubiquinone) 1, subcomplex unknown, 2, 14.5kda nadh dehydrogenase (ubiquinone) fe-s protein ndufs1 – nadh dehydrogenase (ubiquinone) fe-s protein 1, 75kda (nadh-coenzyme q reductase) ndufs2 – nadh dehydrogenase (ubiquinone) fe-s protein 2, 49kda (nadh-coenzyme q reductase) ndufs3 – nadh dehydrogenase (ubiquinone)