Complex I Homepage
What is Complex I?

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About complex I

The NADH-quinone oxidoreductase (complex I) is one of three energy-transducing enzyme complexes of the respiratory chain in mitochondria. It catalyses the reaction:

NADH + Q + H+ + nH+in -> NAD+ + QH2 + nH+out     (Q=quinone; n=3-5)

ComplexIis the point of entry for the major fraction of electrons that traverse the respiratory chain eventually resulting in the reduction of oxygen. Coupled to the electron transfer, protons are pumped from the matrix side totheintermembrace space of mitochondria. It is the most intricate membrane-bound enzyme known to date, being composed of at least 45 different polypeptides. Of these, 7 are encoded by mitochondrial DNA.

Although four decades have passed since the first isolation of complex I from bovine heart mitochondria by Joe Hatefi and coworkers, information on its structure and mechanism of action is still limited. This enzyme complex contains a noncovalently-bound FMN molecule and 2 binuclear and 6 tetranuclear iron-sulfur clusters, of which 2 binuclear and 4 tetranuclear clusters are EPR-visible.

Why research on complex I is important

Research on complex I has recently taken on greater significance since the finding that many human mitochondrial diseases involve structural and functional defects at the level of this enzyme complex. Many cases of Leber's hereditary optic neuropathy (LHON), appear to be associated with a defect in complex I. The defect identified in many cases is a single nucleotide change in the mitochondrial DNA converting the 340th amino acid of the ND4 subunit of complex I from an arginine to a histidine. In addition to these documented cases, complex I inhibitors, 1-methyl-4-phenylpyridium and rotenone, produce drug-induced Parkinsonism in rodents and human, which suggests a link between Parkinson's disease and function of mitochondrial complex I. Complex I is also known to be a target of new pesticides such as acaricides. Moreover, it is suggested that complex I malfunction is involved in the pathogenesis of diabetes. Therefore, complex I research is important to not only basic sciences but also clinical medicine. This is evident in the progressively growing number of publications relating to complex I, as depicted in the figure. There are several milestones in complex I research. In 1973, Ragan and Racker showed that complex I is a proton pump. In the mid-1980s, it was found that the 7 unidentified genes in mtDNA are encoding complex I subunits by Attardi's group. Shortly after that, the first case of mitochondrial diseases caused by complex I defects was reported (Wallace et al., 1988).

Mammalian complex I

Mammalian complex I is composed of 45 different subunits and contains noncovalently bound FMN and several iron-sulfur clusters as prosthetic groups. On the contrary, S. cerevisiae does not bear complex I but has rotenone-insensitive NADH-quinone oxidoreductases which are composed of a single subunit and FAD as cofactor and no iron-sulfur clusters. In mitochondria of certain fungi and plants, complex I and rotenone-insensitive NADH-quinone oxidoreductases coexist.

Bacterial NADH dehydrogenases

The NADH-quinone oxidoreductases of the bacterial respiratory chains can be divided into at least three groups (see TABLE). Those are the proton-translocating NADH-quinone oxidoreductase (NDH-1), the NADH-quinone oxidoreductase lacking an energy coupling site (NDH-2), and Na+-translocating NADH-quinone oxidoreductase (Na+-NDH). The NDH-1 is composed of 14 different subunits, suggesting that the NDH-1 has relatively simpler structure than complex I. It pumps protons from the cytosolic side to the periplasmic side. The NDH-2 is a single subunit enzyme and bears non-covalently bound FAD and has no iron-sulfur clusters similar to mitochondrial rotenone-insensitive NADH-quinone oxidoreductases. Na+-NDH is made up of 6 unlike subunits and contains two covalently bound FMN, one noncovalently bound FAD, one noncovalently bound riboflavin, and one binuclear iron-sulfur cluster. In terms of cofactors and specific inhibitors, NDH-1 is akin to complex I.



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