Respiratory chain NADH:quinone oxidoreductase (or Complex I)

• Cecilia Hägerhäll
• Sindra Peterson Årsköld

Complex I, or NADH:quinone oxidoreductase, is the largest and by far the least understood enzyme in the respiratory chain. The classical Complex I enzyme is composed of seven membrane-spanning protein subunits and seven protein subunits protruding into the cytoplasm (in bacteria) or into the mitochondrial matrix (in eukaryotes). Complex I from eukaryotes also contain up to 32 additional accessory subunits. The NADH binding site, FMN and eight FeS clusters are located in the promontory part, whereas the seven membrane-spanning proteins are all encoded by mitochondrial DNA in eukaryotes, in fact the Complex I encoding genes make up half of the mtDNA in mammals. This results in that Complex I is both a victim of free radical damage and a main culprit in generating such radicals. Defect Complex I is associated with many degenerative diseases, and thus further understanding of Complex I is of great medical importance.

A major breakthrough in Complex I research occurred recently when Leonid Sazanovs group in the UK succeeded in crystallizing the water-soluble half of the enzyme (see Figure and Science 311: 1430-1436). We want to elucidate the molecular details of the energy coupling mechanism of Complex I and thus our research is largely focused on the membrane-spanning part of the enzyme, that must harbour essential parts of the proton pumping machinery. We are mainly working on two outstanding issues that must be solved to  understanding the functional mechanism: 1) determining the number and location of quinone binding sites, and 2) understanding the role of the three antiporter-like membrane spanning protein subunits (denoted L, M and N in the Figure) that harbor the ion conducting pathways used in energy conservation. We have also taken an interest in the evolution of the enzyme as means to understand its present day function.  A small Complex I , consisting of only 11 protein subunits, is investigated to learn more about the role of individual parts.

Find out more about Complex I, and the people working on this topic at

The Complex I web page