Chapter 1
The energy-transducing NADH: quinone oxidoreductase, complex I

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Abstract

The energy-transducing NADH: quinone (Q) oxidoreductase (complex I) is the largest and most complicated enzyme complex in the oxidative phosphorylation system. Complex I is a redox pump that uses the redox energy to translocate H+ (or Na+) ions across the membrane, resulting in a significant contribution to energy production. The need to elucidate the molecular mechanisms of complex I has greatly increased. Many devastating neurodegenerative disorders have been associated with complex I deficiency. The structural and functional complexities of complex I have already been established. However, intricate biogenesis and activity regulation functions of complex I have just been identified. Based upon these recent developments, it is apparent that complex I research is entering a new era. The advancement of our knowledge of the molecular mechanism of complex I will not only surface from bioenergetics, but also from many other fields as well, including medicine. This review summarizes the current status of our understanding of complex I and sheds light on new theories and the future direction of complex I studies.

Section snippets

Complex I in the oxidative phosphorylation system

NADH: ubiquinone oxidoreductase (EC 1.6.5.3), complex I, is a large and very complicated membrane-bound multi-subunit enzyme complex that plays an important role in energy production by the mitochondrial oxidative phosphorylation system (OXPHOS) (Fig. 1(a)). Complex I is located at an entry point of the electron transport chain and initiates electron transfer by oxidizing NADH and the electrons are transferred to a lipid-soluble electron carrier quinone (coenzyme Q) as an electron acceptor.NADH+

Overall structure – two distinct domains and different functions

A high-resolution 3D structure of complex I remains to be determined. Currently, low-resolution structure electron microscopic images of complex I from several sources are available (Guènebaut et al., 1997; Grigorieff, 1998; Guènebaut et al., 1998; Djafarzadeh et al., 2000). Complex I appears to have an “L-shape” and this unique figure is conserved between eukaryote and prokaryote complex I. The enzyme is made of two major parts: a hydrophilic promontory (peripheral) part extruding from the

Kinetic measurements

As has been frequently mentioned, it is difficult to accurately assess the activity of complex I (Lenaz, 1998; Vinogradov, 1998). Complex I activity is generally measured using Q analogues such as UQ-1, UQ-2, or DB as a substrate of endogenous electron acceptors. However, most of these Q analogues accept electrons from non-physiological sites and NADH: quinone oxidoreductase and proton pump activities are different from one Q analogue to another (Degli Esposti et al., 1996). The paucity of

Evolution of complex I: new insights into the structure and function relationship

A rapidly growing genomic sequence database is a valuable source of information and has provided new insight into the structure–function relationship of complex I. A striking similarity of complex I family to the [NiFe] hydrogenases was found, suggesting that they share a common ancestor. Based upon exhaustive sequence analyses, Friedrich and his co-workers proposed an evolutionary scheme of complex I (Friedrich and Weiss, 1997; Friedrich and Scheide, 2000). The “Modular evolution hypothesis”

Energy-coupling mechanism

The mechanism by which complex I utilizes the redox energy to translocate cations such as H+ or Na+ ions across the membrane is still unknown. To date, several energy-coupling hypotheses have been proposed for complex I (Mitchell, 1966; Ohnishi and Salerno, 1982; Krishnamoorthy and Hinkle, 1988; Ragan, 1990; Weiss and Friedrich, 1991; Vinogradov, 1993; Degli Esposti and Ghelli, 1994; Brandt, 1997, Brandt, 1999; Dutton et al., 1998). Recent models proposed by Brandt and by Dutton et al. assume

Neurodegenerative disease associates with complex I

A number of devastating neurodegenerative disorders have been found in connection with the defects of OXPHOS. Considering the fact that neurons demand a large amount of energy for their normal functions, decline of the energy production system considerably affects the ability of the nervous systems to function properly. Isolated complex I deficiency is the most common enzyme defect among the groups of OXPHOS abnormality (Bourgeron et al., 1995). Leigh syndrome or Leigh-like diseases are the

Concluding remarks

Recently, fundamental importance of mitochondrial functions has been re-recognized in many aspects (Skulachev, 1999). As described in this review, it is evident that elucidation of complex I function is of significant importance to improve our understanding of life processes. The field of complex I research has been steadily expanding as exemplified by the exponentially increasing number of publications in the last several years. I would like to stress that there are many topics related to

Acknowledgements

I would like to thank Prof. Tomoko Ohnishi for her encouragement and support. I am thankful to Prof. Fevzi Daldal for his critical comments on the manuscript. This is supported by NIH grant (RO1GM30736 to T. Ohnishi).

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