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Mitochondrial complex I: Structure, function and pathology

  • Review
  • Published:
Journal of Inherited Metabolic Disease

Summary

Oxidative phosphorylation (OXPHOS) has a prominent role in energy metabolism of the cell. Being under bigenomic control, correct biogenesis and functioning of the OXPHOS system is dependent on the finely tuned interaction between the nuclear and the mitochondrial genome. This suggests that disturbances of the system can be caused by numerous genetic defects and can result in a variety of metabolic and biochemical alterations. Consequently, OXPHOS deficiencies manifest as a broad clinical spectrum. Complex I, the biggest and most complicated enzyme complex of the OXPHOS system, has been subjected to thorough investigation in recent years. Significant progress has been made in the field of structure, composition, assembly, and pathology. Important gains in the understanding of the Goliath of the OXPHOS system are: exposing the electron transfer mechanism and solving the crystal structure of the peripheral arm, characterization of almost all subunits and some of their functions, and creating models to elucidate the assembly process with concomitant identification of assembly chaperones. Unravelling the intricate mechanisms underlying the functioning of this membrane-bound enzyme complex in health and disease will pave the way for developing adequate diagnostic procedures and advanced therapeutic treatment strategies.

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Abbreviations

ACP:

acyl carrier protein

ADP:

adenosine 5′-diphosphate

ATP:

adenosine 5′-triphosphate

cyt c :

cytochrome c

EPR:

electron paramagnetic resonance

EPR:

electron paramagnetic resonance

ESI-MS:

electrospray ionization mass spectrometry

FMN:

flavin mononucleotide

GRIM:

gene associated with retinoid-interferon-induced mortality

HPLC:

high-pressure liquid chromatography

IEF:

isoelectric focusing

LDAO:

lauryldimethylamine oxide (N,N-dimethyldodecylamine N-oxide)

LHON:

Leber hereditary optic neuropathy

MELAS:

mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes

MERRF:

myoclonus epilepsy and ragged red fibres

mtDNA:

mitochondrial DNA

nDNA:

nuclear DNA

OXPHOS:

oxidative phosphorylation

Q:

ubiquinone

ROS:

reactive oxygen species

SDS-PAGE:

sodium dodecyl sulfate–polyacrylamide gel electrophoresis

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Authors and Affiliations

  1. Nijmegen Centre for Mitochondrial Disorders, Laboratory of Paediatrics and Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Rolf J. R. J. Janssen, Leo G. Nijtmans, Lambert P. van den Heuvel & Jan A. M. Smeitink

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  1. Rolf J. R. J. Janssen
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  2. Leo G. Nijtmans
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  3. Lambert P. van den Heuvel
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  4. Jan A. M. Smeitink
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Correspondence to Jan A. M. Smeitink.

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Communicating editor: John Christodoulou

Competing interests: None declared

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Janssen, R.J.R.J., Nijtmans, L.G., Heuvel, L.P.v.d. et al. Mitochondrial complex I: Structure, function and pathology. J Inherit Metab Dis 29, 499–515 (2006). https://doi.org/10.1007/s10545-006-0362-4

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  • DOI: https://doi.org/10.1007/s10545-006-0362-4

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