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Generation of Reactive Oxygen Species by Mitochondrial Complex I: Implications in Neurodegeneration

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Abstract

Mitochondrial Complex I [NADH Coenzyme Q (CoQ) oxidoreductase] is the least understood of respiratory complexes. In this review we emphasize some novel findings on this enzyme that are of relevance to the pathogenesis of neurodegenerative diseases. Besides CoQ, also oxygen may be an electron acceptor from the enzyme, with generation of superoxide radical in the mitochondrial matrix. The site of superoxide generation is debated: we present evidence based on the rational use of several inhibitors that the one-electron donor to oxygen is an iron-sulphur cluster, presumably N2. On this assumption we present a novel mechanism of electron transfer to the acceptor, CoQ. Complex I is deeply involved in pathological changes, including neurodegeneration. Complex I changes are involved in common neurological diseases of the adult and old ages. Mitochondrial cytopathies due to mutations of either nuclear or mitochondrial DNA may represent a useful model of neurodegeneration. In this review we discuss Parkinson’s disease, where the pathogenic involvement of Complex I is better understood; the accumulated evidence on the mode of action of Complex I inhibitors and their effect on oxygen radical generation is discussed in terms of the aetiology and pathogenesis of the disease.

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Abbreviations

CoQ (Q):

Coenzyme Q ubiquinone

Cyt. c:

Cytochrome c

EPR:

Electron paramagnetic resonance

FeS:

Iron-sulphur cluster

GPx :

Glutathione peroxidase

DA:

Dopamine

DCIP:

Dichlorophenol indophenol

DPI:

Diphenylene iodonium

Gpx :

Glutathione peroxidase

LB:

Lewy bodies

LHON:

Leber’s hereditary optic neuropathy

MPP+ :

1-Methyl-4-phenylpyridinium

MPTP:

1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine

PD:

Parkinson’s disease

PTP:

Permeability transition pore

ROS:

Reactive oxygen species

SMP:

Submitochondrial particles

SN:

Substantia nigra

SOD:

Superoxide dismutase

α-syn:

α-Synuclein

UCP:

Uncoupling protein

VDAC:

Voltage-dependent anion channel

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Acknowledgements

The experimental work from our laboratory, which has been reported in this paper, was supported by MIUR-Rome (Italy).

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Correspondence to Giorgio Lenaz.

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Special issue article in honor of Dr. Anna Maria Giuffrida-Stella.

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Fato, R., Bergamini, C., Leoni, S. et al. Generation of Reactive Oxygen Species by Mitochondrial Complex I: Implications in Neurodegeneration. Neurochem Res 33, 2487–2501 (2008). https://doi.org/10.1007/s11064-008-9747-0

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