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

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.

Mammalian Mitochondrial Complex I: Biogenesis, Regulation, and Reactive Oxygen Species Generation

“…In addition, they are a continuous source of reactive oxygen species (ROS) (4,5,31,35,73,74,83,89,113,133,154,187,211,212,282,286).…”

Annonacin induces cell cycle-dependent growth arrest and apoptosis in estrogen receptor-α-related pathways in MCF-7 cells

“…Breast epithelial cell-specific overexpression of cyclin D1 induces breast cancer in mice, while cyclin D1-null mice are resistant to oncogene-induced breast cancer (Butt et al, 2008). Moreover, inhibition of Bcl-2 in combination with chemotherapy was effective in some breast cancer patients in a clinical trial (Fato et al, 2008).…”

Anticancer Drugs Targeting the Mitochondrial Electron Transport Chain

“…It is not known precisely how the superoxide is formed, but the flavin group, the N2 iron sulfur cluster and the UbQ binding sites have each been suggested to participate in the process (17,68,86,110,111,113). The basal level of superoxide production from CI is dramatically increased either due to retrograde electron transport or inhibition of CI.…”