Inhibition of complex I of the electron transport chain causes O2-. -mediated mitochondrial outgrowth.

TitleInhibition of complex I of the electron transport chain causes O2-. -mediated mitochondrial outgrowth.
Publication TypeJournal Article
Year of Publication2005
AuthorsKoopman, WJH, Verkaart, S, Visch, H-J, van der Westhuizen, FH, Murphy, MP, van den Heuvel, LWPJ, Smeitink, JAM, Willems, PHGM
JournalAm J Physiol Cell Physiol
Volume288
Issue6
PaginationC1440-50
Date Published2005 Jun
ISSN0363-6143
KeywordsCells, Cultured, Electron Transport, Electron Transport Complex I, Fibroblasts, Humans, Mitochondria, Rotenone, Skin, Superoxides, Uncoupling Agents
Abstract

Recent evidence indicates that oxidative stress is central to the pathogenesis of a wide variety of degenerative diseases, aging, and cancer. Oxidative stress occurs when the delicate balance between production and detoxification of reactive oxygen species is disturbed. Mammalian cells respond to this condition in several ways, among which is a change in mitochondrial morphology. In the present study, we have used rotenone, an inhibitor of complex I of the respiratory chain, which is thought to increase mitochondrial O(2)(-)* production, and mitoquinone (MitoQ), a mitochondria-targeted antioxidant, to investigate the relationship between mitochondrial O(2)(-)* production and morphology in human skin fibroblasts. Video-rate confocal microscopy of cells pulse loaded with the mitochondria-specific cation rhodamine 123, followed by automated analysis of mitochondrial morphology, revealed that chronic rotenone treatment (100 nM, 72 h) significantly increased mitochondrial length and branching without changing the number of mitochondria per cell. In addition, this treatment caused a twofold increase in lipid peroxidation as determined with C11-BODIPY(581/591). Finally, digital imaging microscopy of cells loaded with hydroethidine, which is oxidized by O(2)(-)* to yield fluorescent ethidium, revealed that chronic rotenone treatment caused a twofold increase in the rate of O(2)(-)* production. MitoQ (10 nM, 72 h) did not interfere with rotenone-induced ethidium formation but abolished rotenone-induced outgrowth and lipid peroxidation. These findings show that increased mitochondrial O(2)(-)* production as a consequence of, for instance, complex I inhibition leads to mitochondrial outgrowth and that MitoQ acts downstream of this O(2)(-)* to prevent alterations in mitochondrial morphology.

DOI10.1152/ajpcell.00607.2004
Alternate JournalAm. J. Physiol., Cell Physiol.
Citation Key10.1152/ajpcell.00607.2004
PubMed ID15647387