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

Werner J.H. Koopman, Sjoerd Verkaart, Henk Jan Visch, Francois H. Van Der Westhuizen, Michael P. Murphy, Lambertus W.P.J. Van Den Heuvel, Jan A.M. Smeitink, Peter H.G.M. Willems*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

259 Citations (Scopus)

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 O2-. 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 O2-. to yield fluorescent ethidium, revealed that chronic rotenone treatment caused a twofold increase in the rate of O2-. 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 O2-. production as a consequence of for instance, complex I inhibition leads to mitochondrial outgrowth and that MitoQ acts downstream of this O2-. to prevent alterations in mitochondrial morphology.

Original languageEnglish
Pages (from-to)C1440-C1450
JournalAmerican Journal of Physiology - Cell Physiology
Volume288
Issue number6 57-6
DOIs
Publication statusPublished - Jun 2005
Externally publishedYes

Keywords

  • MitoQ
  • Rhodamine 123
  • Superoxide
  • Video-rate confocal microscopy

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