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CELLULAR METABOLISM

Inhibition of complex I of the electron transport chain causes O₂^–·-mediated mitochondrial outgrowth

¹Microscopical Imaging Center and ²Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, and ³Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen, The Netherlands; and ⁴Medical Research Council Dunn Human Nutrition Unit, Cambridge, United Kingdom

Submitted 10 December 2004 ; accepted in final form 10 January 2005

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 O₂^–· 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.

rhodamine 123; video-rate confocal microscopy; superoxide; MitoQ

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