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1 Pediatrics, NCMD Radboud University, Nijmegen, The Netherlands
2 160 Biochemistry, NCMLS Radboud University Nijmegen, Nijmegen, The Netherlands; Pediatrics, NCMD Radboud University, Nijmegen, The Netherlands
3 Pediatrics, NCMD Radboud University, Nijmegen, The Netherlands; School for Chemistry and Biochemistry, PUCHE, Potchefstroom, South Africa
4 Human Nutrition Unit, MRC Dunn, Cambridge, United Kingdom
5 160 Biochemistry, NCMLS Radboud University Nijmegen, Nijmegen, The Netherlands
* To whom correspondence should be addressed. E-mail: w.koopman{at}ncmls.ru.nl.
Mammalian cells respond to oxidative stress in several ways, among which is a change in mitochondrial morphology. The mechanism underlying this response is still elusive. Here we use rotenone, an inhibitor of complex I of the respiratory chain, which is thought to increase mitochondrial superoxide production, and MitoQ, a mitochondria-targeted antioxidant, to investigate the relationship between mitochondrial superoxide production and morphology change in human skin fibroblasts. Video-rate confocal microscopy of cells pulse-loaded with the mitochondria-specific cation rhodamine 123 (200 µM, 40 seconds) followed by automated analysis of mitochondrial morphology revealed that chronic rotenone treatment (100 nM, 72 hours) caused a significant increase in mitochondrial length and branching without changing the number of mitochondria per cell. Chronic rotenone treatment also caused a 2-fold increase in the extent of lipid peroxidation as was determined by video-rate confocal microscopy of cells loaded with the lipid peroxidation reporter C11-BODIPY581/591 (4 µM, 30 minutes). Finally, digital imaging microscopy of cells loaded with hydroethidine (10 µM, 10 minutes), which is oxidized by superoxide to yield fluorescent ethidium, revealed that chronic rotenone treatment caused a 2-fold increase in the rate of superoxide production. MitoQ (10 nM, 72 hours) did not interfere with rotenone-induced ethidium formation but abolished rotenone-induced outgrowth and lipid peroxidation. These findings show that increased mitochondrial superoxide production as a consequence of, for instance, complex I inhibition leads to mitochondrial outgrowth and that MitoQ acts downstream of this oxygen radical to prevent alterations in mitochondrial morphology.
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