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1 Radboud University Medical Centre Nijmegen, 286 Membrane Biochemistry NCMLS, Radboud University Medical Centre Nijmegen, Nijmegen, Gld, Netherlands
2 286 Membrane Biochemistry NCMLS, Radboud University Medical Centre Nijmegen, Nijmegen, Gld, Netherlands; Paediatrics NCMD, Radboud University Medical Centre Nijmegen, Nijmegen, Gld, Netherlands
3 286 Membrane Biochemistry NCMLS, Radboud University Medical Centre Nijmegen, Nijmegen, Gld, Netherlands; Nijmegen, Gld, Netherlands
4 Paediatrics NCMD, Radboud University Medical Centre Nijmegen, Nijmegen, Gld, Netherlands
5 Nijmegen, Gld, Netherlands; Paediatrics NCMD, Radboud University Medical Centre Nijmegen, Nijmegen, Gld, Netherlands
* To whom correspondence should be addressed. E-mail: p.willems{at}ncmls.ru.nl.
Malfunction of NADH:ubiquinone oxidoreductase or complex I (CI), the first and largest complex of the mitochondrial oxidative phosphorylation system, has been implicated in a wide variety of human disorders. To demonstrate a quantitative relationship between CI amount and activity and mitochondrial shape and cellular reactive oxygen species (ROS) levels, we recently combined native electrophoresis and confocal and video microscopy of dermal fibroblasts of healthy control subjects and children with isolated CI deficiency. Individual mitochondria appeared fragmented and/or less branched in patient fibroblasts with a severely reduced CI amount and activity (class I), whereas patient cells in which these latter parameters were only moderately reduced displayed a normal mitochondrial morphology (class II). Moreover, cellular ROS levels were significantly more increased in class I as compared to class II cells. We propose a mechanism in which a mutation-induced decrease in the cellular amount and activity of CI leads to enhanced ROS levels, which in turn induce mitochondrial fragmentation when not appropriately counterbalanced by the cells antioxidant defense systems.
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