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1 160 Biochemistry NCMLS, Radboud University Nijmegen Medical Centre, Nijmegen, GLD, The Netherlands
* To whom correspondence should be addressed. E-mail: w.koopman{at}ncmls.ru.nl.
Complex I (NADH:ubiquinone oxidoreductase) is the largest multisubunit assembly of the OXPHOS system and its malfunction is associated with a wide variety of clinical syndromes ranging from highly progressive, often early lethal, encephalopathies to neurodegenerative disorders in adult life. The changes in mitochondrial structure and function, which are at the basis of the clinical symptoms, are poorly understood. Video-rate confocal microscopy of cells pulse-loaded with mitochondria-specific rhodamine 123 followed by automated analysis of formfactor (combined measure of length and degree of branching), aspect ratio (measure of length) and number revealed marked differences between primary cultures of skin fibroblasts from 13 patients with an isolated complex I deficiency. These differences were independent of the affected subunit but plotting of the activity of complex I, normalized for that of complex IV, against the ratio of either formfactor or aspect ratio to number revealed a linear relationship. Relatively small reductions in activity were associated with an increase in formfactor and never with a decrease in number, whereas relatively large reductions occurred in association with a decrease in formfactor and/or an increase in number. These results demonstrate that complex I activity and mitochondrial structure are tightly coupled in human complex I deficiency. To prove further the relationship between aberrations in mitochondrial morphology and pathological condition, fibroblasts from two patients with a different mutation but a highly fragmented mitochondrial phenotype were fused. Full restoration of the mitochondrial network demonstrated that this change in mitochondrial morphology was indeed associated with human complex I deficiency.
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