Journal Article

Mitochondrial complex I deficiency: from organelle dysfunction to clinical disease

Felix Distelmaier, Werner J.H. Koopman, Lambertus P. van den Heuvel, Richard J. Rodenburg, Ertan Mayatepek, Peter H.G.M. Willems and Jan A.M. Smeitink

in Brain

Published on behalf of The Guarantors of Brain

Volume 132, issue 4, pages 833-842
Published in print April 2009 | ISSN: 0006-8950
Published online March 2009 | e-ISSN: 1460-2156 | DOI:
Mitochondrial complex I deficiency: from organelle dysfunction to clinical disease

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Mitochondria are essential for cellular bioenergetics by way of energy production in the form of ATP through the process of oxidative phosphorylation. This crucial task is executed by five multi-protein complexes of which mitochondrial NADH:ubiquinone oxidoreductase or complex I is the largest and most complicated one. During recent years, mutations in nuclear genes encoding structural subunits of complex I have been identified as a cause of devastating neurodegenerative disorders with onset in early childhood. Here, we present a comprehensive overview of clinical, biochemical and cell physiological information of 15 children with isolated, nuclear-encoded complex I deficiency, which was generated in a joint effort of clinical and fundamental research. Our findings point to a rather homogeneous clinical picture in these children and drastically illustrate the severity of the disease. In extensive live cell studies with patient-derived skin fibroblasts we uncovered important cell physiological aspects of complex I deficiency, which point to a central regulatory role of cellular reactive oxygen species production and altered mitochondrial membrane potential in the pathogenesis of the disorder. Moreover, we critically discuss possible interconnections between clinical signs and cellular pathology. Finally, our results indicate apparent differences to drug therapy on the cellular level, depending on the severity of the catalytic defect and identify modulators of cellular Ca2+ homeostasis as new candidates in the therapy of complex I deficiency.

Keywords: NADH:ubiquinone oxidoreductase deficiency; Leigh disease; ATP production; reactive oxygen species; treatment

Journal Article.  6255 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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