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Human Molecular Genetics Advance Access originally published online on January 28, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 6 659-667
DOI: 10.1093/hmg/ddh071

Differences in assembly or stability of complex I and other mitochondrial OXPHOS complexes in inherited complex I deficiency

Cristina Ugalde{dagger}, Rolf J.R.J. Janssen{dagger}, Lambert P. van den Heuvel, Jan A.M. Smeitink* and Leo G.J. Nijtmans

Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands

Received November 19, 2003; Revised December 18, 2003; Accepted January 23, 2004

NADH–ubiquinone oxidoreductase (complex I) deficiency is amongst the most encountered defects of the mitochondrial oxidative phosphorylation (OXPHOS) system and is associated with a wide variety of clinical signs and symptoms. Mutations in complex I nuclear structural genes are the most common cause of isolated complex I enzyme deficiencies. The cell biological consequences of such mutations are poorly understood. In this paper we have used blue native electrophoresis in order to study how different nuclear mutations affect the integrity of mitochondrial OXPHOS complexes in fibroblasts from 15 complex I-deficient patients. Our results show an important decrease in the levels of intact complex I in patients harboring mutations in nuclear-encoded complex I subunits, indicating that complex I assembly and/or stability is compromised. Different patterns of low molecular weight subcomplexes are present in these patients, suggesting that the formation of the peripheral arm is affected at an early assembly stage. Mutations in complex I genes can also affect the stability of other mitochondrial complexes, with a specific decrease of fully-assembled complex III in patients with mutations in NDUFS2 and NDUFS4. We have extended this analysis to patients with an isolated complex I deficiency in which no mutations in structural subunits have been found. In this group, we can discriminate between complex I assembly and catalytic defects attending to the fact whether there is a correlation between assembly/activity levels or not. This will help us to point more selectively to candidate genes for pathogenic mutations that could lead to an isolated complex I defect.

* To whom corresponce should be addressed. Tel: +31 243614430; Fax: +31 243616428; Email: j.smeitink{at}cukz.umcn.nl


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