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Clinical Chemistry 52: 860-871, 2006. First published March 16, 2006; 10.1373/clinchem.2005.062414
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(Clinical Chemistry. 2006;52:860-871.)
© 2006 American Association for Clinical Chemistry, Inc.

Endocrinology and Metabolism

Measurement of the Energy-Generating Capacity of Human Muscle Mitochondria: Diagnostic Procedure and Application to Human Pathology

Antoon J.M. Janssen1, Frans J.M. Trijbels1, Rob C.A. Sengers1, Liesbeth T.M. Wintjes1, Wim Ruitenbeek1, Jan A.M. Smeitink1, Eva Morava1, Baziel G.M. van Engelen2, Lambert P. van den Heuvel1 and Richard J.T. Rodenburg1,a

1 Department of Pediatrics and Laboratory of Pediatrics and Neurology, the Nijmegen Centre for Mitochondrial Disorders (NCMD), and 2 Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

aAddress correspondence to this author at: Laboratory of Pediatrics and Neurology, UMC St. Radboud, Geert Grooteplein zuid 10, 6525 GA Nijmegen, The Netherlands. Fax 31-24-3618900; e-mail R.Rodenburg{at}cukz.umcn.nl.

Background: Diagnosis of mitochondrial disorders usually requires a muscle biopsy to examine mitochondrial function. We describe our diagnostic procedure and results for 29 patients with mitochondrial disorders.

Methods: Muscle biopsies were from 43 healthy individuals and 29 patients with defects in one of the oxidative phosphorylation (OXPHOS) complexes, the pyruvate dehydrogenase complex (PDHc), or the adenine nucleotide translocator (ANT). Homogenized muscle samples were used to determine the oxidation rates of radiolabeled pyruvate, malate, and succinate in the absence or presence of various acetyl Co-A donors and acceptors, as well as specific inhibitors of tricarboxylic acid cycle or OXPHOS enzymes. We determined the rate of ATP production from oxidation of pyruvate.

Results: Each defect in the energy-generating system produced a specific combination of substrate oxidation impairments. PDHc deficiencies decreased substrate oxidation reactions containing pyruvate. Defects in complexes I, III, and IV decreased oxidation of pyruvate plus malate, with normal to mildly diminished oxidation of pyruvate plus carnitine. In complex V defects, pyruvate oxidation improved by addition of carbonyl cyanide 3-chlorophenyl hydrazone, whereas other oxidation rates were decreased. In most patients, ATP production was decreased.

Conclusion: The proposed method can be successfully applied to the diagnosis of defects in PDHc, OXPHOS complexes, and ANT.




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