Secondary metabolic effects in complex I deficiency

Ann Neurol. 2005 Oct;58(4):544-52. doi: 10.1002/ana.20570.


The objective of this study was to investigate clinical, biochemical, and genetic features in 7 probands (a total of 11 patients) with nicotine-amide adenine dinucleotide (NADH) dehydrogenase (complex I) deficiency. We screened the mitochondrial DNA for mutations and found pathogenic mutations in complex I genes (mitochondrial NADH dehydrogenase subunit (MTND) genes) in three probands. The 10191T>C mutation in MTND3 and the 14487T>C mutation in MTND6 were present in two probands with Leigh's-like and Leigh's syndrome, respectively. Four siblings with a syndrome consisting of encephalomyopathy with hearing impairment, optic nerve atrophy, and cardiac involvement had the 11778G>A mutation in MTND4, previously associated with Leber hereditary optic neuropathy. These findings demonstrate that mutations in MTND genes are relatively frequent in patients with complex I deficiency. Biochemical measurements of respiratory chain function in muscle mitochondria showed that all patients had a moderate decrease of the mitochondrial adenosine triphosphate production rate. Interestingly, the complex I deficiency caused secondary metabolic alterations with decreased oxaloacetate-induced inhibition of succinate dehydrogenase (complex II) and excretion of Krebs cycle intermediates in the urine. Our results thus suggest that altered regulation of metabolism may play an important role in the pathogenesis of complex I deficiency.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adolescent
  • Adult
  • Blotting, Western / methods
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • Electron Transport Complex I / deficiency*
  • Electron Transport Complex I / genetics*
  • Female
  • Humans
  • Infant
  • Male
  • Metabolism, Inborn Errors* / genetics
  • Metabolism, Inborn Errors* / metabolism
  • Metabolism, Inborn Errors* / physiopathology
  • Models, Biological
  • Mutation*
  • NADH Dehydrogenase / genetics*
  • NADH Dehydrogenase / metabolism
  • Threonine / genetics


  • DNA, Mitochondrial
  • Threonine
  • Adenosine Triphosphate
  • NADH Dehydrogenase
  • Electron Transport Complex I