Children's toxicology from bench to bed--Liver Injury (4): Mitochondrial respiratory chain disorder and liver disease in children

J Toxicol Sci. 2009:34 Suppl 2:SP237-43. doi: 10.2131/jts.34.sp237.


Objectives: The present study was aimed to ascertain the contributions of mitochondrial respiratory chain (MRC) enzymes to the development of liver failure and to the liver pathophysiology of metabolic liver diseases.

Methods: We investigated liver samples obtained from 8 patients with liver failure due to unknown etiology and from 15 patients with metabolic disease: ornithine transcarbamylase deficiency, 6 cases; Wilson disease, 3 cases; metylmalonic aciduria (MMA); 3 cases, neonatal hemochromatosis, 2 cases. The estimation of MRC enzymes was carried out by the following independent methods; i) blue native polyacrylamide gel electrophoresis (BN-PAGE) in gel enzyme staining, ii) BN-PAGE western blotting, iii) in vitro MRC enzyme assay. Furthermore, we estimated the quantities of mtDNA and nDNA using qPCR.

Result: 4 cases with liver failure showed low activities and protein levels of complex I, III and IV. We also performed qPCR and estimated the ratio mtDNA/nDNA using these samples. They all exhibited extremely low ratio. They were diagnosed as mtDNA depletion syndrome. All cases except MMA cases exhibited mildly or moderately suppressed activities of complex I-IV. However, the respective protein levels remained almost normal. MMA cases exhibited low activities and protein levels of complex I, III and IV. In particular, their low activities and protein levels of complex I were noticeable. They all exhibited normal ratios of mtDNA to nDNA.

Conclusion: MRC defect might be an etiology of liver failure in a considerable number of patients in Japan. The present study suggested that considerable disturbance of MRC occurs in children with metabolic diseases and possibly modifies the pathophysiology.

MeSH terms

  • Child
  • DNA, Mitochondrial / metabolism
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex II / metabolism
  • Hemochromatosis / complications
  • Hepatolenticular Degeneration / complications
  • Humans
  • Infant
  • Infant, Newborn
  • Liver Failure / enzymology
  • Liver Failure / etiology*
  • Mevalonate Kinase Deficiency / complications
  • Mitochondrial Diseases / enzymology
  • Mitochondrial Diseases / etiology*
  • Ornithine Carbamoyltransferase Deficiency Disease / complications


  • DNA, Mitochondrial
  • respiratory complex II
  • Electron Transport Complex II
  • Electron Transport Complex I