Exercise intolerance and developmental delay associated with a novel mitochondrial ND5 mutation

Sci Rep. 2015 May 27;5:10480. doi: 10.1038/srep10480.


The aim of this study was to evaluate the contribution of mitochondrial DNA (mtDNA) mutations in oxidative phosphorylation (OXPHOS) deficiency. The complete mitochondrial genomes of 41 families with OXPHOS deficiency were screened for mutations. Mitochondrial functional analysis was then performed in primary and cybrid cells containing candidate mutations identified during the screening. A novel mitochondrial NADH dehydrogenase 5 (ND5) m.12955A > G mutation was identified in a patient with exercise intolerance and developmental delay. A biochemical analysis revealed deficiencies in the activity of complex I (NADH:quinone oxidoreductase) and IV (cytochrome c oxidase) of this patient. Defects in complexes I and IV were confirmed in transmitochondrial cybrid cells containing the m.12955A > G mutation, suggesting that this mutation impairs complex I assembly, resulting in reduced stability of complex IV. Further functional investigations revealed that mitochondria with the m.12955A > G mutation exhibited lower OXPHOS coupling respiration and adenosine triphosphate (ATP) generation. In addition, the cytotoxic effects, determined as reactive oxygen species (ROS) and lactate levels in the present study, increased in the cells carrying a higher m.12955A > G mutant load. In conclusion, we identified m.12955A > G as a mitochondrial disease-related mutation. Therefore, screening of m.12955A > G is advised for the diagnosis of patients with mitochondrial disease.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Base Sequence
  • Brain / diagnostic imaging
  • Child
  • Electron Transport Chain Complex Proteins / metabolism
  • Electron Transport Complex I / genetics*
  • Electron Transport Complex I / metabolism
  • Exercise
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Mitochondria / metabolism*
  • Mitochondrial Diseases / diagnosis*
  • Mitochondrial Diseases / genetics
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Mutation, Missense
  • Oxidative Phosphorylation
  • Oxygen Consumption
  • Pedigree
  • Radiography
  • Reactive Oxygen Species / metabolism
  • Real-Time Polymerase Chain Reaction


  • Electron Transport Chain Complex Proteins
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • Adenosine Triphosphate
  • MT-ND5 protein, human
  • Electron Transport Complex I