Mitochondrial respiratory chain dysfunction in muscle from patients with amyotrophic lateral sclerosis

Arch Neurol. 2010 Jul;67(7):849-54. doi: 10.1001/archneurol.2010.128.


Background: Amyotrophic lateral sclerosis (ALS) is a major cause of neurological disability and its pathogenesis remains elusive despite a multitude of studies. Although defects of the mitochondrial respiratory chain have been described in several ALS patients, their pathogenic significance is unclear.

Objective: To review systematically the muscle biopsy specimens from patients with typical sporadic ALS to search for possible mitochondrial oxidative impairment.

Design: Retrospective histochemical, biochemical, and molecular studies of muscle specimens.

Setting: Tertiary care university. Subjects Fifty patients with typical sporadic ALS (mean age, 55 years). Main Outcome Measure Number of patients showing a clear muscle mitochondrial dysfunction assessed through histochemical and biochemical muscle analysis.

Results: Histochemical data showed cytochrome c oxidase (COX)-negative fibers in 46% patients. Based on COX histochemical activity, patients fell into 4 groups: 27 had normal COX activity; and 8 had mild (2-4 COX-negative fibers of 100 fibers), 8 had moderate (5-10 COX-negative fibers of 100), and 7 had severe (>10 COX-negative fibers of 100) COX deficiency. Spectrophotometric measurement of respiratory chain activities showed that 3 patients with severe histochemical COX deficiency also showed combined enzyme defects. In 1 patient, COX deficiency worsened in a second biopsy taken 9 months after the first. Among the patients with severe COX deficiency, one had a new mutation in the SOD1 gene, another a mutation in the TARDBP gene, and a third patient with biochemically confirmed COX deficiency had multiple mitochondrial DNA deletions detectable by Southern blot analysis.

Conclusions: Our data confirm that the histochemical finding of COX-negative fibers is common in skeletal muscle from patients with sporadic ALS. We did not find a correlation between severity of the oxidative defect and age of the patients or duration of the disease. However, the only patient who underwent a second muscle biopsy did show a correlation between severity of symptoms and worsening of the respiratory chain defect. In 7 patients, the oxidative defect was severe enough to support the hypothesis that mitochondrial dysfunction must play a role in the pathogenesis of the disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / complications*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology*
  • DNA, Mitochondrial / genetics
  • Electron Transport
  • Electron Transport Complex IV / metabolism
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mitochondria, Muscle / metabolism
  • Mitochondria, Muscle / pathology*
  • Mitochondria, Muscle / ultrastructure
  • Mitochondrial Diseases / etiology*
  • Mitochondrial Diseases / genetics
  • Spectrophotometry / methods
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase-1
  • Young Adult


  • DNA, Mitochondrial
  • SOD1 protein, human
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Electron Transport Complex IV