title: Mitochondrial respiratory chain dysfunction in muscle from patients with amyotrophic lateral sclerosis.
abstract: 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.
  
  
  METHODS
  Retrospective histochemical, biochemical, and molecular studies of muscle specimens.
  
  
  METHODS
  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.
authors.affiliation: Department of Neurological Sciences, "Dino Ferrari" Center, Università degli Studi di Milano, Scientific Institute for Research and Treatment Foundation Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena, Milan, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Crugnola
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.forename: Valeria
authors.initials: V
authors.lastname: Lucchini
authors.forename: Dario
authors.initials: D
authors.lastname: Ronchi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Peverelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prelle
authors.forename: Monica
authors.initials: M
authors.lastname: Sciacco
authors.forename: Andreina
authors.initials: A
authors.lastname: Bordoni
authors.forename: Elisa
authors.initials: E
authors.lastname: Fassone
authors.forename: Francesco
authors.initials: F
authors.lastname: Fortunato
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Silani
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Salvatore
authors.initials: S
authors.lastname: Di Mauro
authors.forename: Giacomo Pietro
authors.initials: GP
authors.lastname: Comi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D004272:DNA, Mitochondrial / Q000235:genetics; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000209:etiology* / Q000235:genetics; D013053:Spectrophotometry / Q000379:methods; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003576:Electron Transport Complex IV