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

Veronica Crugnola, Costanza Lamperti, Valeria Lucchini, Dario Ronchi, Lorenzo Peverelli, Alessandro Prelle, Monica Sciacco, Andreina Bordoni, Elisa Fassone, Francesco Fortunato, Stefania Corti, Vincenzo Silani, Nereo Bresolin, Salvatore Di Mauro, Giacomo Pietro Comi, Maurizio Moggio

Research output: Contribution to journalArticlepeer-review


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 datashowedcytochrome c oxidase (COX) - negative fibers in46%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),and7hadsevere (>10COX-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 taken9monthsafter the first.Amongthe patients with severe COX deficiency, one had anewmutation in the SOD1 gene, another a mutation in theTARDBP 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.

Original languageEnglish
Pages (from-to)849-854
Number of pages6
JournalArchives of Neurology
Issue number7
Publication statusPublished - Jul 2010

ASJC Scopus subject areas

  • Clinical Neurology


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