Mitochondrial respiratory chain dysfunction in muscle from patients with amyotrophic lateral sclerosis.
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.
Crugnola
Veronica
V
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.
Lamperti
Costanza
C
Lucchini
Valeria
V
Ronchi
Dario
D
Peverelli
Lorenzo
L
Prelle
Alessandro
A
Sciacco
Monica
M
Bordoni
Andreina
A
Fassone
Elisa
E
Fortunato
Francesco
F
Corti
Stefania
S
Silani
Vincenzo
V
Bresolin
Nereo
N
Di Mauro
Salvatore
S
Comi
Giacomo Pietro
GP
Moggio
Maurizio
M
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
D004272:DNA, Mitochondrial; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003576:Electron Transport Complex IV