Evidence for chronic mitochondrial impairment in the cervical spinal cord of a murine model of motor neuron disease.

Profound alteration of the oxygen consumption rate (QO2) is present in the cervical spinal cord (CS) of the wobbler mice aged 12 weeks (wr12). Early symptomatic mice at 4 weeks (wr4) show less pronounced changes with decreases of basal QO2 (P < 0.03) and of QO2 through complex I (P < 0.04). Mitochondrial respiratory enzyme activities, measured spectrophotometrically in the CS homogenate, show no difference between wr12 and controls, whereas complex I is reduced in the wr4 CS (P < 0.0003). Complex I activity is lower than normal both in wr12 and wr4 CS when measured in motor neurons by mean of a histochemical technique. Electron microscopy (EM) reveals a mixture of normal and morphologically altered mitochondria in wr4 motor neurons. The wobbler lumbar spinal cord is spared even at 12 weeks. Our results demonstrate the presence of mitochondrial abnormalities in the wobbler CS since the first manifestations of the disease. Thus, chronic mitochondrial dysfunction has a contributory role in motor neuron degeneration in the wobbler disease.