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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily motor neurons. Growing evidence suggests a mitochondrial defect in ALS. The precise molecular mechanisms underlying those defects are unknown. We studied the expression of mitochondrial uncoupling proteins (UCPs), key regulators of mitochondrial functions, in tissues from a mouse model of ALS (SOD1 G86R transgenic mice) and from muscular biopsies of human sporadic ALS. Surprisingly, in SOD1 G86R mice, UCPs, and particularly UCP3, were upregulated in skeletal muscle but not in spinal cord. Consistent with this pattern of expression, ATP levels were selectively depleted in muscle but not in neural tissues 1 month before disease onset and the respiratory control ratio of isolated mitochondria is decreased. UCP3 up‐regulation was not observed in experimentally denervated muscles, suggesting that changes in …