Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease 
characterized by motor neuron loss and prominent skeletal muscle wasting. 
Despite more than one hundred years of research efforts, the pathogenic 
mechanisms underlying neuromuscular degeneration in ALS remain elusive. While 
the death of motor neuron is a defining hallmark of ALS, accumulated evidences 
suggested that in addition to being a victim of motor neuron axonal withdrawal, 
the intrinsic skeletal muscle degeneration may also actively contribute to ALS 
disease pathogenesis and progression. Examination of spinal cord and muscle 
autopsy/biopsy samples of ALS patients revealed similar mitochondrial 
abnormalities in morphology, quantity and disposition, which are accompanied by 
defective mitochondrial respiratory chain complex and elevated oxidative stress. 
Detailing the molecular/cellular mechanisms and the role of mitochondrial 
dysfunction in ALS relies on ALS animal model studies. This review article 
discusses the dysregulated mitochondrial Ca2+ and reactive oxygen species (ROS) 
signaling revealed in live skeletal muscle derived from ALS mouse models, and a 
potential role of the vicious cycle formed between the dysregulated 
mitochondrial Ca2+ signaling and excessive ROS production in promoting muscle 
wasting during ALS progression.