Mitochondria, motor neurons and aging.

While the role of mitochondria in aging has been well characterized, their involvement in motor neuron aging remains poorly understood. Thus, we performed an exhaustive ultrastructural study of mitochondria in motor neurons from aged rats that revealed dramatic alterations in the mitochondria of axon terminals at neuromuscular junctions, characterized by swelling, mitochondrial fusion and the presence of megamitochondria. These alterations were not observed in ventral horn motor neurons in the spinal cord of aged rats, which were only altered by the appearance of electron-dense bodies in the dilated matrix cristae. Using X-ray microanalytical techniques we demonstrated the presence of calcium in these bodies, suggesting Ca(2+) overload. Moreover, in motor neurons from aged rats, cytochrome c and activated caspase 3 were detected in the cytoplasm of axon terminals at neuromuscular junctions, factors implicated in the apoptosis. Active caspase 3 was also found in the nucleus, soma and axons of aged alpha motor neuron neurons, where it mainly associated with microtubules. The colocalization of dynein and cleaved caspase 3 in neuromuscular junctions is strongly suggestive of the retrograde transport of apoptotic factors to the soma. These results are consistent with the early stages of degeneration in neuromuscular junctions during aging, which is followed by dying back. Given that aging is a key risk factor for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), the identification of age-related motor neuron degeneration initiated at the distal end of the axon may provide a new therapeutic target for early intervention.