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Diana Santa-Cruz, Luz; Guerrero-Castillo, Sergio; Uribe-Carvajal, Salvador; Tapia, Ricardo (2016)

MITOCHONDRIAL DYSFUNCTION DURING THE EARLY STAGES OF EXCITOTOXIC SPINAL MOTOR NEURON DEGENERATION IN VIVO

ACS Chem Neurosci 7(7):886-896
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Glutamate excitotoxicity and mitochondrial dysfunction are involved in motor neuron degeneration process during amyotrophic lateral sclerosis (ALS). We have previously shown that microdialysis perfusion of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) in the lumbar region of the rat spinal cord produces permanent paralysis of the ipsilateral hindlimb and death of motor neurons by a Ca(2+)-dependent mechanism, in a process that starts 2-3 h after AMPA perfusion. Co-perfusion with different energy metabolic substrates, mainly pyruvate, prevented the paralysis and motor neuron degeneration induced by AMPA, suggesting that mitochondrial energetic deficiencies are involved in this excitotoxic motor neuron death. To test this, in the present work, we studied the functional and ultrastructural characteristics of mitochondria isolated from the ventral horns of lumbar spinal cords of rats, at the beginning of the AMPA-induced degeneration process, when motor neurons are still alive. Animals were divided in four groups: perfused with AMPA, AMPA + pyruvate, and pyruvate alone and Krebs-Ringer medium as controls. Mitochondria from the AMPA-treated group showed decreased oxygen consumption rates, respiratory controls, and transmembrane potentials. Additionally, activities of the respiratory chain complexes I and IV were significantly decreased. Electron microscopy showed that mitochondria from AMPA-treated rats presented swelling, disorganized cristae and disrupted membranes. Remarkably, in the animals co-perfused with AMPA and pyruvate all these abnormalities were prevented. We conclude that mitochondrial dysfunction plays a crucial role in spinal motor neuron degeneration induced by overactivation of AMPA receptors in vivo. These mechanisms could be involved in ALS motor neuron degeneration.