Distal denervation in the SOD1 knockout mouse correlates with loss of mitochondria at the motor nerve terminal

Abstract Impairment of mitochondrial transport has long been implicated in the pathogenesis of neuropathy and neurodegeneration. However, the role of mitochondria in stabilizing motor nerveterminals at neuromuscular junction(NMJ) remains unclear. We previously demonstrated that mice lacking the antioxidant enzyme, superoxide dismutase-1 ( Sod1−/− ), develop progressive NMJ denervation. This was rescued by expression of SOD1exclusively in the mitochondrial intermembrane space( MitoSOD1/ Sod1−/− ), suggesting that oxidative stress within mitochondria drives denervationin these animals. However, we also observed reduced mitochondrial density in Sod1−/− motor axons in vitro. To investigate the relationship between mitochondrial density and NMJ innervation in vivo, we crossed Sod1−/− mice with the fluorescent reporter strains Thy1-YFP and Thy1-mitoCFP . We identified an age-dependent loss of mitochondria at motor nerveterminals in Sod1−/− mice, that closely correlated with NMJ denervation, and was rescued by MitoSOD1 expression. To test whether augmenting mitochondrial transport rescues Sod1−/− axons, we generated transgenic mice overexpressing the mitochondrial cargo adaptor, Miro1. This led to a partial rescue of mitochondrial density at motor nerveterminals by 12 months of age, but was insufficient to prevent denervation. These findings suggest that loss of mitochondria in the distal motor axon may contribute to denervationin Sod1−/− mice, perhaps via loss of key mitochondrial functions such as calcium bufferingand/or energy production.