TY - JOUR
T1 - Distal denervation in the SOD1 knockout mouse correlates with loss of mitochondria at the motor nerve terminal
AU - Hayes, Lindsey R.
AU - Asress, Seneshaw A.
AU - Li, Yingjie
AU - Galkin, Alexander
AU - Stepanova, Anna
AU - Kawamata, Hibiki
AU - Manfredi, Giovanni
AU - Glass, Jonathan D.
N1 - Funding Information:
This work was supported by the Muscular Dystrophy Association (JG), NIH 1R01NS062055 (GM), and an AAN/ALSA Clinician Scientist Development award (LH). The authors declare no competing financial interests.
Funding Information:
This work was supported by the Muscular Dystrophy Association (JG), NIH 1R01NS062055 (GM), and an AAN/ALSA Clinician Scientist Development award (LH).
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/8
Y1 - 2019/8
N2 - Impairment of mitochondrial transport has long been implicated in the pathogenesis of neuropathy and neurodegeneration. However, the role of mitochondria in stabilizing motor nerve terminals 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 SOD1 exclusively in the mitochondrial intermembrane space (MitoSOD1/Sod1−/−), suggesting that oxidative stress within mitochondria drives denervation in 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 nerve terminals 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 nerve terminals 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 denervation in Sod1−/− mice, perhaps via loss of key mitochondrial functions such as calcium buffering and/or energy production.
AB - Impairment of mitochondrial transport has long been implicated in the pathogenesis of neuropathy and neurodegeneration. However, the role of mitochondria in stabilizing motor nerve terminals 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 SOD1 exclusively in the mitochondrial intermembrane space (MitoSOD1/Sod1−/−), suggesting that oxidative stress within mitochondria drives denervation in 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 nerve terminals 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 nerve terminals 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 denervation in Sod1−/− mice, perhaps via loss of key mitochondrial functions such as calcium buffering and/or energy production.
KW - Amyotrophic lateral sclerosis
KW - Axonal degeneration
KW - Mitochondria
KW - Neuromuscular junction
KW - Oxidative stress
KW - Superoxide dismutase-1
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U2 - 10.1016/j.expneurol.2019.05.008
DO - 10.1016/j.expneurol.2019.05.008
M3 - Article
C2 - 31082391
AN - SCOPUS:85065757524
SN - 0014-4886
VL - 318
SP - 251
EP - 257
JO - Experimental Neurology
JF - Experimental Neurology
ER -