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

Lindsey Hayes, Seneshaw A. Asress, Yingjie Li, Alexander Galkin, Anna Stepanova, Hibiki Kawamata, Giovanni Manfredi, Jonathan D. Glass

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)251-257
Number of pages7
JournalExperimental Neurology
Volume318
DOIs
StatePublished - Aug 1 2019

Fingerprint

Denervation
Knockout Mice
Mitochondria
Neuromuscular Junction
Axons
Superoxide Dismutase-1
Transgenic Mice
Oxidative Stress
Antioxidants
Calcium
Enzymes

Keywords

  • Amyotrophic lateral sclerosis
  • Axonal degeneration
  • Mitochondria
  • Neuromuscular junction
  • Oxidative stress
  • Superoxide dismutase-1

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

Distal denervation in the SOD1 knockout mouse correlates with loss of mitochondria at the motor nerve terminal. / Hayes, Lindsey; Asress, Seneshaw A.; Li, Yingjie; Galkin, Alexander; Stepanova, Anna; Kawamata, Hibiki; Manfredi, Giovanni; Glass, Jonathan D.

In: Experimental Neurology, Vol. 318, 01.08.2019, p. 251-257.

Research output: Contribution to journalArticle

Hayes, Lindsey ; Asress, Seneshaw A. ; Li, Yingjie ; Galkin, Alexander ; Stepanova, Anna ; Kawamata, Hibiki ; Manfredi, Giovanni ; Glass, Jonathan D. / Distal denervation in the SOD1 knockout mouse correlates with loss of mitochondria at the motor nerve terminal. In: Experimental Neurology. 2019 ; Vol. 318. pp. 251-257.
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