Defective Mitochondrial Dynamics Underlie Manganese-Induced Neurotoxicity

Patricia Morcillo, Hector Cordero, Omamuyovwi M. Ijomone, Akinyemi Ayodele, Julia Bornhorst, Leslie Gunther, Frank P. Macaluso, Aaron B. Bowman, Michael Aschner

Research output: Contribution to journalArticlepeer-review

Abstract

Perturbations in mitochondrial dynamics have been observed in most neurodegenerative diseases. Here, we focus on manganese (Mn)-induced Parkinsonism-like neurodegeneration, a disorder associated with the preferential of Mn in the basal ganglia where the mitochondria are considered an early target. Despite the extensive characterization of the clinical presentation of manganism, the mechanism by which Mn mediated mitochondrial toxicity is unclear. In this study we hypothesized whether Mn exposure alters mitochondrial activity, including axonal transport of mitochondria and mitochondrial dynamics, morphology, and network. Using primary neuron cultures exposed to 100 μM Mn (which is considered the threshold of Mn toxicity in vitro) and intraperitoneal injections of MnCl2 (25mg/kg) in rat, we observed that Mn increased mitochondrial fission mediated by phosphorylation of dynamin-related protein-1 at serine 616 (p-s616-DRP1) and decreased mitochondrial fusion proteins (MFN1 and MFN2) leading to mitochondrial fragmentation, defects in mitochondrial respiratory capacity, and mitochondrial ultrastructural damage in vivo and in vitro. Furthermore, Mn exposure impaired mitochondrial trafficking by decreasing dynactin (DCTN1) and kinesin-1 (KIF5B) motor proteins and increasing destabilization of the cytoskeleton at protein and gene levels. In addition, mitochondrial communication may also be altered by Mn exposure, increasing the length of nanotunnels to reach out distal mitochondria. These findings revealed an unrecognized role of Mn in dysregulation of mitochondrial dynamics providing a potential explanation of early hallmarks of the disorder, as well as a possible common pathway with neurological disorders arising upon chronic Mn exposure.

Original languageEnglish (US)
JournalMolecular Neurobiology
DOIs
StateAccepted/In press - 2021

Keywords

  • Cytoskeleton
  • Manganese
  • Mitochondrial dynamics
  • Neuron
  • Striatum

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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