Manganese-induced Mitochondrial Dysfunction Is Not Detectable at Exposures Below the Acute Cytotoxic Threshold in Neuronal Cell Types

Emily B. Warren, Miles R. Bryan, Patricia Morcillo, Keisha N. Hardeman, Michael Aschner, Aaron B. Bowman

Research output: Contribution to journalArticle

Abstract

Manganese (Mn) is an essential metal, but excessive exposures have been well-documented to culminate in neurotoxicity. Curiously, the precise mechanisms of Mn neurotoxicity are still unknown. One hypothesis suggests that Mn exerts its toxicity by inhibiting mitochondrial function, which then (if exposure levels are high and long enough) leads to cell death. Here, we used a Huntington's disease cell model with known differential sensitivities to manganese-STHdhQ7/Q7 and STHdhQ111/Q111 cells-to examine the effects of acute Mn exposure on mitochondrial function. We determined toxicity thresholds for each cell line using both changes in cell number and caspase-3/7 activation. We used a range of acute Mn exposures (0-300 µM), both above and below the cytotoxic threshold, to evaluate mitochondria-associated metabolic balance, mitochondrial respiration, and substrate dependence. In both cell lines, we observed no effect on markers of mitochondrial function at subtoxic Mn exposures (below detectable levels of cell death), yet at supratoxic exposures (above detectable levels of cell death) mitochondrial function significantly declined. We validated these findings in primary striatal neurons. In cell lines, we further observed that subtoxic Mn concentrations do not affect glycolytic function or major intracellular metabolite quantities. These data suggest that in this system, Mn exposure impairs mitochondrial function only at concentrations coincident with or above the initiation of cell death and is not consistent with the hypothesis that mitochondrial dysfunction precedes or induces Mn cytotoxicity.

Original languageEnglish (US)
Pages (from-to)446-459
Number of pages14
JournalToxicological sciences : an official journal of the Society of Toxicology
Volume176
Issue number2
DOIs
StatePublished - Aug 1 2020

Keywords

  • Huntington’s disease
  • manganese
  • mitochondria

ASJC Scopus subject areas

  • Toxicology

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