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Environmental toxicants inhibit neuronal Jak tyrosine kinase by mitochondrial disruption

Richard K Monroe1, Stanley W Halvorsen

  • 1Program in Neuroscience, School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo, NY 14214-3000, USA.

Neurotoxicology
|July 29, 2009
PubMed

Insights

Environmental pollutants like cadmium and mercury cause neurotoxicity by disrupting mitochondrial function, inhibiting Janus kinase (Jak)/STAT signaling in nerve cells. This oxidative stress mechanism may contribute to neurodegeneration.

Area of Science:

  • Neuroscience
  • Toxicology
  • Cell Biology

Background:

  • Environmental pollutants cadmium (CdCl2), mercury (HgCl2), and rotenone are known neurotoxins.
  • Their precise neurotoxic mechanisms, particularly concerning Janus kinase (Jak)/signal transducer and activator of transcription (STAT) signaling, remain unclear.
  • Previous research indicated that these agents induce oxidative stress, reversibly blocking Jak/STAT signaling in nerve cells.

Purpose of the Study:

  • To investigate the role of mitochondrial dysfunction in the inhibition of Jak/STAT signaling by environmental pollutants in human neuroblastoma cells (BE(2)-C).
  • To compare the effects of these pollutants on Jak/STAT signaling and mitochondrial function in neuronal (BE(2)-C) versus non-neuronal (HepG2) cells.
  • To elucidate the direct impact of pollutant-induced mitochondrial dysfunction on Jak kinase activity.

Main Methods:

  • Exposure of BE(2)-C neuroblastoma and HepG2 hepatoma cells to CdCl2, HgCl2, and rotenone.
  • Assessment of Jak/STAT signaling pathway activation (interleukin-6, interferon-gamma, ciliary neurotrophic factor-mediated signaling).
  • Measurement of Jak1 and Jak2 auto-phosphorylation and tyrosine nitration.
  • Evaluation of mitochondrial membrane potential and superoxide production.
  • In vitro Jak auto-phosphorylation assays using isolated Jak2 and manipulated mitochondria.
  • Treatment with mitochondrial antioxidant alpha-lipoic acid and a complex III bypass agent.

Main Results:

  • CdCl2, HgCl2, and rotenone inhibited Jak/STAT signaling, reduced Jak auto-phosphorylation, and increased Jak tyrosine nitration in BE(2)-C cells, but not in HepG2 cells.
  • All three pollutants induced mitochondrial dysfunction, characterized by reduced membrane potential and increased superoxide production, in both cell types.
  • Dysfunctional mitochondria isolated from treated cells equally inhibited Jak2 auto-phosphorylation in vitro, irrespective of cell origin.
  • The antioxidant alpha-lipoic acid reversed pollutant-induced pro-oxidant effects, while 2,6-dichloroindophenol partially blocked cadmium's effects.
  • These findings indicate that disrupted mitochondria increase reactive oxygen species (ROS), directly inhibiting neuronal Jak tyrosine kinase activity.

Conclusions:

  • Environmental pollutants CdCl2, HgCl2, and rotenone disrupt mitochondrial function in neuronal cells, leading to increased ROS.
  • This oxidative stress directly inhibits neuronal Janus kinase (Jak) activity, explaining the selective neurotoxicity.
  • Non-neuronal cells possess protective mechanisms against oxidative stress-induced Jak inhibition, warranting further investigation.
  • Pro-oxidant-induced mitochondrial dysfunction offers a potential mechanism for environmental agents contributing to neurodegeneration.

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