Ochratoxin A exerts neurotoxicity in human astrocytes through mitochondria-dependent apoptosis and intracellular calcium overload

Sunwoo Park, Whasun Lim, Seungkwon You, Gwonhwa Song

Research output: Contribution to journalArticle

Abstract

Astrocytes are the major glial cell type in the central nervous system (CNS), and the distal part of the astrocyte forms the blood-brain barrier with nearby blood vessels. They maintain the overall metabolism, growth, homeostasis of neurons, and signaling in the CNS. Ochratoxin A is considered a carcinogen and immunotoxic, nephrotoxic, and neurotoxic mycotoxin. Specifically, it exhibits neurotoxicity with high affinity for the brain. Despite some previous studies about the effects of ochratoxin A in glial cells, the intracellular working mechanism in astrocytes is not fully understood. In this study, we studied the specific working mechanism of ochratoxin A in the human astrocyte cell line, NHA-SV40LT. Ochratoxin A reduced cell proliferation with sub G0/G1 cell cycle arrest by inhibiting CCND1, CCNE1, CDK4, and MYC expression. It induced apoptosis of NHA-SV40LT cells through mitochondrial membrane potential (MMP) loss and up-regulation of BAX and TP53. In addition, ochratoxin A increased cytosolic and mitochondrial calcium levels, resulting in an increase in MMP2 and PLAUR mRNA expression in NHA-SV40LT cells. Furthermore, ochratoxin A regulated the phosphorylation of AKT, ERK1/2, and JNK signal molecules of human astrocytes. Collectively, ochratoxin A exerts neurotoxicity through anti-proliferation and mitochondria-dependent apoptosis in human astrocytes.

Original languageEnglish
Pages (from-to)42-49
Number of pages8
JournalToxicology Letters
Volume313
DOIs
Publication statusPublished - 2019 Oct 1

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Mitochondria
Astrocytes
Apoptosis
Calcium
Neurology
Neuroglia
Central Nervous System
Cells
G1 Phase Cell Cycle Checkpoints
Phosphorylation
Mycotoxins
Mitochondrial Membrane Potential
Blood vessels
Cell proliferation
ochratoxin A
Blood-Brain Barrier
Metabolism
Carcinogens
Neurons
Blood Vessels

Keywords

  • Apoptosis
  • Astrocyte
  • Ochratoxin A
  • Proliferation
  • Toxicity

ASJC Scopus subject areas

  • Toxicology

Cite this

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title = "Ochratoxin A exerts neurotoxicity in human astrocytes through mitochondria-dependent apoptosis and intracellular calcium overload",
abstract = "Astrocytes are the major glial cell type in the central nervous system (CNS), and the distal part of the astrocyte forms the blood-brain barrier with nearby blood vessels. They maintain the overall metabolism, growth, homeostasis of neurons, and signaling in the CNS. Ochratoxin A is considered a carcinogen and immunotoxic, nephrotoxic, and neurotoxic mycotoxin. Specifically, it exhibits neurotoxicity with high affinity for the brain. Despite some previous studies about the effects of ochratoxin A in glial cells, the intracellular working mechanism in astrocytes is not fully understood. In this study, we studied the specific working mechanism of ochratoxin A in the human astrocyte cell line, NHA-SV40LT. Ochratoxin A reduced cell proliferation with sub G0/G1 cell cycle arrest by inhibiting CCND1, CCNE1, CDK4, and MYC expression. It induced apoptosis of NHA-SV40LT cells through mitochondrial membrane potential (MMP) loss and up-regulation of BAX and TP53. In addition, ochratoxin A increased cytosolic and mitochondrial calcium levels, resulting in an increase in MMP2 and PLAUR mRNA expression in NHA-SV40LT cells. Furthermore, ochratoxin A regulated the phosphorylation of AKT, ERK1/2, and JNK signal molecules of human astrocytes. Collectively, ochratoxin A exerts neurotoxicity through anti-proliferation and mitochondria-dependent apoptosis in human astrocytes.",
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T1 - Ochratoxin A exerts neurotoxicity in human astrocytes through mitochondria-dependent apoptosis and intracellular calcium overload

AU - Park, Sunwoo

AU - Lim, Whasun

AU - You, Seungkwon

AU - Song, Gwonhwa

PY - 2019/10/1

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N2 - Astrocytes are the major glial cell type in the central nervous system (CNS), and the distal part of the astrocyte forms the blood-brain barrier with nearby blood vessels. They maintain the overall metabolism, growth, homeostasis of neurons, and signaling in the CNS. Ochratoxin A is considered a carcinogen and immunotoxic, nephrotoxic, and neurotoxic mycotoxin. Specifically, it exhibits neurotoxicity with high affinity for the brain. Despite some previous studies about the effects of ochratoxin A in glial cells, the intracellular working mechanism in astrocytes is not fully understood. In this study, we studied the specific working mechanism of ochratoxin A in the human astrocyte cell line, NHA-SV40LT. Ochratoxin A reduced cell proliferation with sub G0/G1 cell cycle arrest by inhibiting CCND1, CCNE1, CDK4, and MYC expression. It induced apoptosis of NHA-SV40LT cells through mitochondrial membrane potential (MMP) loss and up-regulation of BAX and TP53. In addition, ochratoxin A increased cytosolic and mitochondrial calcium levels, resulting in an increase in MMP2 and PLAUR mRNA expression in NHA-SV40LT cells. Furthermore, ochratoxin A regulated the phosphorylation of AKT, ERK1/2, and JNK signal molecules of human astrocytes. Collectively, ochratoxin A exerts neurotoxicity through anti-proliferation and mitochondria-dependent apoptosis in human astrocytes.

AB - Astrocytes are the major glial cell type in the central nervous system (CNS), and the distal part of the astrocyte forms the blood-brain barrier with nearby blood vessels. They maintain the overall metabolism, growth, homeostasis of neurons, and signaling in the CNS. Ochratoxin A is considered a carcinogen and immunotoxic, nephrotoxic, and neurotoxic mycotoxin. Specifically, it exhibits neurotoxicity with high affinity for the brain. Despite some previous studies about the effects of ochratoxin A in glial cells, the intracellular working mechanism in astrocytes is not fully understood. In this study, we studied the specific working mechanism of ochratoxin A in the human astrocyte cell line, NHA-SV40LT. Ochratoxin A reduced cell proliferation with sub G0/G1 cell cycle arrest by inhibiting CCND1, CCNE1, CDK4, and MYC expression. It induced apoptosis of NHA-SV40LT cells through mitochondrial membrane potential (MMP) loss and up-regulation of BAX and TP53. In addition, ochratoxin A increased cytosolic and mitochondrial calcium levels, resulting in an increase in MMP2 and PLAUR mRNA expression in NHA-SV40LT cells. Furthermore, ochratoxin A regulated the phosphorylation of AKT, ERK1/2, and JNK signal molecules of human astrocytes. Collectively, ochratoxin A exerts neurotoxicity through anti-proliferation and mitochondria-dependent apoptosis in human astrocytes.

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