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Lysosomal membrane permeabilization: carbon nanohorn-induced reactive oxygen species generation and toxicity by this

Mei Yang1, Minfang Zhang1, Yoshio Tahara1

  • 1Nanotube Research Center, National Institute of Advanced Industrial Science and Technology 5-2, 1-1-1 Higashi, Tsukuba 305-8565, Japan.

Toxicology and Applied Pharmacology
|August 12, 2014
PubMed

Insights

Carbon nanohorns trigger cell death by causing lysosomal membrane permeabilization, leading to mitochondrial dysfunction and reactive oxygen species generation. This mechanism explains carbon nanotubule toxicity in macrophages.

Area of Science:

  • Biomedical applications of nanomaterials
  • Cellular toxicology
  • Molecular mechanisms of cell death

Background:

  • Carbon nanotubular materials can cause cell death via reactive oxygen species (ROS).
  • The precise mechanisms of ROS generation and subsequent cytotoxicity remain unclear.
  • Understanding these pathways is crucial for safe biomedical applications of carbon nanomaterials.

Purpose of the Study:

  • To elucidate the molecular mechanism of apoptosis induced by carbon nanohorns (CNHs) in RAW264.7 macrophages.
  • To investigate the role of lysosomal membrane permeabilization (LMP) in CNH-induced cytotoxicity.
  • To identify the source and regulation of ROS generation following CNH uptake.

Main Methods:

  • Investigated CNH uptake and intracellular localization in RAW264.7 macrophages.
  • Assessed lysosomal membrane integrity and cathepsin release.
  • Evaluated mitochondrial dysfunction and ROS production.
  • Examined the involvement of NADPH oxidase and mitochondrial electron transport chain in ROS generation.
  • Analyzed caspase activation and apoptosis induction.

Main Results:

  • CNHs accumulated in lysosomes, inducing lysosomal membrane permeabilization (LMP).
  • LMP led to cathepsin release, mitochondrial dysfunction, and subsequent ROS generation in mitochondria.
  • NADPH oxidase and mitochondrial electron transport chain were not directly involved in CNH-related ROS production.
  • ROS amplified mitochondrial dysfunction, activating caspases and causing apoptosis.
  • Lysosomal dysfunction was identified as a key factor in CNH toxicity.

Conclusions:

  • Lysosomal membrane permeabilization is a critical, often overlooked, mechanism underlying carbon nanotubule toxicity.
  • CNH-induced apoptosis involves a cascade initiated by lysosomal damage, leading to mitochondrial dysfunction and ROS amplification.
  • Targeting lysosomal stability may offer strategies to mitigate the toxic effects of carbon nanomaterials in biomedical applications.
Keywords:
ApoptosisCarbon nanohornsCytotoxicityLysosomal membrane permeabilizationMitochondrial membrane potentialReactive oxygen species

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