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Granzyme a, a stealth killer in the mitochondrion

Safa Lucken-Ardjomande1, Jean-Claude Martinou

  • 1Department of Cell Biology, University of Geneva, 30 quai Ernest-Ansermet, Geneva CH-1211, Switzerland.

Cell
|May 20, 2008
PubMed

Insights

Killer lymphocytes induce cell death using granzyme A (GzmA), a serine protease. GzmA enters mitochondria, cleaves a key enzyme, and triggers reactive oxygen species production, causing cell death.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Killer lymphocytes induce apoptosis via caspase-dependent and -independent pathways.
  • Granzyme A (GzmA) is a serine protease implicated in caspase-independent cell death.
  • The precise mechanism and cellular targets of GzmA in this process remain under investigation.

Purpose of the Study:

  • To elucidate the mitochondrial pathway of granzyme A-mediated cell death.
  • To identify the specific mitochondrial targets of GzmA.
  • To investigate the role of reactive oxygen species in GzmA-induced cytotoxicity.

Main Methods:

  • Mitochondrial localization studies of GzmA.
  • Biochemical assays to identify GzmA cleavage substrates.
  • Analysis of reactive oxygen species production in response to GzmA.

Main Results:

  • Granzyme A (GzmA) was shown to enter the mitochondrial matrix.
  • GzmA does not disrupt normal mitochondrial function upon entry.
  • GzmA cleaves NDUFS3, a component of the electron transport chain.
  • Cleavage of NDUFS3 leads to the production of reactive oxygen species.
  • This process ultimately results in caspase-independent cell death.

Conclusions:

  • Granzyme A utilizes a novel mitochondrial pathway to induce cell death.
  • NDUFS3 is a critical target of GzmA within the mitochondria.
  • Mitochondrial reactive oxygen species generation is a key event in GzmA-mediated cytotoxicity.

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