Mitochondrial translation is required for sustained killing by cytotoxic T cells

Science. 2021 Oct 15;374(6565):eabe9977. doi: 10.1126/science.abe9977. Epub 2021 Oct 15.


T cell receptor activation of naïve CD8+ T lymphocytes initiates their maturation into effector cytotoxic T lymphocytes (CTLs), which can kill cancer and virally infected cells. Although CTLs show an increased reliance on glycolysis upon acquisition of effector function, we found an essential requirement for mitochondria in target cell–killing. Acute mitochondrial depletion in USP30 (ubiquitin carboxyl-terminal hydrolase 30)–deficient CTLs markedly diminished killing capacity, although motility, signaling, and secretion were all intact. Unexpectedly, the mitochondrial requirement was linked to mitochondrial translation, inhibition of which impaired CTL killing. Impaired mitochondrial translation triggered attenuated cytosolic translation, precluded replenishment of secreted killing effectors, and reduced the capacity of CTLs to carry out sustained killing. Thus, mitochondria emerge as a previously unappreciated homeostatic regulator of protein translation required for serial CTL killing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Cell Movement / genetics
  • Cells, Cultured
  • Cytotoxicity, Immunologic / genetics
  • Cytotoxicity, Immunologic / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / enzymology*
  • Mitochondria / genetics
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Protein Biosynthesis
  • T-Lymphocytes, Cytotoxic / enzymology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Thiolester Hydrolases / genetics
  • Thiolester Hydrolases / metabolism*


  • Mitochondrial Proteins
  • Adenosine Triphosphate
  • Thiolester Hydrolases
  • Usp30 protein, mouse