Ian4 is required for mitochondrial integrity and T cell survival

Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10382-7. doi: 10.1073/pnas.1832170100. Epub 2003 Aug 20.


Apoptosis is a regulated cell death program controlled by extrinsic and intrinsic signaling pathways. The intrinsic pathway involves stress signals that activate pro-apoptotic members of the Bcl-2 family, inducing permeabilization of mitochondria and release of apoptogenic factors. These proteins localize to the outer mitochondrial membrane. Ian4, a mitochondrial outer membrane protein with GTP-binding activity, is normally present in thymocytes, T cells, and B cells. We and others have recently discovered that a mutation in the rat Ian4 gene results in severe T cell lymphopenia that is associated with the expression of autoimmune diabetes. The mechanism by which Ian4 controls T cell homeostasis is unknown. Here we show that the absence of Ian4 in T cells causes mitochondrial dysfunction, increased mitochondrial levels of stress-inducible chaperonins and a leucine-rich protein, and T cell-specific spontaneous apoptosis. T cell activation and caspase 8 inhibition both prevented apoptosis, whereas transfection of T cells with Ian4-specific small interfering RNA recapitulated the apoptotic phenotype. The findings establish Ian4 as a tissue-specific regulator of mitochondrial integrity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Caspases / physiology
  • Cell Survival
  • DNA Fragmentation
  • Female
  • GTP-Binding Proteins / physiology*
  • Male
  • Membrane Potentials
  • Membrane Proteins / physiology*
  • Mitochondria / physiology*
  • Mitochondrial Proteins / physiology*
  • RNA, Small Interfering / pharmacology
  • Rats
  • Rats, Inbred WF
  • T-Lymphocytes / physiology*


  • Ian4 protein, mouse
  • Membrane Proteins
  • Mitochondrial Proteins
  • RNA, Small Interfering
  • Caspases
  • GTP-Binding Proteins