Ian4 is required for mitochondrial integrity and T cell survival

UMMS Affiliation

Program in Molecular Medicine; Department of Medicine, Division of Diabetes; Department of Medicine, Division of Endocrinology and Metabolism



Document Type



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


Life Sciences | Medicine and Health Sciences


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.

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Citation: Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10382-7. Epub 2003 Aug 20. Link to article on publisher's site

DOI of Published Version


Related Resources

Link to Article in PubMed

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

PubMed ID