Title

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

Publication Date

8-22-2003

Document Type

Article

Subjects

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

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

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

10.1073/pnas.1832170100

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

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

PubMed ID

12930893