Ian4 is required for mitochondrial integrity and T cell survival
Program in Molecular Medicine; Department of Medicine, Division of Diabetes; Department of Medicine, Division of Endocrinology and Metabolism
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.
DOI of Published Version
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
Proceedings of the National Academy of Sciences of the United States of America
Pandarpurkar, Malini; Wilson-Fritch, Leanne; Corvera, Silvia; Markholst, Helle; Hornum, Lars; Greiner, Dale L.; Mordes, John P.; Rossini, Aldo A.; and Bortell, Rita, "Ian4 is required for mitochondrial integrity and T cell survival" (2003). Open Access Articles. 1768.