Overview of mitochondrial redox and metabolic checkpoints of T-cell activation and apoptosis signals. Antigen binding-initiated signaling through the T-cell receptor complex/CD3 and the CD28 costimulatory molecule activate phosphatidylinositol 3-kinase (PI3K) and protein tyrosine kinases (PTK). Increased cytosolic Ca2+ concentration activates the serine/threonine phosphatase calcineurin, which dephosphorylates the nuclear factor for activated T cells (NFAT). Dephosphorylated NFAT can translocate to the nucleus, where it promotes transcription of IL-2 in concert with AP-1, NF-κB, and Oct-1. Ca2+ flux into mitochondria increases production of ROS and NF-κB activation (88–90). Mitochondrial membrane integrity is maintained by a balance of membrane-stabilizing bcl-2 and bcl-XL and pore-inducing bax and bad (34) as well as the metabolic capacity to synthesize reducing equivalents, NADPH, GSH, and TRX. Controlled increase of ROS levels activates NF-κB and promotes cell growth. Excess ROS production and disruption of ΔΨm lead to AICD executed by caspase-3 (digesting vitally important proteins PARP, 70K U1RNP, lamin, and actin) and caspase-3-dependent DNase (CAD; causing nuclear DNA fragmentation). Cleavage by caspase-3 is thought to expose cryptic epitomes and cause autoantigenicity of self-antigens (91). Activity of redox-sensitive transcription factors NF-κB, p53, AP-1, and Sp1 is regulated through release from inhibitor complexes and conformational changes in their active sites. Intracellular antioxidants reduced glutathione (GSH) and thioredoxin (TRX) are regenerated at the expense of NADPH supplied primarily through metabolism of glucose via the PPP (92). Among PPP products, ribose 5-phosphate is required for nucleotide and DNA synthesis and supports cell growth, C3–C7 sugars influence mitochondrial function and reactive oxygen species (ROS) production, inositol and ADP-ribose serve as precursors for second messengers inositol phosphates and cADP-ribose, respectively. Dehydroascorbate (DHA) is imported through glucose transporter 1 (GLUT1). DHA is metabolized through the PPP, thereby enhancing GSH levels. DHA also increases surface expression of Fas-R (93). Glutathione reductase and TRX reductase synthesize GSH and reduced TRX (TRX-DT) at the expense of NADPH. Formulation of the PPP and its efficiency to provide NADPH is dependent on the expression of G6PD and TAL (14,15). ΔΨm is controlled by intracellular GSH/NADH/NADPH levels; integrity of the permeability transition pore complex (PTPC), largely comprised of adenine nucleotide translocator (ANT; inner membrane); voltage-dependent anion channel (VDAC; outer membrane); and translocation and dimerization of pro- and antiapoptotic bcl-2 family members in the intermembrane space (34). Phosphorylation of BAD by mitochondria-anchored PKA results in antiapoptotic sequestration of BAD into the cytosol (94). Signaling through cell death receptors, such as Fas(15), CD3/CD28 costimulation (36, 7), ROS (24), NO (29), as well as lymphokines, IL-3, IL-10, IFN-γ, and TGF-β1 influence ΔΨm, ATP synthesis, and susceptibility to apoptosis (37).
The mitochondrion ( Fig.
Viewing this image requires a subscription. If you are a subscriber, please log in.
This image is from the chapter titled "Apoptosis and Mitochondrial Dysfunction in Lymphocytes of Patients With Systemic Lupus Erythematosus"
(from Autoimmunity), which is copyrighted by Humana Press Inc., Totowa, NJ For more information on the
copyright for this image, please refer to the full image caption and to the
The image is being made available for non-commercial purposes for subscribers to SpringerImages. For more information on what you are allowed to do with this image, please see our copyright policy.
To request permissions to use any copyrighted material, please visit the source document.
Report a copyright concern regarding this image.
Log in or register to save your favorite images and download them as high-quality PowerPoint or PDF files.
Log in or register to save your search criteria.
© Springer, part of Springer Science+Business Media.
Remote Address: 184.108.40.206 Server: 19