title: Extracellular superoxide released from mitochondria mediates mast cell death by advanced glycation end products.
abstract: Advanced glycation end products (AGEs) accumulate during aging and to higher extents under pathological conditions such as diabetes. Since we previously showed that mast cells expressed the AGE-binding protein, receptor for AGEs (RAGE) on their cell surface, we examined whether AGE affected mast cell survival. Herein, we demonstrate that mast cells undergo apoptosis in response to AGE. Glycated albumin (GA), an AGE, but not stimulation with the high-affinity IgE receptor (FcepsilonRI), can induce mast cell death, as measured by annexin V/propidium iodide double-staining. GA (> or =0.1 mg/ml) exhibited this pro-apoptotic activity in a concentration-dependent manner. GA and FcepsilonRI stimulation increased the cytosolic Ca(2+) levels to a similar extent, whereas GA, but not FcepsilonRI stimulation, caused mitochondrial Ca(2+) overload and membrane potential collapse, resulting in mitochondrial integrity disruption, cytochrome c release and caspase-3/7 activation. In addition, GA, but not FcepsilonRI stimulation, induced extracellular release of superoxide from mitochondria, and this release played a key role in the disruption of Ca(2+) homeostasis. Knockdown of RAGE expression using small interfering RNA abolished GA-induced apoptosis, mitochondrial Ca(2+) overload, and superoxide release, demonstrating that RAGE mediates the GA-induced mitochondrial death pathway. AGE-induced mast cell apoptosis may contribute to the immunocompromised and inflammatory conditions.
authors.affiliation: Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Sciences, 30-1 Oyaguchikami-cho Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yoshimaru
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Toshio
authors.initials: T
authors.lastname: Inoue
authors.forename: Shigeru
authors.initials: S
authors.lastname: Nishida
authors.forename: Chisei
authors.initials: C
authors.lastname: Ra
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001853:Bone Marrow / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006031:Glycosylation; D006801:Humans; D015471:Leukemia, Basophilic, Acute / Q000378:metabolism / Q000473:pathology; D008407:Mast Cells / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D017452:Receptors, IgG / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012709:Serum Albumin / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D000093423:Glycated Serum Albumin
chemical_list: C489017:FCGR1A protein, human; C485701:Fcgr1 protein, mouse; D017127:Glycation End Products, Advanced; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D012709:Serum Albumin; D013481:Superoxides; D045304:Cytochromes c; D053148:Caspase 3; D053179:Caspase 7; D002118:Calcium; D000093423:Glycated Serum Albumin