title: ZnT2 is a critical mediator of lysosomal-mediated cell death during early mammary gland involution.
abstract: Mammary gland involution is the most dramatic example of physiological cell death. It occurs through an initial phase of lysosomal-mediated cell death (LCD) followed by mitochondrial-mediated apoptosis. Zinc (Zn) activates both LCD and apoptosis in vitro. The Zn transporter ZnT2 imports Zn into vesicles and mitochondria and ZnT2-overexpression activates cell death in mammary epithelial cells (MECs). We tested the hypothesis that ZnT2-mediated Zn transport is critical for mammary gland involution in mice. Following weaning, ZnT2 abundance increased in lysosomes and mitochondria, which paralleled Zn accumulation in each of these organelles. Adenoviral expression of ZnT2 in lactating mouse mammary glands in vivo increased Zn in lysosomes and mitochondria and activated LCD and apoptosis, promoting a profound reduction in MECs and alveoli. Injection of TNFα, a potent activator of early involution, into the mammary gland fat pads of lactating mice increased ZnT2 and Zn in lysosomes and activated premature involution. Exposure of cultured MECs to TNFα redistributed ZnT2 to lysosomes and increased lysosomal Zn, which activated lysosomal swelling, cathepsin B release, and LCD. Our data implicate ZnT2 as a critical mediator of cell death during involution and importantly, that as an initial involution signal, TNFα redistributes ZnT2 to lysosomes to activate LCD.
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Hennigar
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Young Ah
authors.initials: YA
authors.lastname: Seo
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Sharma
authors.affiliation: 1] Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA [2] Department of Surgery, Penn State Hershey College of Medicine, Hershey, PA, USA [3] Department of and Cell and Molecular Physiology, Penn State Hershey College of Medicine, Hershey, PA, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Soybel
authors.affiliation: 1] Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA [2] Department of Surgery, Penn State Hershey College of Medicine, Hershey, PA, USA [3] Department of and Cell and Molecular Physiology, Penn State Hershey College of Medicine, Hershey, PA, USA [4] Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, PA, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Kelleher
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D007774:Lactation / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage; D015032:Zinc / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D014409:Tumor Necrosis Factor-alpha; C543309:Znt2 protein, mouse; D002401:Cathepsin B; D015032:Zinc