title: Estrogen receptor mediates a distinct mitochondrial unfolded protein response.
abstract: Unfolded protein responses (UPRs) of the endoplasmic reticulum and mitochondrial matrix have been described. Here, we show that the accumulation of proteins in the inter-membrane space (IMS) of mitochondria in the breast cancer cell line MCF-7 activates a distinct UPR. Upon IMS stress, overproduction of reactive oxygen species (ROS) and phosphorylation of AKT triggers estrogen receptor (ER) activity, which further upregulates the transcription of the mitochondrial regulator NRF1 and the IMS protease OMI (officially known as HTRA2). Moreover, we demonstrate that the IMS stress-induced UPR culminates in increased proteasome activity. Given our previous report on a proteasome- and OMI-dependent checkpoint that limits the import of IMS proteins, the findings presented in this study suggest that this newly discovered UPR acts as a cytoprotective response to overcome IMS stress.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Luena
authors.initials: L
authors.lastname: Papa
authors.forename: Doris
authors.initials: D
authors.lastname: Germain
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000235:genetics / Q000502:physiology; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology*
chemical_list: D024101:Mitochondrial Proteins; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D051057:Proto-Oncogene Proteins c-akt; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2