title: Release of targeted p53 from the mitochondrion as an early signal during mitochondrial dysfunction.
abstract: Increased accumulation of p53 tumor suppressor protein is an early response to low-level stressors. To investigate the fate of mitochondrial-sequestered p53, mouse embryonic fibroblast cells (MEFs) on a p53-deficient genetic background were transfected with p53-EGFP fusion protein led by a sense (m53-EGFP) or antisense (c53-EGFP) mitochondrial import signal. Rotenone exposure (100nM, 1h) triggered the translocation of m53-EGFP from the mitochondrion to the nucleus, thus shifting the transfected cells from a mitochondrial p53 to a nuclear p53 state. Antibodies for p53 serine phosphorylation or lysine acetylation indicated a different post-translational status of recombinant p53 in the nucleus and mitochondrion, respectively. These data suggest that cycling of p53 through the mitochondria may establish a direct pathway for p53 signaling from the mitochondria to the nucleus during mitochondrial dysfunction. PK11195, a pharmacological ligand of mitochondrial TSPO (formerly known as the peripheral-type benzodiazepine receptor), partially suppressed the release of mitochondria-sequestered p53. These findings support the notion that p53 function mediates a direct signaling pathway from the mitochondria to nucleus during mitochondrial dysfunction.
authors.affiliation: Department of Molecular, Cellular and Craniofacial Biology, University of Louisville, 501 S. Preston St., Louisville, KY 40202, USA; Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY 40292, USA. Electronic address: maia.green@merck.com.
authors.forename: M L
authors.initials: ML
authors.lastname: Green
authors.forename: M M
authors.initials: MM
authors.lastname: Pisano
authors.forename: R A
authors.initials: RA
authors.lastname: Prough
authors.forename: T B
authors.initials: TB
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D007546:Isoquinolines; D024101:Mitochondrial Proteins; D016159:Tumor Suppressor Protein p53; D012402:Rotenone; C037850:PK 11195
keywords: Embryo; Mitochondria; PK11195; Rotenone; TspO; p53
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