title: A role for sequestosome 1/p62 in mitochondrial dynamics, import and genome integrity.
abstract: As a signaling scaffold, p62/sequestosome (p62/SQSTM1) plays important roles in cell signaling and degradation of misfolded proteins. While localization of p62 to mitochondria has been reported, a description of its function once there, remains unclear. Here, we report that p62 is localized to mitochondria in non-stressed situations and demonstrate that deficiency in p62 exacerbates defects in mitochondrial membrane potential and energetics leading to mitochondrial dysfunction. We report on the relationship between mitochondrial protein import and p62. In a p62 null background, mitochondrial import of the mitochondrial transcription factor TFAM is disrupted. When p62 is returned, mitochondrial function is restored to more normal levels. We identify for the first time that p62 localization plays a role in regulating mitochondrial morphology, genome integrity and mitochondrial import of a key transcription factor. We present evidence that these responses to the presence of p62 extend beyond the protein's immediate influence on membrane potential.
authors.affiliation: Department of Biological Sciences, Cellular and Molecular Biosciences Program, Auburn University, AL 36849, USA.
authors.forename: M Lamar
authors.initials: ML
authors.lastname: Seibenhener
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Du
authors.forename: Maria-Theresa
authors.initials: MT
authors.lastname: Diaz-Meco
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wooten
authors.forename: Marie W
authors.initials: MW
authors.lastname: Wooten
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D054629:Genome, Mitochondrial; D042822:Genomic Instability; D006360:Heat-Shock Proteins / Q000502:physiology*; D006609:High Mobility Group Proteins / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D063269:Mitochondrial Turnover; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D006609:High Mobility Group Proteins; D017382:Reactive Oxygen Species; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C081930:Tfam protein, mouse; D000255:Adenosine Triphosphate