title: High-mobility group box 1 is essential for mitochondrial quality control.
abstract: Mitochondria are organelles centrally important for bioenergetics as well as regulation of apoptotic death in eukaryotic cells. High-mobility group box 1 (HMGB1), an evolutionarily conserved chromatin-associated protein which maintains nuclear homeostasis, is also a critical regulator of mitochondrial function and morphology. We show that heat shock protein beta-1 (HSPB1 or HSP27) is the downstream mediator of this effect. Disruption of the HSPB1 gene in embryonic fibroblasts with wild-type HMGB1 recapitulates the mitochondrial fragmentation, deficits in mitochondrial respiration, and adenosine triphosphate (ATP) synthesis observed with targeted deletion of HMGB1. Forced expression of HSPB1 reverses this phenotype in HMGB1 knockout cells. Mitochondrial effects mediated by HMGB1 regulation of HSPB1 expression serve as a defense against mitochondrial abnormality, enabling clearance and autophagy in the setting of cellular stress. Our findings reveal an essential role for HMGB1 in autophagic surveillance with important effects on mitochondrial quality control.
authors.affiliation: Department of Surgery, G.27A Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15219, USA.
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Livesey
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D019069:Cell Respiration; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D055786:Gene Knockout Techniques; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D053140:Organelle Shape; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D034622:RNA Interference; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D024243:HMGB1 Protein; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D014475:Uncoupling Agents; D012402:Rotenone; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000255:Adenosine Triphosphate