title: HSP72 is a mitochondrial stress sensor critical for Parkin action, oxidative metabolism, and insulin sensitivity in skeletal muscle.
abstract: Increased heat shock protein (HSP) 72 expression in skeletal muscle prevents obesity and glucose intolerance in mice, although the underlying mechanisms of this observation are largely unresolved. Herein we show that HSP72 is a critical regulator of stress-induced mitochondrial triage signaling since Parkin, an E3 ubiquitin ligase known to regulate mitophagy, was unable to ubiquitinate and control its own protein expression or that of its central target mitofusin (Mfn) in the absence of HSP72. In wild-type cells, we show that HSP72 rapidly translocates to depolarized mitochondria prior to Parkin recruitment and immunoprecipitates with both Parkin and Mfn2 only after specific mitochondrial insult. In HSP72 knockout mice, impaired Parkin action was associated with retention of enlarged, dysmorphic mitochondria and paralleled by reduced muscle respiratory capacity, lipid accumulation, and muscle insulin resistance. Reduced oxygen consumption and impaired insulin action were recapitulated in Parkin-null myotubes, confirming a role for the HSP72-Parkin axis in the regulation of muscle insulin sensitivity. These data suggest that strategies to maintain HSP72 may provide therapeutic benefit to enhance mitochondrial quality and insulin action to ameliorate complications associated with metabolic diseases, including type 2 diabetes.
authors.affiliation: David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Drew
authors.forename: Vicente
authors.initials: V
authors.lastname: Ribas
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Le
authors.forename: Darren C
authors.initials: DC
authors.lastname: Henstridge
authors.forename: Jennifer
authors.initials: J
authors.lastname: Phun
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Zhou
authors.forename: Teo
authors.initials: T
authors.lastname: Soleymani
authors.forename: Pedram
authors.initials: P
authors.lastname: Daraei
authors.forename: Daniel
authors.initials: D
authors.lastname: Sitz
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wanagat
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Hevener
mesh_terms: D000818:Animals; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D050884:HSP72 Heat-Shock Proteins; D007328:Insulin; D017382:Reactive Oxygen Species; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein