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HSP72 is a mitochondrial stress sensor critical for Parkin action, oxidative metabolism, and insulin sensitivity in skeletal muscle


Drew, BG and Ribas, V and Le, JA and Henstridge, DC and Phun, J and Zhou, Z and Soleymani, T and Daraei, P and Sitz, D and Vergnes, L and Wanagat, J and Reue, K and Febbraio, MA and Hevener, AL, HSP72 is a mitochondrial stress sensor critical for Parkin action, oxidative metabolism, and insulin sensitivity in skeletal muscle, Diabetes, 63, (5) pp. 1488-1505. ISSN 0012-1797 (2014) [Refereed Article]

Copyright Statement

2014 by the American Diabetes Association.

DOI: doi:10.2337/db13-0665


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.

Item Details

Item Type:Refereed Article
Keywords:animals, cell respiration, HEK293 cells, HSP72 heat-shock proteins, humans, insulin, insulin resistance, lipid metabolism, mice, mice, knockout; mitochondria, muscle, skeletal, oxidative stress, oxygen consumption, reactive oxygen species
Research Division:Biological Sciences
Research Group:Biochemistry and cell biology
Research Field:Cell metabolism
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Henstridge, DC (Dr Darren Henstridge)
ID Code:133348
Year Published:2014
Web of Science® Times Cited:80
Deposited By:Health Sciences
Deposited On:2019-06-24
Last Modified:2019-08-22

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