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HSP72 Is a Mitochondrial Stress Sensor Critical for Parkin Action, Oxidative Metabolism, and Insulin Sensitivity in Skeletal Muscle
- Source :
- Diabetes
- Publication Year :
- 2014
- Publisher :
- American Diabetes Association, 2014.
-
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.
- Subjects :
- medicine.medical_specialty
Ubiquitin-Protein Ligases
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
Cell Respiration
MFN2
HSP72 Heat-Shock Proteins
Mitochondrion
Parkin
Mice
Oxygen Consumption
Insulin resistance
Internal medicine
Mitophagy
Internal Medicine
medicine
Animals
Humans
Insulin
Muscle, Skeletal
Mice, Knockout
biology
Skeletal muscle
Lipid Metabolism
medicine.disease
Mitochondria
nervous system diseases
Ubiquitin ligase
Oxidative Stress
Metabolism
HEK293 Cells
Endocrinology
medicine.anatomical_structure
biology.protein
Insulin Resistance
Reactive Oxygen Species
Subjects
Details
- ISSN :
- 1939327X and 00121797
- Volume :
- 63
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....429f0649af1d9168004a84c26cfb4972
- Full Text :
- https://doi.org/10.2337/db13-0665