HSP72Is a Mitochondrial Stress Sensor Critical for Parkin Action, Oxidative Metabolism, and Insulin Sensitivity in Skeletal Muscle

被引:104
作者
Drew, Brian G. [1 ]
Ribas, Vicente [1 ]
Le, Jamie A. [1 ]
Henstridge, Darren C. [2 ]
Phun, Jennifer [1 ]
Zhou, Zhenqi [1 ]
Soleymani, Teo [1 ]
Daraei, Pedram [1 ]
Sitz, Daniel [1 ]
Vergnes, Laurent [3 ]
Wanagat, Jonathan [4 ]
Reue, Karen [3 ]
Febbraio, Mark A. [2 ]
Hevener, Andrea L. [1 ]
机构
[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Endocrinol Diabet & Hypertens, Los Angeles, CA 90095 USA
[2] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia
[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA
[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Geriatr, Los Angeles, CA 90095 USA
基金
美国国家卫生研究院; 英国医学研究理事会;
关键词
STIMULATED GLUCOSE-UPTAKE; HEAT-SHOCK FACTOR; CAENORHABDITIS-ELEGANS; DISEASE; FUSION; MICE; PROTEOSTASIS; INFLAMMATION; HOMEOSTASIS; MUTATIONS;
D O I
10.2337/db13-0665
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:1488 / 1505
页数:18
相关论文
共 57 条
[1]   DETERMINATION OF COENZYME A AND ACETYL COA IN TISSUE EXTRACTS [J].
ALLRED, JB ;
GUY, DG .
ANALYTICAL BIOCHEMISTRY, 1969, 29 (02) :293-+
[2]   Mitochondria, oxidants, and aging [J].
Balaban, RS ;
Nemoto, S ;
Finkel, T .
CELL, 2005, 120 (04) :483-495
[3]   Adapting proteostasis for disease intervention [J].
Balch, William E. ;
Morimoto, Richard I. ;
Dillin, Andrew ;
Kelly, Jeffery W. .
SCIENCE, 2008, 319 (5865) :916-919
[4]   Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging [J].
Ben-Zvi, Anat ;
Miller, Elizabeth A. ;
Morimoto, Richard I. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (35) :14914-14919
[5]   A guided tour into subcellular colocalization analysis in light microscopy [J].
Bolte, S. ;
Cordelieres, F. P. .
JOURNAL OF MICROSCOPY, 2006, 224 (213-232) :213-232
[6]   Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve High-Fat Diet-Induced Insulin Resistance [J].
Bruce, Clinton R. ;
Hoy, Andrew J. ;
Turner, Nigel ;
Watt, Matthew J. ;
Allen, Tamara L. ;
Carpenter, Kevin ;
Cooney, Gregory J. ;
Febbraio, Mark A. ;
Kraegen, Edward W. .
DIABETES, 2009, 58 (03) :550-558
[7]   Intramuscular heat shock protein 72 and heme oxygenase-1 mRNA are reduced in patients with type 2 diabetes - Evidence that insulin resistance is associated with a disturbed antioxidant defense mechanism [J].
Bruce, CR ;
Carey, AL ;
Hawley, JA ;
Febbraio, MA .
DIABETES, 2003, 52 (09) :2338-2345
[8]   Mitochondria: Dynamic organelles in disease, aging, and development [J].
Chan, David C. .
CELL, 2006, 125 (07) :1241-1252
[9]   Fusion and Fission: Interlinked Processes Critical for Mitochondrial Health [J].
Chan, David C. .
ANNUAL REVIEW OF GENETICS, VOL 46, 2012, 46 :265-287
[10]   Physiological functions of mitochondrial fusion [J].
Chen, Hsiuchen ;
Chan, David C. .
MITOCHONDRIAL RESEARCH IN TRANSLATIONAL MEDICINE, 2010, 1201 :21-25