PMID- 20012595
OWN - NLM
STAT- MEDLINE
DCOM- 20101022
LR  - 20211020
IS  - 1432-0428 (Electronic)
IS  - 0012-186X (Linking)
VI  - 53
IP  - 3
DP  - 2010 Mar
TI  - Human ATP synthase beta is phosphorylated at multiple sites and shows abnormal 
      phosphorylation at specific sites in insulin-resistant muscle.
PG  - 541-51
LID - 10.1007/s00125-009-1624-0 [doi]
AB  - AIMS/HYPOTHESIS: Insulin resistance in skeletal muscle is linked to mitochondrial 
      dysfunction in obesity and type 2 diabetes. Emerging evidence indicates that 
      reversible phosphorylation regulates oxidative phosphorylation (OxPhos) proteins. 
      The aim of this study was to identify and quantify site-specific phosphorylation 
      of the catalytic beta subunit of ATP synthase (ATPsyn-beta) and determine protein 
      abundance of ATPsyn-beta and other OxPhos components in skeletal muscle from 
      healthy and insulin-resistant individuals. METHODS: Skeletal muscle biopsies were 
      obtained from lean, healthy, obese, non-diabetic and type 2 diabetic volunteers 
      (each group n = 10) for immunoblotting of proteins, and hypothesis-driven 
      identification and quantification of phosphorylation sites on ATPsyn-beta using 
      targeted nanospray tandem mass spectrometry. Volunteers were metabolically 
      characterised by euglycaemic-hyperinsulinaemic clamps. RESULTS: Seven 
      phosphorylation sites were identified on ATPsyn-beta purified from human skeletal 
      muscle. Obese individuals with and without type 2 diabetes were characterised by 
      impaired insulin-stimulated glucose disposal rates, and showed a approximately 
      30% higher phosphorylation of ATPsyn-beta at Tyr361 and Thr213 (within the 
      nucleotide-binding region of ATP synthase) as well as a coordinated 
      downregulation of ATPsyn-beta protein and other OxPhos components. Insulin 
      increased Tyr361 phosphorylation of ATPsyn-beta by approximately 50% in lean and 
      healthy, but not insulin-resistant, individuals. CONCLUSIONS/INTERPRETATION: 
      These data demonstrate that ATPsyn-beta is phosphorylated at multiple sites in 
      human skeletal muscle, and suggest that abnormal site-specific phosphorylation of 
      ATPsyn-beta together with reduced content of OxPhos proteins contributes to 
      mitochondrial dysfunction in insulin resistance. Further characterisation of 
      phosphorylation of ATPsyn-beta may offer novel targets of treatment in human 
      diseases with mitochondrial dysfunction, such as diabetes.
FAU - Hojlund, K
AU  - Hojlund K
AD  - Center for Metabolic Biology, School of Life Sciences, Arizona State University, 
      PO Box 87370, Tempe, AZ 85287, USA. k.hojlund@dadlnet.dk
FAU - Yi, Z
AU  - Yi Z
FAU - Lefort, N
AU  - Lefort N
FAU - Langlais, P
AU  - Langlais P
FAU - Bowen, B
AU  - Bowen B
FAU - Levin, K
AU  - Levin K
FAU - Beck-Nielsen, H
AU  - Beck-Nielsen H
FAU - Mandarino, L J
AU  - Mandarino LJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091212
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (ATP5F1B protein, human)
RN  - 0 (Insulin)
RN  - 42HK56048U (Tyrosine)
RN  - EC 3.6.3.- (Mitochondrial Proton-Translocating ATPases)
SB  - IM
MH  - Adult
MH  - Binding Sites
MH  - Catalysis
MH  - Cohort Studies
MH  - Female
MH  - Humans
MH  - Insulin/metabolism
MH  - *Insulin Resistance
MH  - Male
MH  - Middle Aged
MH  - Mitochondrial Proton-Translocating ATPases/*chemistry/metabolism
MH  - Muscle, Skeletal/metabolism/pathology
MH  - Muscles/*metabolism
MH  - Phosphorylation
MH  - Tyrosine/chemistry
EDAT- 2009/12/17 06:00
MHDA- 2010/10/23 06:00
CRDT- 2009/12/17 06:00
PHST- 2009/09/16 00:00 [received]
PHST- 2009/11/10 00:00 [accepted]
PHST- 2009/12/17 06:00 [entrez]
PHST- 2009/12/17 06:00 [pubmed]
PHST- 2010/10/23 06:00 [medline]
AID - 10.1007/s00125-009-1624-0 [doi]
PST - ppublish
SO  - Diabetologia. 2010 Mar;53(3):541-51. doi: 10.1007/s00125-009-1624-0. Epub 2009 
      Dec 12.