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Disruption of Hexokinase II-Mitochondrial Binding Blocks Ischemic Preconditioning and Causes Rapid Cardiac Necrosis.
MedLine Citation:
PMID:  21527739     Owner:  NLM     Status:  Publisher    
Rationale: Isoforms I and II of the glycolytic enzyme hexokinase (HKI and HKII) are known to associate with mitochondria. It is unknown whether mitochondria-bound hexokinase is mandatory for ischemic preconditioning and normal functioning of the intact, beating heart. Objective: We hypothesized that reducing mitochondrial hexokinase would abrogate ischemic preconditioning and disrupt myocardial function. Methods and Results: Ex vivo perfused HKII(+/-) hearts exhibited increased cell death after ischemia and reperfusion injury compared with wild-type hearts; however, ischemic preconditioning was unaffected. To investigate acute reductions in mitochondrial HKII levels, wild-type hearts were treated with a TAT control peptide or a TAT-HK peptide that contained the binding motif of HKII to mitochondria, thereby disrupting the mitochondrial HKII association. Mitochondrial hexokinase was determined by HKI and HKII immunogold labeling and electron microscopy analysis. Low-dose (200 nmol/L) TAT-HK treatment significantly decreased mitochondrial HKII levels without affecting baseline cardiac function but dramatically increased ischemia-reperfusion injury and prevented the protective effects of ischemic preconditioning. Treatment for 15 minutes with high-dose (10 μmol/L) TAT-HK resulted in acute mitochondrial depolarization, mitochondrial swelling, profound contractile impairment, and severe cardiac disintegration. The detrimental effects of TAT-HK treatment were recapitulated by mitochondrial membrane depolarization after mild mitochondrial uncoupling that did not cause mitochondrial permeability transition opening. Conclusions: Acute low-dose dissociation of HKII from mitochondria in heart prevented ischemic preconditioning, whereas high-dose HKII dissociation caused cessation of cardiac contraction and tissue disruption, likely through an acute mitochondrial membrane depolarization mechanism. The results suggest that the association of HKII with mitochondria is essential for the protective effects of ischemic preconditioning and normal cardiac function through maintenance of mitochondrial potential.
Kirsten M A Smeele; Richard Southworth; Rongxue Wu; Chaoqin Xie; Rianne Nederlof; Alice Warley; Jessica K Nelson; Pepijn van Horssen; Jeroen P van den Wijngaard; Sami Heikkinen; Markku Laakso; Anneke Koeman; Maria Siebes; Otto Eerbeek; Fadi G Akar; Hossein Ardehali; Markus W Hollmann; Coert J Zuurbier
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-4-28
Journal Detail:
Title:  Circulation research     Volume:  -     ISSN:  1524-4571     ISO Abbreviation:  -     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-4-29     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology, Department of Physiology, and Department of Biomedical Engineering & Physics, Academic Medical Center, Amsterdam, Netherlands; Department of Imaging Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, Centre for Ultrastructural Imaging, King's College, London, United Kingdom; Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, IL; Department of Medicine, Mount Sinai School of Medicine, New York, NY; and A.I. Virtanen Institute and Department of Biochemistry and Biotechnology, University of Kuopio, Kuopio, Finland.
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