Document Detail


Mitochondrial fusion is essential for organelle function and cardiac homeostasis.
MedLine Citation:
PMID:  22052916     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: Mitochondria constitute 30% of myocardial mass. Mitochondrial fusion and fission appear essential for health of most tissues. Mitochondrial fission occurs in neonatal cardiomycyte and is implicated in cardiomyocyte death. Mitochondrial fusion has not been observed in postmitotic myocytes of adult hearts, and its occurrence and function in this context are controversial.
OBJECTIVE: Determine the consequences on organelle and organ function of disrupting cardiomyocyte mitochondrial fusion in vivo.
METHODS AND RESULTS: The murine mfn1 and mfn2 genes, encoding mitofusins (Mfn) 1 and 2 that mediate mitochondrial tethering and outer mitochondrial membrane fusion, were interrupted by Cre-mediated excision of essential exons in neonatal (Nkx2.5-Cre) and adult (MYH6 modified estrogen receptor-Cre-modified estrogen receptor plus tamoxifen or Raloxifene) hearts. Embryonic combined Mfn1/Mfn2 ablation was lethal after e9.5. Conditional combined Mfn1/Mfn2 ablation in adult hearts induced mitochondrial fragmentation, cardiomyocyte and mitochondrial respiratory dysfunction, and rapidly progressive and lethal dilated cardiomyopathy. Before heart failure developed, cardiomyocyte shortening and calcium cycling were unaffected by absence of Mfn1 and Mfn2. Based on the time course over which fusion-defective mitochondrial size decreases, a mitochondrial fusion/fission cycle in adult mouse hearts occurs approximately every 16 days.
CONCLUSIONS: Mitochondrial fusion in adult cardiac myocytes is necessary to maintain normal mitochondrial morphology and is essential for normal cardiac respiratory and contractile function. Interruption of mitochondrial fusion causes lethal cardiac failure at a time corresponding to 3 or 4 cycles of unopposed mitochondrial fission.
Authors:
Yun Chen; Yingqiu Liu; Gerald W Dorn
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-11-03
Journal Detail:
Title:  Circulation research     Volume:  109     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-13     Completed Date:  2012-02-07     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1327-31     Citation Subset:  IM    
Affiliation:
Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. gdorn@dom.wustl.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / metabolism
GTP Phosphohydrolases / deficiency,  genetics,  physiology
Gene Deletion
Heart / embryology,  physiology*
Homeostasis / physiology*
Membrane Fusion / physiology*
Mice
Mice, Knockout
Mitochondria, Heart / physiology*
Mitochondrial Membranes / physiology*
Models, Animal
Myocardial Contraction / physiology
Myocytes, Cardiac / physiology
Grant Support
ID/Acronym/Agency:
R01 HL059888-01A1/HL/NHLBI NIH HHS; R01 HL059888-02/HL/NHLBI NIH HHS; R01 HL059888-03/HL/NHLBI NIH HHS; R01 HL059888-04/HL/NHLBI NIH HHS; R01 HL059888-05/HL/NHLBI NIH HHS; R01 HL059888-06/HL/NHLBI NIH HHS; R01 HL059888-07/HL/NHLBI NIH HHS; R01 HL059888-08/HL/NHLBI NIH HHS; R01 HL059888-09A1/HL/NHLBI NIH HHS; R01 HL059888-09A1W1/HL/NHLBI NIH HHS; R01 HL059888-10/HL/NHLBI NIH HHS; R01 HL059888-11/HL/NHLBI NIH HHS; R01 HL059888-12/HL/NHLBI NIH HHS; R01 HL059888-13/HL/NHLBI NIH HHS; R01 HL59888/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
7440-70-2/Calcium; EC 3.6.1.-/GTP Phosphohydrolases; EC 3.6.1.-/Mfn1 protein, mouse; EC 3.6.1.-/Mfn2 protein, mouse
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