Document Detail


Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart.
MedLine Citation:
PMID:  22904094     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: At birth, there is a switch from placental to pulmonary circulation and the heart commences its aerobic metabolism. In cardiac myocytes, this transition is marked by increased mitochondrial biogenesis and remodeling of the intracellular architecture. The mechanisms governing the formation of new mitochondria and their expansion within myocytes remain largely unknown. Mitofusins (Mfn-1 and Mfn-2) are known regulators of mitochondrial networks, but their role during perinatal maturation of the heart has yet to be examined.
OBJECTIVE: The objective of this study was to determine the significance of mitofusins during early postnatal cardiac development.
METHODS AND RESULTS: We genetically inactivated Mfn-1 and Mfn-2 in midgestational and postnatal cardiac myocytes using a loxP/Myh6-cre approach. At birth, cardiac morphology and function of double-knockout (DKO) mice are normal. At that time, DKO mitochondria increase in numbers, appear to be spherical and heterogeneous in size, but exhibit normal electron density. By postnatal day 7, the mitochondrial numbers in DKO myocytes remain abnormally expanded and many lose matrix components and membrane organization. At this time point, DKO mice have developed cardiomyopathy. This leads to a rapid decline in survival and all DKO mice die before 16 days of age. Gene expression analysis of DKO hearts shows that mitochondria biogenesis genes are downregulated, the mitochondrial DNA is reduced, and mitochondrially encoded transcripts and proteins are also reduced. Furthermore, mitochondrial turnover pathways are dysregulated.
CONCLUSIONS: Our findings establish that Mfn-1 and Mfn-2 are essential in mediating mitochondrial remodeling during postnatal cardiac development, a time of dramatic transitions in the bioenergetics and growth of the heart.
Authors:
Kyriakos N Papanicolaou; Ryosuke Kikuchi; Gladys A Ngoh; Kimberly A Coughlan; Isabel Dominguez; William C Stanley; Kenneth Walsh
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-17
Journal Detail:
Title:  Circulation research     Volume:  111     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-10-01     Completed Date:  2012-12-17     Revised Date:  2014-03-27    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1012-26     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Newborn
DNA, Mitochondrial / genetics,  metabolism
Female
GTP Phosphohydrolases / genetics,  physiology*
Gene Expression Regulation, Developmental / physiology
Heart / embryology*,  growth & development*,  physiology
Heart Failure / genetics,  pathology,  physiopathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Electron
Mitochondria / pathology,  physiology,  ultrastructure
Myocardium / pathology
Myocytes, Cardiac / pathology,  physiology*,  ultrastructure
Myofibrils / pathology,  physiology,  ultrastructure
Survival Rate
Grant Support
ID/Acronym/Agency:
AG15052/AG/NIA NIH HHS; AG34972/AG/NIA NIH HHS; GM098367/GM/NIGMS NIH HHS; HL007224/HL/NHLBI NIH HHS; HL102874/HL/NHLBI NIH HHS; HL68758/HL/NHLBI NIH HHS; P01 HL068758/HL/NHLBI NIH HHS; R01 AG015052/AG/NIA NIH HHS; R01 AG034972/AG/NIA NIH HHS; R01 GM098367/GM/NIGMS NIH HHS; R01 HL120160/HL/NHLBI NIH HHS; R21 HL102874/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Mitochondrial; EC 3.6.1.-/GTP Phosphohydrolases; EC 3.6.1.-/Mfn1 protein, mouse; EC 3.6.1.-/Mfn2 protein, mouse
Comments/Corrections

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