| Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart. | |
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MedLine Citation:
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PMID: 22904094 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Kyriakos N Papanicolaou; Ryosuke Kikuchi; Gladys A Ngoh; Kimberly A Coughlan; Isabel Dominguez; William C Stanley; Kenneth Walsh |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-08-17 |
Journal Detail:
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Title: Circulation research Volume: 111 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2012 Sep |
Date Detail:
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Created Date: 2012-10-01 Completed Date: 2012-12-17 Revised Date: 2013-05-13 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 1012-26 Citation Subset: IM |
Affiliation:
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Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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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; R21 HL102874/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA, Mitochondrial; EC 3.6.1.-/GTP Phosphohydrolases; EC 3.6.1.-/Mfn1 protein, mouse; EC 3.6.1.-/Mfn2 protein, mouse |
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