Publication Date:
2016-01-20
Description:
In developing hearts, changes in the cardiac metabolic milieu during the perinatal period redirect mitochondrial substrate preference from carbohydrates to fatty acids. Mechanisms responsible for this mitochondrial plasticity are unknown. Here, we found that PINK1-Mfn2-Parkin-mediated mitophagy directs this metabolic transformation in mouse hearts. A mitofusin (Mfn) 2 mutant lacking PINK1 phosphorylation sites necessary for Parkin binding (Mfn2 AA) inhibited mitochondrial Parkin translocation, suppressing mitophagy without impairing mitochondrial fusion. Cardiac Parkin deletion or expression of Mfn2 AA from birth, but not after weaning, prevented postnatal mitochondrial maturation essential to survival. Five-week-old Mfn2 AA hearts retained a fetal mitochondrial transcriptional signature without normal increases in fatty acid metabolism and mitochondrial biogenesis genes. Myocardial fatty acylcarnitine levels and cardiomyocyte respiration induced by palmitoylcarnitine were concordantly depressed. Thus, instead of transcriptional reprogramming, fetal cardiomyocyte mitochondria undergo perinatal Parkin-mediated mitophagy and replacement by mature adult mitochondria. Mitophagic mitochondrial removal underlies developmental cardiomyocyte mitochondrial plasticity and metabolic transitioning of perinatal hearts.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747105/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747105/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gong, Guohua -- Song, Moshi -- Csordas, Gyorgy -- Kelly, Daniel P -- Matkovich, Scot J -- Dorn, Gerald W 2nd -- HL058493/HL/NHLBI NIH HHS/ -- HL108943/HL/NHLBI NIH HHS/ -- HL122124/HL/NHLBI NIH HHS/ -- HL128071/HL/NHLBI NIH HHS/ -- HL59888/HL/NHLBI NIH HHS/ -- R01 HL058493/HL/NHLBI NIH HHS/ -- R01 HL059888/HL/NHLBI NIH HHS/ -- R01 HL108943/HL/NHLBI NIH HHS/ -- R01 HL128071/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2015 Dec 4;350(6265):aad2459. doi: 10.1126/science.aad2459. Epub 2015 Dec 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA. ; Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA. ; Center for Metabolic Origins of Disease, Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL, USA. ; Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA. gdorn@dom.wustl.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26785495" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cellular Reprogramming
;
GTP Phosphohydrolases/genetics/metabolism
;
Heart/*embryology
;
Mice
;
Mice, Inbred C57BL
;
Mice, Knockout
;
Mitochondria, Heart/metabolism/*physiology/ultrastructure
;
Mitochondrial Degradation/genetics/*physiology
;
Mitochondrial Dynamics
;
Myocardium/*metabolism/ultrastructure
;
Myocytes, Cardiac/metabolism/ultrastructure
;
Protein Kinases/metabolism
;
Ubiquitin-Protein Ligases/genetics/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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