title: Hypoxia signaling controls postnatal changes in cardiac mitochondrial morphology and function.
abstract: Fetal cardiomyocyte adaptation to low levels of oxygen in utero is incompletely understood, and is of interest as hypoxia tolerance is lost after birth, leading to vulnerability of adult cardiomyocytes. It is known that cardiac mitochondrial morphology, number and function change significantly following birth, although the underlying molecular mechanisms and physiological stimuli are undefined. Here we show that the decrease in cardiomyocyte HIF-signaling in cardiomyocytes immediately after birth acts as a physiological switch driving mitochondrial fusion and increased postnatal mitochondrial biogenesis. We also investigated mechanisms of ATP generation in embryonic cardiac mitochondria. We found that embryonic cardiac cardiomyocytes rely on both glycolysis and the tricarboxylic acid cycle to generate ATP, and that the balance between these two metabolic pathways in the heart is controlled around birth by the reduction in HIF signaling. We therefore propose that the increase in ambient oxygen encountered by the neonate at birth acts as a key physiological stimulus to cardiac mitochondrial adaptation.
authors.affiliation: MRC National Institute for Medical Research, Mill Hill, London NW7 1AA.
authors.forename: Marianne T
authors.initials: MT
authors.lastname: Neary
authors.affiliation: MRC National Institute for Medical Research, Mill Hill, London NW7 1AA.
authors.forename: Keat-Eng
authors.initials: KE
authors.lastname: Ng
authors.affiliation: UCL Institute of Neurology, Queen Square, London WC1N 3BG.
authors.forename: Marthe H R
authors.initials: MH
authors.lastname: Ludtmann
authors.affiliation: The Hatter Cardiovascular Institute, London WC1E 6HX.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hall
authors.affiliation: MRC National Institute for Medical Research, Mill Hill, London NW7 1AA.
authors.forename: Izabela
authors.initials: I
authors.lastname: Piotrowska
authors.affiliation: The Hatter Cardiovascular Institute, London WC1E 6HX.
authors.forename: Sang-Bing
authors.initials: SB
authors.lastname: Ong
authors.affiliation: The Hatter Cardiovascular Institute, London WC1E 6HX.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Hausenloy
authors.affiliation: MRC National Institute for Medical Research, Mill Hill, London NW7 1AA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mohun
authors.affiliation: UCL Institute of Neurology, Queen Square, London WC1N 3BG.
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
authors.affiliation: MRC National Institute for Medical Research, Mill Hill, London NW7 1AA; UCL Division of Medicine, London WC1E 6JJ.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Breckenridge
mesh_terms: D000222:Adaptation, Physiological; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002952:Citric Acid Cycle / Q000187:drug effects / Q000235:genetics; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000255:Adenosine Triphosphate; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D024101:Mitochondrial Proteins; D010100:Oxygen; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C494469:VHL protein, mouse
keywords: Cardiac; Hypoxia; Mitochondria; Mitofusin; Neonatal