title: Genome-scale methods converge on key mitochondrial genes for the survival of human cardiomyocytes in hypoxia.
abstract: BACKGROUND
  Any reduction in myocardial oxygen delivery relative to its demands can impair cardiac contractile performance. Understanding the mitochondrial metabolic response to hypoxia is key to understanding ischemia tolerance in the myocardium. We used a novel combination of 2 genome-scale methods to study key processes underlying human myocardial hypoxia tolerance. In particular, we hypothesized that computational modeling and evolution would identify similar genes as critical to human myocardial hypoxia tolerance.
  
  
  RESULTS
  We analyzed a reconstruction of the cardiac mitochondrial metabolic network using constraint-based methods, under conditions of simulated hypoxia. We used flux balance analysis, random sampling, and principal component analysis to explore feasible steady-state solutions. Hypoxia blunted maximal ATP (-17%) and heme (-75%) synthesis and shrank the feasible solution space. Tricarboxylic acid and urea cycle fluxes were also reduced in hypoxia, but phospholipid synthesis was increased. Using mathematical optimization methods, we identified reactions that would be critical to hypoxia tolerance in the human heart. We used data regarding single-nucleotide polymorphism frequency and distribution in the genomes of Tibetans (whose ancestors have resided in persistent high-altitude hypoxia for several millennia). Six reactions were identified by both methods as being critical to mitochondrial ATP production in hypoxia: phosphofructokinase, phosphoglucokinase, complex II, complex IV, aconitase, and fumarase.
  
  
  CONCLUSIONS
  Mathematical optimization and evolution converged on similar genes as critical to human myocardial hypoxia tolerance. Our approach is unique and completely novel and demonstrates that genome-scale modeling and genomics can be used in tandem to provide new insights into cardiovascular genetics.
authors.affiliation: From the Centre of Human and Aerospace Physiological Sciences, School of Biomedical Science, King's College London, London, United Kingdom (L.M.E.); Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (M.I.S.); Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom (P.A.R.); Department of Medical and Molecular Genetics, King's College London School of Medicine, London, United Kingdom (M.E.W.); Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (G.L.C.); Institute for Human Health and Performance, University College London, London, United Kingdom (H.E.M.); and Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg (I.T.). lindsay.edwards@kcl.ac.uk.
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Edwards
authors.affiliation: From the Centre of Human and Aerospace Physiological Sciences, School of Biomedical Science, King's College London, London, United Kingdom (L.M.E.); Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (M.I.S.); Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom (P.A.R.); Department of Medical and Molecular Genetics, King's College London School of Medicine, London, United Kingdom (M.E.W.); Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (G.L.C.); Institute for Human Health and Performance, University College London, London, United Kingdom (H.E.M.); and Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg (I.T.).
authors.forename: Martin I
authors.initials: MI
authors.lastname: Sigurdsson
authors.affiliation: From the Centre of Human and Aerospace Physiological Sciences, School of Biomedical Science, King's College London, London, United Kingdom (L.M.E.); Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (M.I.S.); Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom (P.A.R.); Department of Medical and Molecular Genetics, King's College London School of Medicine, London, United Kingdom (M.E.W.); Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (G.L.C.); Institute for Human Health and Performance, University College London, London, United Kingdom (H.E.M.); and Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg (I.T.).
authors.forename: Peter A
authors.initials: PA
authors.lastname: Robbins
authors.affiliation: From the Centre of Human and Aerospace Physiological Sciences, School of Biomedical Science, King's College London, London, United Kingdom (L.M.E.); Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (M.I.S.); Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom (P.A.R.); Department of Medical and Molecular Genetics, King's College London School of Medicine, London, United Kingdom (M.E.W.); Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (G.L.C.); Institute for Human Health and Performance, University College London, London, United Kingdom (H.E.M.); and Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg (I.T.).
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weale
authors.affiliation: From the Centre of Human and Aerospace Physiological Sciences, School of Biomedical Science, King's College London, London, United Kingdom (L.M.E.); Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (M.I.S.); Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom (P.A.R.); Department of Medical and Molecular Genetics, King's College London School of Medicine, London, United Kingdom (M.E.W.); Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (G.L.C.); Institute for Human Health and Performance, University College London, London, United Kingdom (H.E.M.); and Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg (I.T.).
authors.forename: Gianpiero L
authors.initials: GL
authors.lastname: Cavalleri
authors.affiliation: From the Centre of Human and Aerospace Physiological Sciences, School of Biomedical Science, King's College London, London, United Kingdom (L.M.E.); Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (M.I.S.); Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom (P.A.R.); Department of Medical and Molecular Genetics, King's College London School of Medicine, London, United Kingdom (M.E.W.); Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (G.L.C.); Institute for Human Health and Performance, University College London, London, United Kingdom (H.E.M.); and Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg (I.T.).
authors.forename: Hugh E
authors.initials: HE
authors.lastname: Montgomery
authors.affiliation: From the Centre of Human and Aerospace Physiological Sciences, School of Biomedical Science, King's College London, London, United Kingdom (L.M.E.); Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (M.I.S.); Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom (P.A.R.); Department of Medical and Molecular Genetics, King's College London School of Medicine, London, United Kingdom (M.E.W.); Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (G.L.C.); Institute for Human Health and Performance, University College London, London, United Kingdom (H.E.M.); and Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg (I.T.).
authors.forename: Ines
authors.initials: I
authors.lastname: Thiele
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D015894:Genome, Human; D006418:Heme / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D053858:Metabolic Networks and Pathways; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010743:Phospholipids / Q000096:biosynthesis; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D040901:Proteomics; D059467:Transcriptome
chemical_list: D010743:Phospholipids; D006418:Heme; D000255:Adenosine Triphosphate
keywords: computational biology; genomics; mitochondria; systems biology