title: Analysis of Mitochondrial Proteins in the Surviving Myocardium after Ischemia Identifies Mitochondrial Pyruvate Carrier Expression as Possible Mediator of Tissue Viability.
abstract: The endogenous mechanisms contributing to tissue survival following myocardial infarction are not fully understood. We investigated the alterations in the mitochondrial proteome after ischemia-reperfusion (I/R) and its possible implications on cell survival. Mitochondrial proteomic analysis of cardiac tissue from an in vivo porcine I/R model found that surviving tissue in the peri-infarct border zone showed increased expression of several proteins. Notably, these included subunits of the mitochondrial pyruvate carrier (MPC), namely MPC1 and MPC2. Western blot, immunohistochemistry, and mRNA analysis corroborated the elevated expression of MPC in the surviving tissue. Furthermore, MPC1 and MPC2 protein levels were found to be markedly elevated in the myocardium of ischemic cardiomyopathy patients. These findings led to the hypothesis that increased MPC expression is cardioprotective due to enhancement of mitochondrial pyruvate uptake in the energy-starved heart following I/R. To test this, isolated mouse hearts perfused with a modified Krebs buffer (containing glucose, pyruvate, and octanoate as metabolic substrates) were subjected to I/R with or without the MPC transport inhibitor UK5099. UK5099 increased myocardial infarction and attenuated post-ischemic recovery of left ventricular end-diastolic pressure. However, aerobically perfused control hearts that were exposed to UK5099 did not modulate contractile function, although pyruvate uptake was blocked as evidenced by increased cytosolic lactate and pyruvate levels. Our findings indicate that increased expression of MPC leads to enhanced uptake and utilization of pyruvate during I/R. We propose this as a putative endogenous mechanism that promotes myocardial survival to limit infarct size.
authors.affiliation: From the ‡Cardiovascular Division, King's College London, The Rayne Institute, and St. Thomas' Hospital, London SE1 7EH, United Kingdom;
authors.forename: Mariana
authors.initials: M
authors.lastname: Fernández-Caggiano
authors.affiliation: From the ‡Cardiovascular Division, King's College London, The Rayne Institute, and St. Thomas' Hospital, London SE1 7EH, United Kingdom;
authors.forename: Oleksandra
authors.initials: O
authors.lastname: Prysyazhna
authors.affiliation: the §Cardiovascular Division, King's College London James Black Centre, London SE5 9NU, United Kingdom;
authors.forename: Javier
authors.initials: J
authors.lastname: Barallobre-Barreiro
authors.affiliation: ¶the Interventional Cardiology Unit.
authors.forename: Ramón
authors.initials: R
authors.lastname: CalviñoSantos
authors.affiliation: ¶the Interventional Cardiology Unit.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Aldama López
authors.affiliation: ‖Advanced Heart Failure and Heart Transplant Unit.
authors.forename: Maria
authors.initials: M
authors.lastname: Generosa Crespo-Leiro
authors.affiliation: From the ‡Cardiovascular Division, King's College London, The Rayne Institute, and St. Thomas' Hospital, London SE1 7EH, United Kingdom;
authors.forename: Philip
authors.initials: P
authors.lastname: Eaton
authors.affiliation: **Cardiac Biomarkers Group, Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, As Xubias 84, 15006 A Coruña, Spain nieves.domenech.garcia@sergas.es.
authors.forename: Nieves
authors.initials: N
authors.lastname: Doménech
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins; D015153:Blotting, Western; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D025341:Principal Component Analysis; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D053719:Tandem Mass Spectrometry; D014022:Tissue Survival
chemical_list: D027321:Anion Transport Proteins; C573718:MPC1 protein, human; C000595573:MPC1 pyruvate carrier protein, mouse; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D027501:Monocarboxylic Acid Transporters; D020543:Proteome