title: Cardiac mitochondrial biogenesis in endotoxemia is not accompanied by mitochondrial function recovery.
abstract: Mitochondrial biogenesis emerges as a compensatory mechanism involved in the recovery process in endotoxemia and sepsis. The aim of this work was to analyze the time course of the cardiac mitochondrial biogenesis process occurring during endotoxemia, with emphasis on the quantitative analysis of mitochondrial function. Female Sprague-Dawley rats (45 days old) were ip injected with LPS (10 mg/kg). Measurements were performed at 0-24 h after LPS administration. PGC-1α and mtTFA expression for biogenesis and p62 and LC3 expression for autophagy were analyzed by Western blot; mitochondrial DNA levels by qPCR, and mitochondrial morphology by transmission electron microscopy. Mitochondrial function was evaluated as oxygen consumption and respiratory chain complex activity. PGC-1α and mtTFA expression significantly increased in every time point analyzed, and mitochondrial mass was increased by 20% (P<0.05) at 24 h. p62 expression was significantly decreased in a time-dependent manner. LC3-II expression was significantly increased at all time points analyzed. Ultrastructurally, mitochondria displayed several abnormalities (internal vesicles, cristae disruption, and swelling) at 6 and 18 h. Structures compatible with fusion/fission processes were observed at 24 h. A significant decrease in state 3 respiration was observed in every time point analyzed (LPS 6h: 20%, P<0.05). Mitochondrial complex I activity was found decreased by 30% in LPS-treated animals at 6 and 24h. Complex II and complex IV showed decreased activity only at 24 h. The present results show that partial restoration of cardiac mitochondrial architecture is not accompanied by improvement of mitochondrial function in acute endotoxemia. The key implication of our study is that cardiac failure due to bioenergetic dysfunction will be overcome by therapeutic interventions aimed to restore cardiac mitochondrial function.
authors.affiliation: Institute of Biochemistry and Molecular Medicine, School of Pharmacy and Biochemistry, University of Buenos Aires-CONICET, Junín 956, C1113AAD Buenos Aires, Argentina.
authors.forename: Virginia
authors.initials: V
authors.lastname: Vanasco
authors.affiliation: Institute of Cellular Biology and Neuroscience, School of Medicine, University of Buenos Aires-CONICET, Paraguay 2155, C1121ABG Buenos Aires, Argentina.
authors.forename: Trinidad
authors.initials: T
authors.lastname: Saez
authors.affiliation: Institute of Biochemistry and Molecular Medicine, School of Pharmacy and Biochemistry, University of Buenos Aires-CONICET, Junín 956, C1113AAD Buenos Aires, Argentina.
authors.forename: Natalia D
authors.initials: ND
authors.lastname: Magnani
authors.affiliation: Institute of Biochemistry and Molecular Medicine, School of Pharmacy and Biochemistry, University of Buenos Aires-CONICET, Junín 956, C1113AAD Buenos Aires, Argentina.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pereyra
authors.affiliation: Institute of Biochemistry and Molecular Medicine, School of Pharmacy and Biochemistry, University of Buenos Aires-CONICET, Junín 956, C1113AAD Buenos Aires, Argentina.
authors.forename: Timoteo
authors.initials: T
authors.lastname: Marchini
authors.affiliation: Servicio de Huellas Digitales Genéticas, School of Pharmacy and Biochemistry, University of Buenos Aires-CONICET, Junín 956, C1113AAD Buenos Aires, Argentina.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Corach
authors.affiliation: Institute of Biochemistry and Molecular Medicine, School of Pharmacy and Biochemistry, University of Buenos Aires-CONICET, Junín 956, C1113AAD Buenos Aires, Argentina.
authors.forename: María Inés
authors.initials: MI
authors.lastname: Vaccaro
authors.affiliation: Servicio de Huellas Digitales Genéticas, School of Pharmacy and Biochemistry, University of Buenos Aires-CONICET, Junín 956, C1113AAD Buenos Aires, Argentina.
authors.forename: Daniel
authors.initials: D
authors.lastname: Corach
authors.affiliation: Institute of Biochemistry and Molecular Medicine, School of Pharmacy and Biochemistry, University of Buenos Aires-CONICET, Junín 956, C1113AAD Buenos Aires, Argentina.
authors.forename: Pablo
authors.initials: P
authors.lastname: Evelson
authors.affiliation: Institute of Biochemistry and Molecular Medicine, School of Pharmacy and Biochemistry, University of Buenos Aires-CONICET, Junín 956, C1113AAD Buenos Aires, Argentina. Electronic address: salvarez@ffyb.uba.ar.
authors.forename: Silvia
authors.initials: S
authors.lastname: Alvarez
mesh_terms: D000818:Animals; D001343:Autophagy; D001831:Body Temperature; D019446:Endotoxemia / Q000276:immunology / Q000378:metabolism; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008929:Mitochondria, Heart / Q000502:physiology*; D063269:Mitochondrial Turnover; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D008869:Microtubule-Associated Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; C526109:Anxa3 protein, rat; C501429:Ppargc1a protein, rat; C489030:Tfam protein, rat
keywords: Endotoxemia; LPS; Mitochondrial biogenesis; Mitochondrial function; O(2) metabolism; Rat heart