info:eu-repo/semantics/article
Abnormal mitochondrial fusion-fission balance contributes to the progression of experimental sepsis
Fecha
2014-04Registro en:
Gonzalez, Analia Silvia; Elguero, María Eugenia; Finocchietto, P.; Holod, Silvia; Romorini, Leonardo; et al.; Abnormal mitochondrial fusion-fission balance contributes to the progression of experimental sepsis; Taylor & Francis; Free Radical Research; 48; 7; 4-2014; 769-783
1071-5762
CONICET Digital
CONICET
Autor
Gonzalez, Analia Silvia
Elguero, María Eugenia
Finocchietto, P.
Holod, Silvia
Romorini, Leonardo
Miriuka, Santiago Gabriel
Peralta, J. G.
Poderoso, Juan José
Carreras, Maria Cecilia
Resumen
Sepsis-associated multiple organ failure is a major cause of mortality characterized by a massive increase of reactive oxygen and nitrogen species (ROS/RNS) and mitochondrial dysfunction. Despite intensive research, determining events in the progression or reversal of the disease are incompletely understood. Herein, we studied two prototype sepsis models: endotoxemia and cecal ligation and puncture (CLP) - which showed very different lethality rates (2.5% and 67%, respectively) - , evaluated iNOS, ROS and respiratory chain activity, and investigated mitochondrial biogenesis and dynamics, as possible processes involved in sepsis outcome. Endotoxemia and CLP showed different iNOS, ROS/RNS, and complex activities time-courses. Moreover, these alterations reverted after 24-h endotoxemia but not after CLP. Mitochondrial biogenesis was not elicited during the first 24 h in either model but instead, 50% mtDNA depletion was observed. Mitochondrial fusion and fission were evaluated using real-time PCR of mitofusin-2 (Mfn2), dynamin-related protein-1 (Drp1), and using electron microscopy. During endotoxemia, we observed a decrease of Mfn2-mRNA levels at 4-6 h, and an increase of mitochondrial fragmentation at 6 h. These parameters reverted at 24 h. In contrast, CLP showed not only decreased Mfn2-mRNA levels at 12-18 h but also increased Drp1-mRNA levels at 4 h, and enhanced and sustained mitochondrial fragmentation. The in vivo pretreatment with mdivi-1 (Drp1 inhibitor) significantly attenuated mitochondrial dysfunction and apoptosis in CLP. Therefore, abnormal fusion-to-fission balance, probably evoked by ROS/RNS secondary to iNOS induction, contributes to the progression of sepsis. Pharmacological targeting of Drp1 may be a potential novel therapeutic tool for sepsis.