INVESTIGADORES
MIRIUKA Santiago Gabriel
artículos
Título:
Abnormal mitochondrial fusion-fission balance contributes to the progression of experimental sepsis
Autor/es:
GONZALEZ AS; ELGUERO ME; FINOCCHIETO P; HOLOD S; ROMORINI L; MIRIUKA SG; PERALTA JG; PODEROSO JJ; CARRERAS MC
Revista:
FREE RADICAL RESEARCH
Editorial:
TAYLOR & FRANCIS LTD
Referencias:
Año: 2014 vol. 48 p. 769 - 783
ISSN:
1071-5762
Resumen:
Abstract 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.