Abnormal mitochondrial fusion-fission balance contributes to the progression of experimental sepsis.
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.
Laboratory of Oxygen Metabolism, University of Buenos Aires, INIGEM-CONICET , Buenos Aires , Argentina.
A S
AS
Gonzalez
M E
ME
Elguero
P
P
Finocchietto
S
S
Holod
L
L
Romorini
S G
SG
Miriuka
J G
JG
Peralta
J J
JJ
Poderoso
M C
MC
Carreras
D000818:Animals; D018450:Disease Progression; D008026:Ligation; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D063154:Mitochondrial Dynamics / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D052999:Quinazolinones / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism / Q000473:pathology*; D015996:Survival Rate
C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D008070:Lipopolysaccharides; D052999:Quinazolinones; D017382:Reactive Oxygen Species
iNOS; lipopolysaccharide; mitochondria; nitric oxide; reactive oxygen species