RGD Reference Report - Abnormal mitochondrial fusion-fission balance contributes to the progression of experimental sepsis. - Rat Genome Database

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Abnormal mitochondrial fusion-fission balance contributes to the progression of experimental sepsis.

Authors: Gonzalez, A S  Elguero, M E  Finocchietto, P  Holod, S  Romorini, L  Miriuka, S G  Peralta, J G  Poderoso, J J  Carreras, M C 
Citation: Gonzalez AS, etal., Free Radic Res. 2014 Jul;48(7):769-83. doi: 10.3109/10715762.2014.906592. Epub 2014 Apr 10.
RGD ID: 13204837
Pubmed: PMID:24720571   (View Abstract at PubMed)
DOI: DOI:10.3109/10715762.2014.906592   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MFN2HumanSepsis  ISOMfn2 (Rattus norvegicus)mRNA:decreased expression:liver (rat)RGD 
Mfn2RatSepsis  IEP mRNA:decreased expression:liver (rat)RGD 
Mfn2MouseSepsis  ISOMfn2 (Rattus norvegicus)mRNA:decreased expression:liver (rat)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mfn2  (mitofusin 2)

Genes (Mus musculus)
Mfn2  (mitofusin 2)

Genes (Homo sapiens)
MFN2  (mitofusin 2)


Additional Information