Protective effects of farnesyltransferase inhibitor on sepsis-induced morphological aberrations of mitochondria in muscle and increased circulating mitochondrial DNA levels in mice.
Biochem Biophys Res Commun
; 556: 93-98, 2021 06 04.
Article
in En
| MEDLINE
| ID: mdl-33845310
ABSTRACT
Sepsis remains a leading cause of mortality in critically ill patients and is characterized by multi-organ dysfunction. Mitochondrial damage has been proposed to be involved in the pathophysiology of sepsis. In addition to metabolic impairments resulting from mitochondrial dysfunction, mitochondrial DNA (mtDNA) causes systemic inflammation as a damage-associated molecular pattern when it is released to the circulation. Metabolic derangements in skeletal muscle are a major complication of sepsis and negatively affects clinical outcomes of septic patients. However, limited knowledge is available about sepsis-induced mitochondrial damage in skeletal muscle. Here, we show that sepsis induced profound abnormalities in cristae structure, rupture of the inner and outer membranes and enlargement of the mitochondria in mouse skeletal muscle in a time-dependent manner, which was associated with increased plasma mtDNA levels. Farnesyltransferase inhibitor, FTI-277, prevented sepsis-induced morphological aberrations of the mitochondria, and blocked the increased plasma mtDNA levels along with improved survival. These results indicate that protein farnesylation plays a role in sepsis-induced damage of the mitochondria in mouse skeletal muscle. Our findings suggest that mitochondrial disintegrity in skeletal muscle may contribute to elevated circulating mtDNA levels in sepsis.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA, Mitochondrial
/
Sepsis
/
Muscle, Skeletal
/
Protective Agents
/
Farnesyltranstransferase
/
Mitochondria
Limits:
Animals
Language:
En
Journal:
Biochem Biophys Res Commun
Year:
2021
Document type:
Article
Affiliation country:
Japan