Use of
metal carbonyl-based compounds capable of releasing
carbon monoxide (CO) in biological systems have emerged as a potential adjunctive
therapy for
sepsis via their
antioxidant, anti-inflammatory, and antiapoptotic effects. The role of CO in regulation of
mitochondrial dysfunction and biogenesis associated with
sepsis has not been investigated. In the present study, we employed a
ruthenium-based water-soluble CO carrier, tricarbonylchoro(glycinato)
ruthenium (II) (CORM-3), one of the novel CO-releasing molecules (CO-RMs), to test whether CO can improve cardiac
mitochondrial dysfunction and survival in
peritonitis-induced
sepsis.
Peritonitis was performed in mice by cecal
ligation and perforation.
Tumor necrosis factor-alpha,
interleukin-10, and
nitrite/
nitrate plasma levels were tested to evaluate the systemic inflammatory response. Functional mitochondrial studies included determination of membrane potential, respiration, and redox status. Oxidative stress was evaluated by measurements of mitochondrial
hydrogen peroxide, carbonyl
protein and GSH levels. Mitochondrial biogenesis was assessed by
peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha
protein expression and
mitochondrial DNA (
mtDNA) copy number. The systemic inflammatory response elicited by
peritonitis was accompanied by mitochondrial energetic metabolism deterioration and reduced PGC-1alpha
protein expression. CORM-3 treatment in septic mice restored the deleterious effects of
sepsis on mitochondrial membrane potential, respiratory control ratio, and energetics. It is interesting that administration of CORM-3 during
sepsis elicited a mild oxidative stress response that stimulated mitochondrial biogenesis with PGC-1alpha
protein expression and
mtDNA copy number increases. Our results reveal that delivery of controlled amounts of CO dramatically reduced mortality in septic mice, indicating that CO-RMs could be used therapeutically to prevent organ dysfunction and death in
sepsis.