Attenuation of cardiac mitochondrial dysfunction by melatonin in septic mice

Abstract

Sepsis-induced multiple organ failure is the major cause of mortality in critically ill patients, and its incidence is rising [1]. The heart and cardiovascular systems are seriously affected during sepsis [2]. Although myocardial impairment in sepsis has been extensively studied, its etiology remains unclear [3]. Some reports The existence of an inducible mitochondrial nitric oxide synthase has been recently related to the nitrosative ⁄ oxidative damage and mitochondrial dysfunction that occurs during endotoxemia. Melatonin inhibits both inducible nitric oxide synthase and inducible mitochondrial nitric oxide synthase activities, a finding related to the antiseptic properties of the indoleamine. Hence, we examined the changes in inducible nitric oxide synthase ⁄ inducible mitochondrial nitric oxide synthase expression and activity, bioenergetics and oxidative stress in heart mitochondria following cecal ligation and puncture-induced sepsis in wild-type (iNOS + ⁄ + ) and inducible nitric oxide synthase-deficient (iNOS -⁄ -) mice. We also evaluated whether melatonin reduces the expression of inducible nitric oxide synthase ⁄ inducible mitochondrial nitric oxide synthase, and whether this inhibition improves mitochondrial function in this experimental paradigm. The results show that cecal ligation and puncture induced an increase of inducible mitochondrial nitric oxide synthase in iNOS + ⁄ + mice that was accompanied by oxidative stress, respiratory chain impairment, and reduced ATP production, although the ATPase activity remained unchanged. Real-time PCR analysis showed that induction of inducible nitric oxide synthase during sepsis was related to the increase of inducible mitochondrial nitric oxide synthase activity, as both inducible nitric oxide synthase and inducible mitochondrial nitric oxide synthase were absent in iNOS -⁄ -mice. The induction of inducible mitochondrial nitric oxide synthase was associated with mitochondrial dysfunction, because heart mitochondria from iNOS -⁄ -mice were unaffected during sepsis. Melatonin treatment blunted sepsis-induced inducible nitric oxide synthase ⁄ inducible mitochondrial nitric oxide synthase isoforms, prevented the impairment of mitochondrial homeostasis under sepsis, and restored ATP production. These properties of melatonin should be considered in clinical sepsis.

Mitochondrial DNA and inflammatory diseases

“…Moreover, inducible nitric oxide synthase (iNOS) induction during inflammation led to increased mitochondrial iNOS (i-mtNOS) enzyme activity, producing high levels of nitric oxide (NO Á ) responsible for the respiratory chain (RC) inhibition, ATP reduction Lopez et al 2006b), and mtDNA damage (Bartz et al 2011), all of them related to the severity of the inflammatory process (Brealey et al 2002). In these conditions, mitochondrial impairment produces ROS and RNS that in turn reduces mitochondrial bioenergetics, favoring cell damage and death (Escames et al 2007;Lopez et al 2006b). On the other hand, there are specific pathophysiological conditions directly derived from mtDNA mutations, causing chronic inflammatory diseases including neuromuscular and neurodegenerative disorders (Acuna et al 2011;DiMauro 2010;Muller et al 2010;Reddy 2008).…”

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…Mitochondrial impairment produces ROS and reactive nitrogen species (RNS) that in turn reduce mitochondrial bioenergetics, favoring cell damage and death [142,143]. Effectively, melatonin treatment significantly inhibits cholangiocarcinoma development [141].…”

Mitochondrial dysfunction and HIF1α stabilization in inflammation

“…These findings prompted us to suggest that tissue dysoxia, which is characteristic of septic shock, is due to overproduction of NO, resulting in a mitochondrial defect with the consequent decrease in the extraction of O 2 by tissues, leading ultimately to multiple organ failure and death (Rees et al, 1998;Orsi et al, 2000b). In recent years, evidence in favour of this hypothesis has been accumulating, including the demonstration of a significant mitochondrial defect in biopsies of skeletal muscle of individuals with sepsis (Brealey et al, 2002), the observation of an NO-dependent defect in complex I of biopsies obtained from animals with septic shock (Protti et al, 2007) and the preservation of mitochondrial activity in a septic shock model in inducible nitric oxide synthase (iNOS) knockout mice (Escames et al, 2007). As NO, which is produced in large quantities by iNOS, is also known to be involved in localized acute and/or chronic inflammatory and degenerative disorders, we suggested that a similar mitochondrial defect to that observed in septic shock is likely to occur in such conditions (Moncada and Erusalimsky, 2002).…”