Limits...
Highlight: Mitochondrial Mechanisms in Septic Cardiomyopathy

View Article: PubMed Central

ABSTRACT

The Authors Explain:

Sepsis is a heterogeneous and dynamic syndrome caused by imbalances in the inflammatory network and nowadays still represents a major challenge in medicine due to the complexity of the disease, its rapid progression, the heterogeneity of the patient population and the lack of organ-specific treatment. Besides neutralizing the pathogen with antibiotics, the currently recommended therapeutic strategies are symptomatic, and mortality rates remain unacceptably high. The search for a specific treatment to restore organ dysfunction began with the discovery of additional pathophysiological mechanisms other than the already accepted ones. In this context, several decades ago, it was recognized that tissue hypoperfusion may lead to tissue hypoxia during sepsis, thereby contributing to impaired ATP generation. However, it was demonstrated later that O2 delivery to some tissues was not impaired or even improved during sepsis. Recent studies strongly suggest that organ dysfunction in sepsis is rather related to an impairment in cellular O2 utilization leading to cellular energy depletion, thus shifting the attention to mitochondrial function.

End-organ damage and organ failure in sepsis affects the most significant organs of the body, including the heart. Myocardial dysfunction is a well-described complication of severe sepsis, also referred to as septic cardiomyopathy, which includes both systolic and diastolic dysfunction. The occurrence of septic cardiomyopathy can increase the mortality rate up to 70% and is considered one of the major predictors of mortality. It was widely reported that decreased cardiac contractility correlated with impaired cardiac mitochondrial function in several animal models of sepsis. Some authors also reported alterations in myocardial mitochondrial structure in septic humans. Evidence of mitochondrial dysfunction in septic or endotoxemic animals includes decreased rates of State 3 respiration and ATP synthesis, decreased respiratory control ratios and membrane potential, decreased activities or expression of mitochondrial oxidative phosphorylation (OXPHOS) complexes, increased rates of State 4 respiration, increased structural alterations, and/or increased reactive oxygen species (ROS) production. However, the underlying mechanisms of cardiac mitochondrial dysfunction still remain incompletely understood. In the current issue of the International Journal of Molecular Sciences, we reviewed the publications of the last 15 years reporting mitochondrial alterations in the heart of septic or endotoxemic animals. As shown on the cover figure, the existing evidence suggests that diverse pathways can converge in the mitochondria, leading to dysfunction. Increased mitochondrial superoxide (O2•−) and nitric oxide (NO) production can cause direct oxidative or nitrosative damage and inhibition of OXPHOS complexes, resulting in decreased O2 consumption and decreased mitochondrial membrane potential (Δψ). In addition, Δψ may drop due to increased uncoupling protein (UCP)-mediated proton leak, increased Ca2+-induced mitochondrial permeability transition pore (mPTP) opening and by direct oxidative damage of the inner mitochondrial membrane. On the other side, increased mitophagy may eliminate dysfunctional mitochondria, which may be replaced by increased mitochondrial biogenesis, mediated by activation of peroxisome proliferator-activated receptor γ coactivator 1α/β (PGC-1α/β). However, if uncoordinatedly activated, mitophagy and mitochondrial biogenesis may lead to decreased mitochondrial mass or to the production of new, but dysfunctional mitochondria. As a consequence, mitochondrial ATP regeneration is compromised and energy depletion may contribute to cardiac contractile dysfunction.

Taken together, myocardial mitochondria may be considered both as a source and a target of damaging mechanisms that evolve during increased energy demands in sepsis. Future studies should elucidate the order of appearance of the above mentioned mechanisms in order to identify the critical mechanisms which may serve as potential targets of pharmacological intervention. In addition, studies using pharmacological modulators to prevent or reverse specific mitochondrial mechanisms are needed to further clarify the importance of mitochondrial mechanisms in the pathophysiology of septic cardiomyopathy and to define a feasible therapeutic approach.

No MeSH data available.


© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4581343&req=5


Highlight: Mitochondrial Mechanisms in Septic Cardiomyopathy
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581343&req=5

View Article: PubMed Central

ABSTRACT

The Authors Explain:

Sepsis is a heterogeneous and dynamic syndrome caused by imbalances in the inflammatory network and nowadays still represents a major challenge in medicine due to the complexity of the disease, its rapid progression, the heterogeneity of the patient population and the lack of organ-specific treatment. Besides neutralizing the pathogen with antibiotics, the currently recommended therapeutic strategies are symptomatic, and mortality rates remain unacceptably high. The search for a specific treatment to restore organ dysfunction began with the discovery of additional pathophysiological mechanisms other than the already accepted ones. In this context, several decades ago, it was recognized that tissue hypoperfusion may lead to tissue hypoxia during sepsis, thereby contributing to impaired ATP generation. However, it was demonstrated later that O2 delivery to some tissues was not impaired or even improved during sepsis. Recent studies strongly suggest that organ dysfunction in sepsis is rather related to an impairment in cellular O2 utilization leading to cellular energy depletion, thus shifting the attention to mitochondrial function.

End-organ damage and organ failure in sepsis affects the most significant organs of the body, including the heart. Myocardial dysfunction is a well-described complication of severe sepsis, also referred to as septic cardiomyopathy, which includes both systolic and diastolic dysfunction. The occurrence of septic cardiomyopathy can increase the mortality rate up to 70% and is considered one of the major predictors of mortality. It was widely reported that decreased cardiac contractility correlated with impaired cardiac mitochondrial function in several animal models of sepsis. Some authors also reported alterations in myocardial mitochondrial structure in septic humans. Evidence of mitochondrial dysfunction in septic or endotoxemic animals includes decreased rates of State 3 respiration and ATP synthesis, decreased respiratory control ratios and membrane potential, decreased activities or expression of mitochondrial oxidative phosphorylation (OXPHOS) complexes, increased rates of State 4 respiration, increased structural alterations, and/or increased reactive oxygen species (ROS) production. However, the underlying mechanisms of cardiac mitochondrial dysfunction still remain incompletely understood. In the current issue of the International Journal of Molecular Sciences, we reviewed the publications of the last 15 years reporting mitochondrial alterations in the heart of septic or endotoxemic animals. As shown on the cover figure, the existing evidence suggests that diverse pathways can converge in the mitochondria, leading to dysfunction. Increased mitochondrial superoxide (O2•−) and nitric oxide (NO) production can cause direct oxidative or nitrosative damage and inhibition of OXPHOS complexes, resulting in decreased O2 consumption and decreased mitochondrial membrane potential (Δψ). In addition, Δψ may drop due to increased uncoupling protein (UCP)-mediated proton leak, increased Ca2+-induced mitochondrial permeability transition pore (mPTP) opening and by direct oxidative damage of the inner mitochondrial membrane. On the other side, increased mitophagy may eliminate dysfunctional mitochondria, which may be replaced by increased mitochondrial biogenesis, mediated by activation of peroxisome proliferator-activated receptor γ coactivator 1α/β (PGC-1α/β). However, if uncoordinatedly activated, mitophagy and mitochondrial biogenesis may lead to decreased mitochondrial mass or to the production of new, but dysfunctional mitochondria. As a consequence, mitochondrial ATP regeneration is compromised and energy depletion may contribute to cardiac contractile dysfunction.

Taken together, myocardial mitochondria may be considered both as a source and a target of damaging mechanisms that evolve during increased energy demands in sepsis. Future studies should elucidate the order of appearance of the above mentioned mechanisms in order to identify the critical mechanisms which may serve as potential targets of pharmacological intervention. In addition, studies using pharmacological modulators to prevent or reverse specific mitochondrial mechanisms are needed to further clarify the importance of mitochondrial mechanisms in the pathophysiology of septic cardiomyopathy and to define a feasible therapeutic approach.

No MeSH data available.