Current Perspectives of Mitochondria in Sepsis-Induced Cardiomyopathy

Abstract

Sepsis-induced cardiomyopathy (SICM) is one of the leading indicators for poor prognosis associated with sepsis. Despite its reversibility, prognosis varies widely among patients. Mitochondria play a key role in cellular energy production by generating adenosine triphosphate (ATP), which is vital for myocardial energy metabolism. Over recent years, mounting evidence suggests that severe sepsis not only triggers mitochondrial structural abnormalities such as apoptosis, incomplete autophagy, and mitophagy in cardiomyocytes but also compromises their function, leading to ATP depletion. This metabolic disruption is recognized as a significant contributor to SICM, yet effective treatment options remain elusive. Sepsis cannot be effectively treated with inotropic drugs in failing myocardium due to excessive inflammatory factors that blunt β-adrenergic receptors. This review will share the recent knowledge on myocardial cell death in sepsis and its molecular mechanisms, focusing on the role of mitochondria as an important metabolic regulator of SICM, and discuss the potential for developing therapies for sepsis-induced myocardial injury.

Keywords: SICM; adrenergic receptor; cell death; lncRNAs; metabolic switch; mitochondria; mitophagy; sepsis.

Figure 1

A schematic figure of mechanisms of mitochondrial dysfunction in SICM. The inflammatory response of sepsis attenuates Ca²⁺ uptake in the sarcoplasmic reticulum by upregulation of RyR and downregulation of SERCA. This abnormal Ca²⁺ flux increases Ca²⁺ concentration in mitochondria, followed by abnormal mitochondrial membrane potential and promoting mPTP opening. Theses leads to excess ROS generation, mitochondrial DNA damage, mitochondrial mitophagy, incomplete autophagy, and cell apoptotic pathway. Red arrows indicate increased expression or activity. Blue arrows indicate decreased expression or activity. A cross mark indicates no function. Abbreviations are described at the end of this manuscript.

Figure 2

A schematic figure of metabolic dysregulation in SICM. ATP synthesis in the heart is mainly dependent on fatty acid oxidation (FAO). The inflammatory response in sepsis is induced by many inflammatory mediators such as NFκB, iNOS, cytokines, and ROS, which dysregulate various genes related to FAO. Inflammation reduces CD36, FABP, and ACLS, which are cell surface transporters for fatty acids (FAs) into cells, and also reduces CPT1, which is an important enzyme for intracellular FAs to enter mitochondria. In addition, inflammatory mediators also decrease PPARs and PGC1α essential for β-oxidation. As a result, compromised ATP production induces intracellular lipid accumulation, called lipotoxicity, leading to cell death. Red arrows indicate increased expression or production. Blue arrows indicate decreased expression or production. Cross marks indicate no function. Abbreviations are described at the end of this manuscript.

Figure 3

Histological analysis of septic myocardium. Oil Red O staining demonstrates the accumulation of lipid droplets (LDs) in heart tissues of LPS injected mice. β3AR antagonist significantly reduces LDs in heart tissues post LPS injection. Electron microscope analyses also exhibits a lot of LDs around mitochondria in LPS treated heart tissues. β3AR antagonist clearly attenuates accumulation of LDs. Red arrows show lipid droplets. LPS, lipopolysaccharide; β3AR, beta 3 adrenergic receptor.