The pathology of SCM is primarily caused by mitochondrial dysfunction (35, 36). Using a mouse and cell model of LPS-induced sepsis, we discovered that curcumin regulated mitochondrial function by enhancing mitochondrial quality, reversed septic myocardial structural and functional damage, and significantly reduced the levels of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6 (Fig. 6). These findings provide crucial evidence supporting the protective effects of curcumin against SCM, with potential therapeutic applications.
Curcumin is a traditional Chinese medicine with hypolipidemic, anti-tumor, anti-inflammatory, choleretic, and antioxidant effects, and it has been widely used to treat cardiovascular diseases (37, 38). Prior studies have explored the cellular protective mechanisms of curcumin, including its ability to reduce pro-inflammatory mediator releases, such as IL-6, IL-1, and TNF-α, and inhibit the anti-inflammatory effect of NF-κB (23, 39, 40). Curcumin has high antioxidant activity, which can protect cell membranes by inhibiting lipid peroxidation (23). Similar to findings from previous research (3, 22), curcumin demonstrated potent anti-inflammatory antioxidant properties and maintained myocardial function in LPS-induced mouse models. Furthermore, maintaining a healthy mitochondrial network is vital for preserving heart function. Curcumin treatment protects mitochondria in diseases, such as myocardial ischemia-reperfusion injury, and heart failure (41, 42). However, previous studies have not confirmed that curcumin alleviates SCM by regulating mitochondrial function. Our study provides novel evidence supporting the use of curcumin in the prevention and treatment of SCM.
Sepsis frequently affects the heart, and sepsis-induced cardiac dysfunction is a severe complication characterized by reduced myocardial contractility and cardiac output. Severe cardiac dysfunction may require mechanical ventilation, renal replacement therapy, extracorporeal membrane oxygenation, and other therapies, and it may induce life-threatening conditions, such as decreased blood pressure, inadequate organ perfusion, and pulmonary edema (43). Therefore, investigating the pathogenesis of SCM and identifying new therapeutic targets is crucial for improving patient prognosis. This study explored the relationship between sepsis-induced cardiac and mitochondrial dysfunction.
Sepsis decreased the mitochondrial biogenesis-related gene expression and increased DRP1-mediated mitochondrial fission, resulting in mitochondrial dysfunction. Our findings are consistent with those of previous studies, including a previous study showing that sepsis and shock-induced severe ischemia-reperfusion injury activate DRP1-mediated mitochondrial fission, causing myofibrillar protein depletion and cytoskeleton disintegration in myocardial cells (44). Mitochondrial fragmentation can lead to oxidative stress, and ROS-induced lipid peroxidation can damage mitochondrial membrane integrity, causing the release of pro-apoptotic factors and worsening mitochondrial dysfunction (29). Additionally, sepsis can reduce mitochondrial biogenesis by causing excessive inflammatory responses and oxidative damage to mitochondrial DNA, resulting in energy metabolism disorders and cellular dysfunction (17). Our study revealed that curcumin treatment enhanced the sepsis-induced excessive mitochondrial fission and inhibited mitochondrial biogenesis. By restoring mitochondrial quality control, curcumin can mitigate excessive inflammation and myocardial damage caused by sepsis, thereby achieving therapeutic goals.
We focused on the SIRT1-Drp1/PGC-1α signaling pathway, which is pivotal in mitochondrial dynamics and biogenesis, to investigate the potential mechanisms underlying curcumin treatment. SIRT1 can regulate various protein activities through deacetylation and is involved in mitochondrial quality control processes such as mitochondrial ROS production (45), mitophagy (46), mitochondrial dynamics (34), and biogenesis (16). PGC-1α is a crucial transcription factor involved in mitochondrial biogenesis, and its upregulation promotes the transcription of genes involved in this process, improving mitochondrial quality and function (44). Our findings demonstrate that curcumin upregulates SIRT1 expression, and SIRT1 can activate nuclear PGC-1α activity and expression through deacetylation, promoting mitochondrial biogenesis.
Furthermore, in LPS-stimulated HL-1 cells, curcumin treatment improved the mitochondrial translocation of Drp1, which depended on SIRT1 activation. Although there was no significant change in the Drp1 expression, its translocation from the cytoplasm to the mitochondria induced mitochondrial division, resulting in fragmented and abnormal mitochondria. These results are supported by other studies that reported that SIRT1 could activate the AKT pathway in patients with diabetic myocardial infarction, leading to the AKT phosphorylation at the Ser637 site and reducing the Drp1 activation and mitochondrial Drp1 expression (47). Melatonin can protect the hearts of diabetic mice from Drp1-mediated mitochondrial fission in a SIRT1/PGC-1α-dependent manner, and PGC-1α directly regulates DRP1 expression by binding to its promoter (34). However, the mitochondrial translocation of Drp1 may be influenced by multiple factors, including Drp1-Ser616 phosphorylation and Drp1-Ser637 dephosphorylation (48, 49), Drp1-Thr585/Thr595 glycosylation modification (50), and choline metabolism-mediated mitochondrial membrane phospholipid remodeling (51). Therefore, the effect of SIRT1 on Drp1 translocation may be related to these mechanisms; however, further validation is required.
Our experimental findings demonstrate that curcumin improves sepsis-induced cardiac dysfunction by reducing mitochondrial fission and promoting mitochondrial biogenesis. However, this study has some limitations. We only investigated the effects of curcumin in animal models and in vitro cardiomyocyte cultures. Additionally, the SIRT1-mediated mechanism of regulating the mitochondrial translocation of DRP1 is still unclear.