Under physiological conditions, mitochondria reduce monovalent O₂ by generating O²⁻ During substrate oxidation, a small amount of O₂ is reduced by Mn superoxide dismutase to H₂O₂. However, a steady state concentration of ROS causes reversible or irreversible modifications to biomolecules, such as protein carbonylation or lipid peroxidation (28,29). In addition, mitochondrial enzymes function normally and mitochondrial DNA is particularly susceptible to damage caused by ROS, leading to incomplete reduction of oxygen and superoxide formation, which leads to ROS production (30). Decreased production of ROS prevents mitochondrial dysfunction in LPS-induced animal models (31,32). In LPS-induced rat models, increased ROS causes mitochondrial respiratory dysfunction, which leads to septic cardiac disease and performance (33,34). In addition, ROS production is decreased by increasing the activity of complex enzymes in mitochondria in CLP-induced mouse models (35,36).

Mitochondria also produce NO via the activity of mitochondrial NO synthase (mtNOS), which physiologically regulates mitochondrial respiration by inhibition of cytochrome C oxidase (37,38). Under physiological conditions, abundant O²⁻ and NO react to form peroxynitrite (ONOO⁻), which acts as a strong oxidizing agent. The enhanced expression of mtNOS is induced in CLP-induced mouse models, which contributes to increased mitochondrial ONOO⁻ levels (39,40). The critical causative factors responsible for mitochondrial dysfunction include inducible NOS (iNOS) synthase and mtNOS. It has been reported that mitochondrial dysfunction is not observed in the iNOS knockout mouse model (41). Pharmacological inhibition or genetic deletion of iNOS improves heart function in mouse models (41,42). Moreover, studies have found that the activities of complexes I and IV on the IMM are decreased by significantly boosting NO for a long time (43). Therefore, mitochondrial disorders attributed to NO may be primarily caused by abnormal iNOS expression. At present, most of the aforementioned studies have been conducted on iNOS-induced NO production, which may have some limitations, such as focus only on iNOS induced NO production, with a lack of mtNOS studies. However, NO is produced by multiple NOS isoforms (not only mitochondria) in different intracellular locations and cell types. In summary, one of the major causes of mitochondrial dysfunction involves ROS and NO, which may be key mechanisms of action in sepsis (Table I).

Mitochondrial membrane permeability occurs within the mitochondrial membrane via the Ca²⁺ transport channel mPTP (44), the primary components of which are ATP synthase dimers and mitochondrial phosphate transporters (45). The three key processes involved in calcium transport are as follows: Firstly, cyclophilin D activates the pores in response to changes in mitochondrial calcium levels (46). Secondly, mPTP activation facilitates release of calcium from the mitochondria into the cytosol, where it activates calcium-dependent pathways (47,48). Ca²⁺ overload triggers the mPTP to open and release cytochrome C into the cytoplasm and the cytoplasm is released (45). In addition, the Ca²⁺-dependent state of the mPTP is influenced by the calcium concentration within the cell (49). Generally, calcium transport causes mitochondrial swelling and dysfunction as a result of calcium transport. A study has shown mitochondrial vacuolation and damaged mitochondrial cristae in cardiomyocytes of septic rats with increased cytochrome C in the cytoplasm (50). At the same time, the amount of Ca²⁺ able to enter the cytoplasm is determined by the number of membrane L-type calcium channels and the amount of Ca²⁺ stored in the sarcoplasmic reticulum (51). Additionally, dantrolene prevents mitochondrial Ca²⁺ overload, which improves mitochondrial dysfunction, by inhibiting sarcoplasmic reticulum Ca²⁺ leaks (52). Taken together, these conditions may result in cytoplasmic calcium overload, leading to mitochondrial deterioration and contractile dysfunction due to mPTP opening.

Triphenylphosphonium (TPP), covalent quinone (MitoQ) and vitamin E have been prescribed as medications for treating SC. A powerful antioxidant targeting mitochondria, MitoQ binds coenzyme Q10 via triphenylphosphine, used for improving mitochondrial function in SC (53). In a rat model of sepsis, treatment with vitamin E conjugated to TPP decreased ROS-related damage (54). Additionally, as an antioxidant, lipoic acid might improve mitochondrial performance and alleviate septic shock (55). To determine whether the treatment modality used to treat mitochondrial dysfunction could be a viable therapeutic option in the future, researchers need to use drugs to prevent or reverse specific mitochondrial functions.

During sepsis, there is a significant demand for energy, which is met by lipid mobilization (59). To make up for energy loss, adipose tissue undergoes increased lipolysis to release fatty acid and glycerol into the bloodstream (60). Sepsis is characterized by notable deregulation of genes typically involved in lipid metabolism due to the inflammatory response, such as PPARα, PGC1α and PPARγ. At the same time, FA metabolism stops when carnitine palmitoyltransferase 1, acyl coenzyme a synthetase and carnitine palmitoyltransferase-1 expression is impaired. Studies have shown that LPS reduces PPARα and PGC1α expression in LPS-induced rats, thereby regulating the β-oxidation pathway (61,62). The inhibition of PPARγ activation protects mice from sepsis-related cardiac dysfunction (63). In addition, studies have found that defects in the enzymes carnitine palmitoyl transferase 1 and CD36 cause inefficient fatty acid transport, which contributes to fatty acid oxidation (64). Finally, studies have found that LPS reduces enzymes activity related to FA metabolism, such as acyl-CoA synthetase and carnitine palmitoyl transferase-1 (65,66). Imbalance of FA demand and supply between the cytoplasm and mitochondria may cause lipid accumulation in the cytoplasm (67). Moreover, patients with sepsis exhibit fat buildup in cardiac muscle, kidney and liver (68). Taken together, lipid metabolism and associated enzyme transport are notable energy providers in sepsis (Table II).

Sepsis may lead to a high metabolic state throughout the body, which increases ketone body production and lipid breakdown (69). During prolonged fasting, hypoglycemia occurs, resulting in promotion of ketogenesis in hepatocyte mitochondria. The ketogenic effect may serve a valuable role in biodefense as ketone bodies confer resistance to ROS (70). Ketone body metabolism may increase ATP production or contribute to systemic hypercatabolism associated with calorie restriction (71,72). Ketone metabolism is a method to maintain cardiac energy homeostasis. Studies have found that LPS injection in mice lacking fatty acid binding protein 4 (FABP4) and FABP5 inhibits hepatic and cardiac ketogenesis, as FABP4 serves an active role in FA transport (73,74). At the same time, gene expression associated with 3-oxoacid coenzyme was significantly reduced in both DoubleClick and wild-type mice (73,74).

The aforementioned studies suggest that ketone bodies may represent a pathogenic mechanism in sepsis (Table II).

During SC, glucose oxidation does not increase to compensate for the decrease in FAO caused by insulin resistance and glucose metabolism inhibition (75,76). In mice models of endotoxic shock, there is a rapid drop in myocardial glucose levels compared with hemorrhagic shock (77,78) Increased levels of pyruvate dehydrogenase kinase 2 (PDK2) and PDK4 protein inhibit glucose oxidation (79). Moreover, 2-deoxy-D-glucose (2-DG) also improves cardiac function and survival outcomes in a mouse model of sepsis (80). The aforementioned findings indicate that increased glycolytic metabolism contributes to cardiac dysfunction in sepsis and that modulating metabolism following sepsis would be an appropriate strategy (Table II).

Amino acids play crucial roles in both the synthesis and breakdown of proteins, which is vital for maintaining cellular homeostasis. Sepsis activates proteolysis, which splits proteins into smaller polypeptides and amino acids, allowing them to rebuild energy-rich molecules (81–83). It is reported that amino acid uptake by the heart is 90% lower compared with other organs in CLP-induced mouse models (84,85). Moreover, studies have demonstrated that decreases in alanine and glutamate lead to changes in cardiac metabolism in rats (86,87). Collectively, amino acids may be required for the liver to maintain protein hydrolysis in sepsis (Table II).

Nuclear receptor transcription factors regulate metabolic homeostasis, inflammatory response and cell death through nuclear receptors (76,77). Studies have found that PPARα is present in the liver, PPARβ is highly active in skeletal muscle and PPARγ is associated with the control of the inflammatory reaction, apoptosis and sepsis (88,89). PPARγ suppresses expression of pro-inflammatory genes, mainly by scavenging transcription factors and their cofactors, thus preventing binding to their cognate binding sites in the promoters of target genes (90,91). In addition, immune cells can produce large amounts of pro-inflammatory mediators in the early stages of sepsis, and PPARγ regulates sepsis by promoting apoptosis (92,93). In a mouse model of CLP-induced inflammation, inhibition of NF-κB p65 phosphorylation and activation via upregulation of PPARγ attenuates inflammation (94). Studies have found that total protein concentration, neutrophils and macrophages are reduced in LPS-induced mice (95,96) Decreased inflammatory factor release is attributed to the conversion of macrophages from type M1 to M2. Moreover, the M1 macrophage increases chemokine ligand production in a CLP-induced mouse model by increasing endothelial cell hyperpermeability and phosphorylation of p38 by inhibiting PPARγ (97). In conclusion, activation of PPARγ may contribute to reduction of pro-inflammatory properties during SC (Table III).

The predominant form of NF-κB is a heterodimer of p50 and p65 proteins (98). The protein is normally sequestered in the cytosol by a class of inhibitory proteins known as IκBs. These comprise seven members, including IκBα, IκBβ and IκΒγ (99). Under physiological conditions, NF-κB forms a complex with IκBα to undergo cytoplasmic sequestration. When stimulated by activating signals, NF-κB undergoes phosphorylation, ubiquitination and degradation, which leads to an activated NF-κB form that travels to the nucleus to induce gene transcription (100). NF-κB attenuates sepsis-induced systemic inflammation and myocardial injury by inhibiting NF-κB signaling (101). Additionally, studies have demonstrated that suppressing NF-κB activation decreases systemic hypotension, improves septic myocardial dysfunction and vascular abnormality, inhibits expression of numerous pro-inflammatory genes, decreases intravascular coagulation and neutrophil infiltration and prevents endothelial leakage (102,103).

When the NF-κB signaling pathway is engaged, phosphorylation of NF-κB pathway factors such as p65 and inhibitor κBα occurs (104,105). Moreover, studies have shown that decreasing TNF-α and IL-6 secretion, cytokines that promote inflammation in a LPS-induced rat model, stimulates the NF-κB signaling pathway (106,107). In summary, NF-κB suppresses inflammatory factors and proinflammatory genes that might be involved in sepsis symptoms (Table III).

Ferroptosis pathways are iron-dependent, non-apoptotic and characterized by specific biochemical and morphological changes (108). The majority of iron in the body is bound to hemoglobin and myoglobin, with the rest primarily bound to ferritin and transferrin (109). In some cases, the cellular defense mechanism limits the cell iron export system, leading to an overload of cellular iron. Peroxylated lipids are produced as a result of the Fenton reaction, resulting in the damage of organelles (110). The bloodstream contains tetrapyrrole hemoglobin containing iron during SC. Under the action of heme oxygenase 1 (HO-1) enzyme, stable heme is degraded to biliverdin, carbon monoxide and iron in vivo (111,112). Additionally, HO-1 induces immunosuppression during sepsis, promotes helper T cell 1(Th1) to Th2 cytokine transfer and induces apoptosis in immune cells (113). The product of the HO-1 reaction is unstable iron, which promotes synthesis of ferritin and reduces the toxic effects of iron. The abnormal activation of HO-1 may result in the loss of the antioxidant action, increase levels of the labile iron pool (LIP) and eventually cause iron deficiency (114). In a mouse model of sepsis, the expression of HO-1 leads to altered iron metabolism protein levels and ferroptosis (115). Taken together, HO-1 causes ferroptosis by degrading heme and elevating LIP to release ferritin into the body.

Hepcidin, a liver-derived peptide hormone, maintains iron homeostasis in the body. Studies have shown that hepcidin ubiquitinates ferroportin (FPN) and reduces its activity, thus lowering iron concentrations (116,117) Patients with sepsis have significantly higher concentrations of hepcidin. Expression of hepcidin is induced by IL-6 and IL-1β when inflammation takes place (118). The serum iron levels are effectively regulated by hepcidin in a mouse model induced by LPS (119). Furthermore, studies have shown that high hepcidin expression decreases FPN activity, which decreases iron levels in plasma (120,121) Hence, hepcidin protein expression inhibits iron transport, causing an imbalance in iron homeostasis, which results in death from iron deficiency (Fig. 3).

Under physiological conditions, pyroptosis is mediated by inflammasome-activated caspases and gasdermin D (GSDMD), final effectors of the GSDM protein family, leading to pore formation in the plasma membrane and leakage of inflammatory mediators (122,123). Under pathogenic conditions, LPS from Gram-negative bacteria directly activates caspase 4/5/11, in the inflammasome pathway, without the need for the inflammasome or caspase-1. GSDMD can be cleaved to produce N-GSDMD by activated caspase 4/5/11. N-GSDMD indirectly promotes NLRP3 inflammasome assembly via K⁺ efflux, which aggravates pyroptosis (124,125). Studies have found that doxorubicin upregulates NADPH oxidase 1 and NADPH oxidase 4 expression, thereby activating dynamin-related protein-1and promoting mitochondrial fission, leading to excessive accumulation of ROS in mitochondria and activation of the NLRP3 inflammasome and caspase-1dependent apoptosis (126,127) Certain studies have found that GSDMD knockout significantly decreases NLRP3 and caspase-1 expression, increases survival and improves cardiac dysfunction in mice (128,129). Moreover, LPS directly affects nuclear localization of sting and interferon regulatory factor-3-activated sting then activates NLRP3, leading to cardiac dysfunction as well as pyroptosis (130). Collectively, pyroptosis is induced in most forms of cardiomyopathy and blocking pyroptosis by direct or indirect approaches that target the pyroptotic machinery or upstream regulators may exert a protective effect.