Abstract

Sepsis-associated encephalopathy (SAE) is a devastating neurological complication of sepsis, leading to diffuse brain dysfunction, long-term cognitive deficits, and increased mortality. Its pathogenesis is complex, with mitochondrial dysfunction and neuroinflammation emerging as central, interconnected drivers. This review systematically elucidates the pathogenic crosstalk between these two processes. We detail how dysregulated mitochondrial dynamics (e.g., Drp1-mediated fission), impaired biogenesis (via the proliferator-activated receptor-gamma coactivator-1α axis), oxidative stress, and the activation of mitochondria-dependent cell death pathways (ferroptosis, pyroptosis) contribute to neuronal injury. Concurrently, microglial activation, particularly through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, creates a vicious cycle that exacerbates mitochondrial damage and synaptic loss. Furthermore, we summarize emerging therapeutic strategies that target this mitochondrial-neuroinflammatory axis, including molecular hydrogen, mitochondria-targeted peptides (SS-31), natural compounds, and specific inhibitors (e.g., Mdivi-1, MCC950). The integration of recent insights on the gut-brain axis and cerebral metabolomics further expands the therapeutic landscape. Ultimately, targeting this core axis offers a promising paradigm for developing effective interventions to improve neurological outcomes in septic patients.

1 Introduction

Sepsis-associated encephalopathy (SAE) is a prevalent and devastating neurological complication of sepsis, affecting approximately 50–70% of patients in intensive care units (Li et al., 2025; Hong et al., 2023). It is associated with significantly increased in-hospital mortality, with rates ranging from 30 to 60% depending on disease severity and comorbid conditions (Li et al., 2025; Han et al., 2025). Survivors often experience long-term cognitive impairment, including deficits in memory, attention, and executive function, which profoundly diminish their quality of life and impose substantial burdens on caregivers and healthcare systems (Pan et al., 2022; Andonegui et al., 2018). Despite its clinical significance, the underlying pathophysiology of SAE remains incompletely understood, and no specific pharmacological treatment is currently available (Hong et al., 2023; Catarina et al., 2021). The diffuse cerebral dysfunction in SAE is not caused by direct central nervous system (CNS) infection but rather by a systemic inflammatory response that triggers a cascade of events within the brain.

Historically, research has focused on neuroinflammation, blood–brain barrier (BBB) disruption, and neurotransmitter imbalances (Hong et al., 2023). However, in recent years, mitochondrial dysfunction has emerged as a cornerstone of SAE pathogenesis. Mitochondria, essential for cellular energy production, calcium homeostasis, and regulation of apoptosis, are highly vulnerable to inflammatory insults (Liu et al., 2025). In SAE, mitochondrial impairment encompasses defective oxidative phosphorylation, Adenosine Triphosphate (ATP) depletion, excessive reactive oxygen species (ROS) production, altered dynamics (fission/fusion imbalance), and compromised quality control mechanisms like mitophagy (Liu et al., 2025). These defects directly contribute to bioenergetic failure, oxidative stress, and initiation of cell death pathways in neurons and glial cells.

Concurrently, neuroinflammation, predominantly mediated by activated microglia and astrocytes, amplifies brain injury (Modafferi et al., 2024). The release of pro-inflammatory cytokines (e.g., tumor necrosis factor-alpha [TNF-α], interleukin-1β [IL-1β], interleukin-6[IL-6]) and the activation of multiprotein complexes like the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome lead to synaptic damage, neuronal apoptosis, and exacerbated mitochondrial dysfunction (Ko et al., 2021). A vicious cycle ensues, where mitochondrial damage releases damage-associated molecular patterns (DAMPs) that further fuel neuroinflammation (Dela Cruz and Kang, 2018).

This review synthesizes current knowledge on the interplay between mitochondrial dysfunction and neuroinflammation in SAE. It delves into specific mechanisms—including mitochondrial dynamics, biogenesis, ferroptosis, pyroptosis, and BBB breakdown—and evaluates promising therapeutic strategies targeting these interconnected pathways, drawing from extensive in vivo and in vitro evidence.

2 Mitochondrial dysfunction: a central player in SAE2.1 Disruption of mitochondrial dynamics

Mitochondria are highly dynamic organelles that undergo continuous cycles of fission and fusion, a process critical for maintaining their structural integrity, functional efficiency, and quality control (Nunnari and Suomalainen, 2012). In SAE, this delicate balance is profoundly disrupted, leading to a pronounced shift toward excessive fission, which is now recognized as a seminal event in the progression of neuronal injury and cognitive deficits (Nunnari and Suomalainen, 2012).

2.1.1 Excessive fission mediated by dynamin-related protein 1 (Drp1)

Excessive Mitochondrial Fission is predominantly driven by the upregulation and activation of Drp1, a cytosolic GTPase that translocates to the mitochondrial outer membrane to execute fission (Kleele et al., 2021). Preclinical models of SAE, whether induced by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP), consistently demonstrate increased Drp1 expression and enhanced recruitment to mitochondria in hippocampal neurons and microglia (Haileselassie et al., 2020; Zhong et al., 2023). This activation is often facilitated by post-translational modifications or interactions with adaptor proteins such as Fis1 (Mitochondrial fission 1 protein) (Wang et al., 2025). The consequence is widespread mitochondrial fragmentation, characterized by smaller, punctate mitochondria with disrupted cristae. This fragmented state is inherently dysfunctional, leading to impaired oxidative phosphorylation, collapse of the mitochondrial membrane potential (MMP), and exacerbated production of ROS. The critical role of Drp1 is further corroborated by interventional studies. Pharmacological inhibition of Drp1 with Mdivi-1 effectively attenuates mitochondrial fragmentation, restores ATP production, reduces oxidative stress, and ultimately rescues cognitive and synaptic function in murine models of SAE (Dai et al., 2025; Hong et al., 2025). Beyond neuronal damage, Drp1-mediated fission in cerebral endothelial cells compromises BBB integrity by disrupting tight junction (TJ) proteins (Hao et al., 2025). The inhibitor P110, which specifically blocks the Drp1-Fis1 interaction, was shown to mitigate this BBB dysfunction, highlighting the central role of this specific interaction in sepsis-induced brain injury (Haileselassie et al., 2020) (Table 1).

CategoryKey alterationsKey regulatorsFunctional consequencesDynamics imbalanceExcessive fission, Impaired fusion↑Drp1, Fis1; ↓MFN1/2, OPA1Fragmentation, bioenergetic failure, ROS ↑Impaired biogenesisSuppressed PGC-1α/NRF1/2/TFAM axis↓PGC-1α, NRF1, NRF2, TFAMFailed mitochondrial renewal, energy crisisOxidative stressROS overload, antioxidant defense failuremtROS, NOX; ↓Nrf2, GPX4, GSH, UCP2Macromolecular damage, NLRP3 activationMitophagy dysfunctionImpaired clearance of damaged mitochondria↓PINK1, PARKIN, BNIP3/NIXAccumulation of dysfunctional mitochondriaCell death pathwaysApoptosis, Pyroptosis, FerroptosisBax/Bak, Omi/HtrA2, Caspase-3; NLRP3, GSDMD; GPX4↓Neuronal and glial loss

Mechanisms of mitochondrial dysfunction in sepsis-associated encephalopathy.

This table summarizes the key mechanisms and consequences of mitochondrial dysfunction in SAE, including alterations in dynamics, biogenesis, oxidative stress, quality control, and cell death pathways. SAE, Sepsis-associated encephalopathy; Drp1, Dynamin-related protein 1; Fis1, Mitochondrial fission 1 protein; MFN1/2, Mitofusin 1/2; OPA1, Optic atrophy 1; PGC-1α, Peroxisome proliferator-activated receptor-gamma coactivator-1α; NRF1/2, Nuclear respiratory factor 1/2; TFAM, Mitochondrial transcription factor A; ROS, Reactive oxygen species; ETC, Electron transport chain; NOX, NADPH oxidase; Nrf2, Nuclear factor erythroid 2–related factor 2; GPX4, Glutathione peroxidase 4; GSH, Glutathione; UCP2, Uncoupling protein 2; PINK1, PTEN-induced kinase 1; BNIP3, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3; NIX, Nip3-like protein X; Bax, BCL2-associated X protein; Bak, BCL2 antagonist/killer; Omi/HtrA2, Serine protease Omi/mitochondrial; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; GSDMD, Gasdermin D.

2.1.2 Impaired fusion and network integrity

Impaired Mitochondrial Fusion constitutes the other facet of the imbalance. Fusion, which allows for the complementation of damaged mitochondrial components, is mediated by mitofusins (MFN1, MFN2) on the outer membrane and optic atrophy 1 on the inner membrane (von der Malsburg et al., 2023). In SAE, the expression of these fusion proteins is often downregulated. For instance, the protective effects of hydrogen (H2) gas have been linked to its ability to upregulate MFN2 expression, thereby promoting fusion and contributing to improved mitochondrial network integrity and function (Cui et al., 2024). The loss of fusion activity prevents the dilution of damaged components and the optimization of energy distribution across the mitochondrial network, thereby compounding the deleterious effects of excessive fission (Cui et al., 2024).

The pathological significance of disrupted mitochondrial dynamics extends beyond bioenergetic failure. A fragmented mitochondrial network is more prone to being targeted for autophagic clearance; however, when excessive, it can overwhelm the mitophagy system, leading to the accumulation of damaged organelles. Furthermore, mitochondrial fission is intimately linked to the activation of inflammatory and cell death pathways. For example, the gasdermin D (GSDMD)/Drp1 signaling pathway has been identified as a key mechanism mediating hippocampal synaptic damage and abnormalities in neural oscillations, bridging mitochondrial dysfunction to pyroptotic cell death (Fu et al., 2024). Similarly, nuclear respiratory factor 2(Nrf2) and Yes-associated protein 1(Yap1) have been shown to mitigate ferroptosis partly by maintaining mitochondrial dynamic homeostasis, suppressing the expression of fission proteins like Drp1 and Fis1 (Duan et al., 2024; Yang et al., 2024) (Table 1).

In conclusion, the disruption of mitochondrial dynamics, marked by Drp1-dominated excessive fission and compromised fusion, is a pivotal mechanism in SAE pathogenesis. It serves as a convergence point for multiple injurious processes, including bioenergetic crisis, oxidative stress, neuroinflammation, and programmed cell death, making it a promising therapeutic target for intervention.

2.2 Impairment of mitochondrial biogenesis

Mitochondrial biogenesis is the essential process through which cells generate new mitochondria to maintain energy homeostasis, replace damaged organelles, and adapt to increased metabolic demands. This complex process is predominantly regulated by a central signaling axis, and its impairment in SAE represents a fundamental failure of the brain’s adaptive and reparative capacity, directly contributing to bioenergetic crisis and neuronal vulnerability.

2.2.1 The core regulatory axis: proliferator-activated receptor-gamma coactivator-1α (PGC-1α), nuclear respiratory factor 1/2 (NRF1/2), and mitochondrial transcription factor a (TFAM)

The master regulator of mitochondrial biogenesis is the peroxisome PGC-1α. Under physiological conditions, PGC-1α serves as a transcriptional coactivator that integrates signals from various pathways, including those involved in energy sensing and stress response. Once activated, PGC-1α coordinately upregulates the expression of several nuclear transcription factors, principally NRF1 and NRF2 (not to be confused with NF-E2-related factor 2, also abbreviated Nrf2, which is primarily involved in antioxidant response) (Meng et al., 2024). NRF1 and NRF2 then transactivate a suite of nuclear genes encoding mitochondrial proteins, including those essential for the electron transport chain (ETC) (Meng et al., 2024). Crucially, NRF1 also induces the expression of TFAM (U-Pathi et al., 2023). TFAM is imported into the mitochondrial matrix, where it plays an indispensable role in mitochondrial DNA (mtDNA) replication, transcription, and maintenance (U-Pathi et al., 2023). Therefore, the PGC-1α/NRF1/NRF2/TFAM pathway acts as the primary conduit for signaling from the nucleus to the mitochondrion, driving the synthesis of both nuclear- and mitochondrial-encoded components required for new mitochondrion formation (Table 1).

2.2.2 Dysregulation and energetic failure in SAE

In the context of SAE, this finely tuned biogenetic program is significantly disrupted. The septic insult, characterized by an overwhelming inflammatory and oxidative milieu, can suppress the expression and/or activity of PGC-1α (Li et al., 2021). This suppression leads to a downstream reduction in the expression of NRF1, NRF2, and TFAM. Consequently, the synthesis of critical ETC subunits is compromised, mtDNA copy number may decline, and the overall capacity for oxidative phosphorylation is diminished (Li et al., 2021). This failure to generate new, functional mitochondria occurs precisely when energy demand is heightened due to inflammatory processes and cellular stress, creating a critical bioenergetic deficit. The resulting ATP depletion impairs essential neuronal functions, including the maintenance of synaptic plasticity and ion gradients, ultimately leading to synaptic dysfunction and cognitive decline. It is noteworthy that in certain cell types, such as astrocytes, an initial increase in mitochondrial biogenesis has been observed as a compensatory response to septic injury (Wang et al., 2014); however, this compensatory mechanism appears insufficient or becomes maladaptive over time, failing to overcome the global bioenergetic failure in the brain (Table 1).

2.2.3 Therapeutic activation of biogenesis

Therapeutic activation of impaired mitochondrial biogenesis has emerged as a highly promising strategy for SAE treatment, with multiple interventions demonstrating efficacy through direct or indirect activation of this core regulatory axis. Molecular H2 has been shown to robustly activate the PGC-1α pathway in the brains of septic mice following inhalation (e.g., 2% concentration). This activation results in increased protein levels of NRF2 and TFAM, enhanced mitochondrial membrane potential, elevated ATP content, and ultimately improved cognitive function (Cui et al., 2024; Xie et al., 2021). Notably, H2’s simultaneous mitigation of oxidative stress likely creates a more favorable cellular environment for PGC-1α activation. In the realm of mitochondrial-targeted peptides, the tetrapeptide SS-31 (Elamipretide) selectively accumulates in the inner mitochondrial membrane. In SAE models, SS-31 not only indirectly facilitates biogenesis by preserving mitochondrial cristae structure and reducing ROS, but has also been demonstrated to directly support the PGC-1α pathway, promoting the synthesis of functional mitochondria and subsequently inhibiting hippocampal apoptosis and neuroinflammation (Wu et al., 2015). Furthermore, natural compounds and other agents show significant regulatory potential: Sodium Tanshinone IIA Sulfonate (STS), an active component of Danshen, ameliorates mitochondrial dysfunction and enhances synaptic plasticity by activating the SIRT1/PGC-1α/NRF1/TFAM pathway (Song et al., 2026), while inhibition of Fgr kinase attenuates SAE through the SIRT1/PGC-1α signaling pathway (Liu et al., 2023). These findings collectively underscore the pivotal role of upstream regulators like SIRT1 in activating mitochondrial biogenesis, highlighting multiple therapeutic avenues for addressing mitochondrial impairment in SAE (Table 1).

Beyond pharmacological activation of endogenous biogenesis, intercellular mitochondrial transfer has recently emerged as a revolutionary therapeutic strategy for restoring mitochondrial function in damaged cells (Kan et al., 2025; Liu et al., 2024). This process involves the horizontal transfer of functional mitochondria from healthy donor cells (e.g., mesenchymal stem cells, astrocytes) to stressed or injured recipient cells (e.g., neurons, endothelial cells). In the context of SAE, Kan et al. (2025) demonstrated that astrocyte-to-neuron mitochondrial transfer confers neuroprotection by delivering healthy mitochondria to LPS-stressed neurons, thereby restoring ATP production, reducing oxidative stress, and suppressing apoptosis.

Mechanistically, mitochondrial transfer activates multiple downstream signaling pathways in recipient cells. The incorporation of exogenous functional mitochondria has been shown to reactivate the PGC-1α/NRF2/TFAM biogenesis axis, potentially through improved cellular energetics and reduced ROS-mediated inhibition of this pathway (Liu et al., 2024). Additionally, mitochondrial transfer can enhance mitophagy clearance of remaining damaged mitochondria via the PINK1/Parkin pathway, thereby improving overall mitochondrial quality control (Zhang et al., 2023). The transferred mitochondria also deliver mitochondrial-derived DAMPs at controlled levels, which may precondition recipient cells by mildly activating stress-responsive pathways such as AMP-activated protein kinase (AMPK) and SIRT1, ultimately enhancing cellular resilience (Hu et al., 2019).

Emerging therapeutic strategies are now exploring engineered mitochondrial transplantation using isolated mitochondria or mitochondria-loaded extracellular vesicles. These approaches aim to harness the therapeutic potential of mitochondrial transfer while overcoming limitations such as donor cell availability and immune compatibility. Future research should focus on optimizing delivery methods, elucidating the full spectrum of signaling pathways activated by transferred mitochondria, and evaluating the long-term safety and efficacy of this innovative approach in SAE models.”

In summary, the impairment of mitochondrial biogenesis, mediated through the suppression of the PGC-1α/NRF/TFAM axis, is a critical pathogenic mechanism in SAE that deprives the brain of its metabolic and reparative potential. Therapeutic strategies aimed at reactivating this pathway demonstrate considerable promise in restoring mitochondrial mass and function, thereby offering a powerful approach to preserving neurological function in sepsis.

2.3 Mitochondrial oxidative stress

In sepsis, the massive and systemic inflammatory response triggers an overwhelming production of ROS, creating a state of profound oxidative stress that is particularly detrimental to the metabolically active and vulnerable brain. Mitochondria are central players in this process, acting as both a primary source and a critical target of ROS, thereby initiating a vicious cycle of oxidative damage that propagates mitochondrial dysfunction, amplifies neuroinflammation, and drives neuronal death in SAE.

2.3.1 Sources and mechanisms of ROS production

Under physiological conditions, mitochondria produce low levels of ROS, primarily at complexes I and III of the ETC, as byproducts of oxidative phosphorylation. In SAE, this process is drastically accelerated. Systemic inflammation and circulating endotoxins like LPS disrupt the ETC, leading to electron leakage and excessive reduction of electron carriers (Zhao et al., 2024). This results in a significant surge in superoxide anion production. This primary ROS is rapidly converted to hydrogen peroxide and, in the presence of free iron via the Fenton reaction, to the highly reactive hydroxyl radical (•OH) (Zhao et al., 2024). This “oxidative burst” from mitochondria is compounded by extra-mitochondrial sources, such as activated microglia and infiltrating neutrophils that generate ROS via NADPH oxidase enzymes. The integrated result is a veritable storm of ROS that overwhelms the brain’s intrinsic antioxidant defenses (Table 1).

2.3.2 Consequences of oxidative damage

Uncontrolled ROS production inflicts comprehensive damage to critical macromolecules within neurons and glial cells, initiating a cascade of molecular deterioration. The peroxidation of polyunsaturated fatty acids in mitochondrial and cellular membranes compromises membrane integrity and fluidity while generating toxic reactive aldehydes including malondialdehyde (MDA) and 4-hydroxynonenal, which themselves propagate oxidative damage (Kiyuna et al., 2018). Concurrently, ROS induce protein oxidation through amino acid side chain modification and carbonylation, leading to enzymatic dysfunction, misfolding, and aggregation—particularly devastating to electron transport chain components and antioxidant systems, thereby crippling mitochondrial energy production and cellular defense mechanisms (Kiyuna et al., 2018). mtDNA suffers exceptional vulnerability due to its proximity to ROS generation sites and lack of histone protection; oxidative damage to mtDNA results in mutations and deletions that impair synthesis of essential ETC subunits, establishing a vicious cycle of progressive ETC dysfunction and sustained ROS production (Yan et al., 2019).

Beyond direct macromolecular damage, ROS function as pivotal signaling molecules that significantly exacerbate SAE pathology. They potently activate the NLRP3 inflammasome in microglia, thereby bridging oxidative stress to neuroinflammation. Furthermore, ROS promote mitochondrial permeability transition pore (mPTP) opening and serve as core drivers of ferroptosis—an iron-dependent cell death pathway characterized by uncontrolled lipid peroxidation. These coordinated mechanisms underscore how oxidative assault extends beyond simple chemical damage to actively regulate multiple pathological processes in SAE (Zhong et al., 2024) (Table 1).

2.3.3 Endogenous antioxidant defenses

The body employs a sophisticated antioxidant defense system to counter oxidative stress, and enhancing this endogenous system represents a crucial therapeutic approach for SAE. The Nrf2-Kelch-like ECH-associated protein 1(Keap1) axis serves as a master regulator of this defense mechanism (Cui et al., 2021). Under basal conditions, the transcription factor Nrf2 remains bound to its inhibitor Keap1 and undergoes continuous degradation. During oxidative stress or upon specific pharmacological activation, Nrf2 dissociates from Keap1 and translocates to the nucleus, where it initiates the expression of numerous cytoprotective genes (Cui et al., 2021). These include enzymes for glutathione synthesis (GCLC and GCLM), the key anti-ferroptosis enzyme glutathione peroxidase 4 (GPX4), and phase II detoxifying enzymes such as heme oxygenase-. Research has demonstrated that molecular H2 and the myokine irisin confer significant neuroprotection in SAE models primarily through activating this Nrf2 pathway, leading to enhanced antioxidant capacity and improved mitochondrial function (Xie et al., 2020; Zhang et al., 2023; Wang et al., 2022).

The AMPK-uncoupling protein 2 (UCP2) axis represents another crucial defense pathway that mitigates oxidative damage through a distinct mechanism (Lei et al., 2021). AMPK, a cellular energy sensor, becomes activated under metabolic stress conditions and subsequently phosphorylates and activates UCP2 (Zhao et al., 2022). Located in the mitochondrial inner membrane, activated UCP2 mildly uncouples oxidative phosphorylation from ATP production, reducing mitochondrial membrane potential and consequently decreasing ROS generation (Zhao et al., 2022). The natural compound Malvidin has been shown to protect against SAE by activating this AMPK-α/UCP2 axis, directly reducing mitochondrial ROS (mtROS) accumulation, which in turn inhibits NLRP3 inflammasome activation and protects neurons from apoptosis (Zhao et al., 2022) (Table 1).

In summary, the pathogenesis of SAE is critically determined by the dynamic equilibrium between oxidative stress damage and endogenous antioxidant defense systems. Under physiological conditions, a delicate balance exists between mitochondrial ROS production and the scavenging capacity of antioxidant enzymes (e.g., GPX4, catalase, SOD) and non-enzymatic molecules (e.g., glutathione [GSH]). In SAE, this balance is profoundly disrupted: the septic insult triggers an overwhelming burst of mtROS from dysfunctional mitochondria, while simultaneously suppressing key antioxidant defense pathways, particularly the Nrf2-Keap1 and AMPK-UCP2 axes. This imbalance leads to a self-perpetuating cycle of oxidative macromolecular damage (lipid peroxidation, protein carbonylation, mtDNA injury), which further impairs ETC function and exacerbates ROS production. The resulting oxidative stress not only directly injures neurons and glial cells but also serves as a critical signaling mediator that activates the NLRP3 inflammasome, promotes mitochondrial-dependent cell death (apoptosis, pyroptosis, ferroptosis), and disrupts the BBB. Therefore, therapeutic strategies aimed at restoring the oxidative-antioxidative balance, either by reducing mtROS production (e.g., mitochondrial protectants), enhancing endogenous antioxidant capacity (e.g., Nrf2 activators), or both, represent a rational approach to breaking this vicious cycle and preserving neurological function in SAE.

2.4 Mitochondria-dependent cell death pathways

Mitochondria are not only the powerhouses of the cell but also central executioners of programmed cell death. In SAE, the convergence of intense bioenergetic stress, oxidative damage, and inflammatory signaling on this organelle triggers the activation of multiple, often interconnected, cell death pathways. The pivotal role of mitochondria in integrating these signals and initiating apoptosis, pyroptosis, and ferroptosis represents a fundamental mechanism underlying the widespread neuronal and glial loss observed in this condition.

2.4.1 Mitochondrial apoptosis: the classic pathway to neuronal demise

The intrinsic, or mitochondrial, apoptotic pathway is a well-established contributor to SAE-associated neuronal death. This pathway is characterized by mitochondrial outer membrane permeabilization (MOMP), a decisive event controlled by the Bcl-2 protein family (Kan et al., 2025). Under the stress of sepsis, pro-apoptotic proteins like Bax and Bak are activated and oligomerize on the outer mitochondrial membrane, forming pores. Concurrently, anti-apoptotic proteins like Bcl-2 are suppressed (Kan et al., 2025). This imbalance leads to MOMP, resulting in the release of several lethal proteins from the mitochondrial intermembrane space into the cytosol. Key among these is cytochrome c, which, once released, forms the “apoptosome” with Apaf-1 and procaspase-9, leading to the activation of the executioner caspase-3 and subsequent systematic cellular dismantlement (Liu et al., 2024; Zhang et al., 2023).

A critical regulator of this process unique to SAE is the mitochondrial serine protease Omi/HtrA2. During septic insult, Omi/HtrA2 translocates from the mitochondrial intermembrane space to the cytosol (Hu et al., 2019; Wang et al., 2018). Once in the cytosol, it exacerbates apoptosis by cleaving and degrading the X-linked inhibitor of apoptosis protein (XIAP), a potent endogenous suppressor of caspase activity. The administration of UCF-101, a specific Omi/HtrA2 inhibitor, has been shown to prevent this cytosolic translocation, attenuate XIAP degradation, suppress caspase-3 activation, and ultimately reduce neuronal apoptosis and improve cognitive outcomes in septic models (Hu et al., 2019; Wang et al., 2018). The critical role of Omi/HtrA2 in SAE-induced apoptosis has been further validated by genetic approaches. Omi/HtrA2 knockout or kinase-dead knockin mice exhibit significantly reduced neuronal apoptosis and improved survival in sepsis models, confirming that the protease activity of Omi/HtrA2 is essential for its pro-apoptotic function (Wang et al., 2018; Wang et al., 2022). Similarly, the inhibition of the purinergic receptor P2X7 receptor (P2X7R) also confers protection by dampening this Omi/HtrA2-mediated apoptotic signaling cascade (Wang et al., 2022) (Table 1).

2.4.2 Mitochondrial regulation of pyroptosis: inflaming cell death

Pyroptosis is a highly inflammatory form of programmed cell death, critically involved in microglial activation and subsequent neuronal injury in SAE. It is primarily executed by GSDMD, which, upon cleavage, forms pores in the plasma membrane, leading to cytokine release and lytic cell death. The cleavage of GSDMD is typically mediated by inflammatory caspases, such as caspase-1, which is itself activated by inflammasome complexes like NLRP3 (Ma et al., 2024; Zhan et al., 2024).

Mitochondria are intimately involved in initiating and amplifying pyroptotic signaling. mtROS serve as a key danger signal for NLRP3 inflammasome activation (Huang et al., 2023). Furthermore, a direct link between mitochondrial dynamics and pyroptosis has been established. The GSDMD/Drp1 signaling pathway illustrates this connection: cleaved GSDMD can promote Drp1-mediated mitochondrial fission, and conversely, mitochondrial fission can facilitate NLRP3 inflammasome assembly, creating a feed-forward loop that amplifies inflammation and cell death (Fu et al., 2024). Another novel mechanism involves OTUD1, a deubiquitinase that exacerbates SAE by promoting the dissociation of hexokinase 2 (HK2) from mitochondria (Jing et al., 2025). This HK2 release triggers microglial pyroptosis via NLRP3 activation, highlighting how mitochondrial metabolic coupling directly regulates this inflammatory death pathway (Jing et al., 2025) (Table 1). Genetic ablation of key pyroptosis mediators has provided definitive evidence for their involvement in SAE. GSDMD knockout mice are protected from LPS-induced cognitive deficits and exhibit reduced hippocampal neuronal loss, accompanied by attenuated Drp1-mediated mitochondrial fission (Fu et al., 2024). Similarly, NLRP3−/− mice display markedly reduced microglial pyroptosis, lower IL-1β and IL-18 levels, and preserved synaptic function following septic challenge (Ma et al., 2024).

2.4.3 Mitochondria at the crossroads of ferroptosis: a metabolic catastrophe

Ferroptosis is an iron-dependent form of cell death driven by the catastrophic accumulation of lipid peroxides. Its connection to mitochondria in SAE is profound. Mitochondria are a major site of cellular iron metabolism and ROS generation, both central to ferroptosis execution. In SAE, the delicate balance between lipid peroxidation and its reduction is disrupted. Key defenders against ferroptosis, such as GPX4 and its substrate GSH, are downregulated, while pro-ferroptotic factors like labile iron and lipid peroxidation products (e.g., MDA) increase (Niu et al., 2025).

The central antioxidant transcription factor Nrf2 emerges as a critical suppressor of hippocampal ferroptosis in SAE. Nrf2 activation upregulates genes involved in iron metabolism (e.g., FTH1), GSH synthesis, and antioxidant defense, thereby maintaining mitochondrial lipid membrane integrity. Irisin, an exercise-induced myokine, has been demonstrated to protect against SAE by activating the Nrf2/GPX4 signal axis, thereby inhibiting ferroptosis and preserving neuronal viability (Wang et al., 2022). Similarly, Maresin1 alleviates cognitive impairment by activating the Solute Carrier Family 7 Member 11/GPX4 pathway, which is the core defense system against ferroptosis (Wu et al., 2024). The role of mitochondrial dynamics in this process is further highlighted by findings that Yap1 alleviates ferroptosis partly by inhibiting Drp1-mediated mitochondrial fission, thereby maintaining mitochondrial metabolic homeostasis and reducing lipid peroxidation (Yang et al., 2024) (Table 1). The essential protective role of the Nrf2-GPX4 axis against ferroptosis in SAE has been firmly established through gene knockout models. Nrf2 knockout mice exhibit exacerbated hippocampal ferroptosis, characterized by increased lipid peroxidation, mitochondrial shrinkage, and cognitive decline following CLP-induced sepsis (Duan et al., 2024). Conversely, GPX4 conditional knockout in forebrain neurons recapitulates key features of SAE-associated neurodegeneration, including profound memory impairment and hippocampal neuronal loss, even in the absence of an external septic insult (Wang et al., 2022).

In summary, mitochondria serve as a central platform that coordinates the activation of apoptosis, pyroptosis, and ferroptosis in SAE. These pathways are not isolated but are mechanistically intertwined—mtROS can trigger both pyroptosis and ferroptosis, and Drp1-mediated fission is a common amplifier. The intricate crosstalk between these mitochondria-dependent cell death mechanisms significantly amplifies the initial septic insult, leading to extensive neural damage. Consequently, therapeutic interventions that target these pathways at the mitochondrial level hold immense potential for mitigating brain injury in SAE.

3 Neuroinflammation and microglial activation

Neuroinflammation, driven predominantly by the aberrant activation of microglia, the resident immune sentinels of the CNS, constitutes a cornerstone of SAE pathogenesis. In response to peripheral inflammatory signals, microglia undergo a dramatic phenotypic and functional transformation, shifting from a homeostatic surveillance state to a potent pro-inflammatory effector state. This activation initiates a cascade of events that disrupts neuronal function, compromises synaptic integrity, and perpetuates a self-sustaining cycle of inflammation and injury.

3.1 Microglial polarization: M1/M2 phenotypes

The initial activation of microglia in SAE is triggered by a multitude of signals, including circulating pathogen-associated molecular patterns (PAMPs, e.g., LPS), DAMPs released from injured cells, and pro-inflammatory cytokines (e.g., TNF-α, IL-1β) (Yan et al., 2022). This triggers a spectrum of activation states, broadly categorized into the classical pro-inflammatory M1 phenotype and the alternative anti-inflammatory, pro-repair M2 phenotype. In the acute phase of SAE, the M1 phenotype predominates. These activated microglia upregulate surface markers like CD86 and release a storm of pro-inflammatory mediators, including TNF-α, IL-1β, IL-6, inducible nitric oxide synthase, and cyclooxygenase-2 (COX-2) (Yan et al., 2022). This toxic milieu directly damages neurons, inhibits neurogenesis, and contributes to synaptic pruning and loss. The persistence of this M1-skewed inflammation is a key driver of chronic cognitive impairment. Conversely, the M2 phenotype, associated with the release of anti-inflammatory factors like IL-10 and growth factors, is crucial for resolution of inflammation and tissue repair. The imbalance between M1 and M2 polarization is therefore a critical determinant of SAE outcome (Yan et al., 2022). Pharmacological interventions, such as the Drp1 inhibitor Mdivi-1, have been shown to alleviate cognitive damage not only by improving mitochondrial function but also by shifting microglial polarization from the detrimental M1 state toward the protective M2 state (Hong et al., 2025) (Table 2).

AspectPhenotype/MechanismKey mediators/pathwaysFunctional outcomesMicroglial polarizationM1 (Pro-inflammatory)TNF-α, IL-1β, IL-6, iNOS, COX-2Neuronal damage, synaptic lossM2 (Anti-inflammatory/Repair)IL-10, growth factorsResolution, tissue repairCore amplifierNLRP3 Inflammasome activationmtROS, mtDNA, Drp1 → Caspase-1, IL-1β, GSDMDPyroptosis, synaptic lossOther modulatorsTRIM45 (↑)Atg5 → NLRP3 activationPromotes pyroptosisNogo-A (↑)SHP-2/NLRP3 imbalance → M1 polarizationROS ↑, inflammation ↑Fgr Kinase (↑)Inhibits SIRT1/PGC-1αWorsens mitochondrial functionProtective mechanismsM2 exosomes (miR-124-3p)Inhibits ROCK/PTEN pathwayReduces neuronal apoptosisStanniocalcin-1 (↑)Suppresses microglial inflammationPreserves mitochondrial function

Neuroinflammation and microglial activation in SAE.

This table outlines the roles of microglial polarization, key inflammatory pathways, regulatory modulators, and protective mechanisms in SAE pathogenesis. SAE, Sepsis-associated encephalopathy; TNF-α, Tumor necrosis factor-alpha; IL-1β, Interleukin-1 beta; IL-6, Interleukin-6; iNOS, Inducible nitric oxide synthase; COX-2, Cyclooxygenase-2; IL-10, Interleukin-10; mtROS, Mitochondrial reactive oxygen species; mtDNA, Mitochondrial DNA; TRIM45, Tripartite motif-containing protein 45; Atg5, Autophagy related 5; Nogo-A, Neurite outgrowth inhibitor A; SHP-2, Src homology region 2-containing protein tyrosine phosphatase-2; Fgr, Gardner-Rasheed feline sarcoma viral oncogene homolog; SIRT1, Sirtuin 1; PGC-1α, Peroxisome proliferator-activated receptor-gamma coactivator-1α; ROCK1/2, Rho-associated coiled-coil containing protein kinase 1/2; PTEN, Phosphatase and tensin homolog; Akt, Protein kinase B; mTOR, Mechanistic target of rapamycin.

3.2 The NLRP3 inflammasome as an inflammation amplifier

The NLRP3 inflammasome is a multi-protein complex that serves as a critical intracellular platform for amplifying the inflammatory response in SAE (Luo et al., 2025). Its activation within microglia is a two-step process: priming (initiated by signals like LPS that upregulate NLRP3 and pro-IL-1β) and activation (triggered by a second signal such as extracellular ATP or mitochondrial DAMPs). Once assembled, the NLRP3 inflammasome activates caspase-1, which then cleaves pro-IL-1β and pro-IL-18 into their active, secreted forms and cleaves GSDMD to execute pyroptosis (Luo et al., 2025).

Mitochondrial dysfunction is a key trigger for NLRP3 activation. mtROS, released from damaged mitochondria, and mtDNA, when released into the cytosol, are potent DAMPs that directly promote NLRP3 inflammasome assembly (Moraes et al., 2023). Furthermore, the process of mitochondrial fission, mediated by Drp1, facilitates NLRP3 activation, creating a pathogenic link between mitochondrial dynamics and inflammation (Fu et al., 2024). The consequences are severe: NLRP3-driven release of IL-1β induces excitatory synaptic loss, either directly or through the release of IL-1β-enriched microvesicles from microglia, which have been shown to suppress neurite outgrowth and damage synapses (Moraes et al., 2023). The significance of this pathway is underscored by studies showing that inhibition of NLRP3 (e.g., with MCC950) or its upstream regulators (e.g., mtROS) effectively reduces neuroinflammation and cognitive deficits in SAE models (Xie et al., 2020) (Table 2).

3.3 Additional signaling pathways and modulators

Beyond the NLRP3 inflammasome, microglial-mediated neuroinflammation in SAE is finely regulated by a network of additional signaling molecules and pathways. The E3 ubiquitin ligase TRIM45 exacerbates disease progression by facilitating NLRP3 inflammasome activation through its regulation of Autophagy Related 5 expression, thereby disrupting autophagic flux and promoting microglial pyroptosis (Huang et al., 2023). Genetic knockdown of TRIM45 has been demonstrated to reduce neuronal damage and improve cognitive outcomes (Huang et al., 2023). Similarly, Nogo-A, traditionally recognized for its role in inhibiting neurite outgrowth, contributes to SAE pathogenesis by modulating the SHP-2/NLRP3 balance in microglia. This modulation promotes polarization toward the pro-inflammatory M1 phenotype and induces ROS production, thereby amplifying the inflammatory cascade (Liu et al., 2024).

In the realm of kinase signaling, inhibition of Fgr, a member of the Src family kinases, attenuates SAE by ameliorating both mitochondrial dysfunction and neuroinflammation through the SIRT1/PGC-1α signaling pathway (Liu et al., 2023). This highlights the potential of targeting upstream kinases to modulate the inflammatory response. Furthermore, metabolic reprogramming represents another crucial regulatory layer, wherein activated microglia undergo a Warburg-like effect, shifting toward glycolysis to meet their heightened energetic and biosynthetic demands. Interestingly, the sedative agent propofol has been found to inhibit this LPS-induced metabolic reprogramming by suppressing the ROS/PI3K/Akt/mTOR/HIF-1α axis, thereby exerting anti-inflammatory effects (Guan et al., 2023) (Table 2).

Collectively, these diverse signaling pathways and modulators work in concert to fine-tune microglial activation and neuroinflammatory responses, offering multiple potential intervention points for SAE treatment beyond the canonical inflammasome pathway.

3.4 Protective and resolving mechanisms

Not all microglial responses are detrimental. The M2 phenotype and its derivatives play a vital role in limiting damage. A key mechanism of protection is through the release of exosomes. M2 microglia-derived exosomes have been shown to carry miR-124-3p, which, upon delivery to neurons, targets and inhibits ROCK1 and ROCK2. This action attenuates the ROCK/PTEN/Akt/mTOR signaling pathway, thereby reducing glutamate-induced neuronal apoptosis and conferring neuroprotection (Zhu et al., 2024). This represents a sophisticated form of intercellular communication whereby microglia can exert a paracrine protective effect. Additionally, proteins like Stanniocalcin-1 inhibit the pro-inflammatory response in microglia and protect mitochondrial function, offering significant neuroprotection against SAE (Bonfante et al., 2021) (Table 2).

In conclusion, microglial activation is a central orchestrator of SAE pathology. The transition to a pro-inflammatory state, powerfully amplified by the NLRP3 inflammasome and modulated by a network of signaling pathways and metabolic shifts, creates a hostile CNS environment that drives neuronal dysfunction and death. Understanding the nuanced interplay between these mechanisms, in