Mitochondrial dysfunction in sepsis: mechanisms and therapeutic perspectives

Abstract

Sepsis is a severe medical condition characterized by a systemic inflammatory response, often culminating in multiple organ dysfunction and high mortality rates. In recent years, there has been a growing recognition of the pivotal role played by mitochondrial damage in driving the progression of sepsis. Various factors contribute to mitochondrial impairment during sepsis, encompassing mechanisms such as reactive nitrogen/oxygen species generation, mitophagy inhibition, mitochondrial dynamics change, and mitochondrial membrane permeabilization. Damaged mitochondria actively participate in shaping the inflammatory milieu by triggering key signaling pathways, including those mediated by Toll-like receptors, NOD-like receptors, and cyclic GMP-AMP synthase. Consequently, there has been a surge of interest in developing therapeutic strategies targeting mitochondria to mitigate septic pathogenesis. This review aims to delve into the intricate mechanisms underpinning mitochondrial dysfunction during sepsis and its significant impact on immune dysregulation. Moreover, we spotlight promising mitochondria-targeted interventions that have demonstrated therapeutic efficacy in preclinical sepsis models.

Keywords: Immune response; Mitochondria-targeted therapy; Mitochondrial dysfunction; Sepsis.

Fig. 1

Pathways of RNS and ROS production in sepsis. Excessive nitric oxide is generated by both cytosolic and mitochondrial iNOS during sepsis. The nitric oxide can be converted to other reactive nitrogen species (RNS), such as nitrite and nitrogen dioxide. On the other hand, excessive reactive oxygen species (ROS) are produced by NOXs and mitochondrial electron transport chain (ETC). Nitric oxide and superoxide react to form additional derivatives, notably the highly toxic peroxynitrite. The accumulation of these reactive species inflicts damage to cellular components, including lipids, proteins, and nucleic acids, thereby compromising mitochondrial respiration and integrity

Fig. 2

Pathways of mitophagy and mitochondrial dynamics. a The most extensively studied mitophagy pathway involves PTEN-induced kinase 1 (PINK1) and E3 ubiquitin ligase Parkin. Upon ΔΨm loss, PINK1 is stabilized on the OMM, where it recruits and activates Parkin. Parkin subsequently ubiquitinates mitochondrial surface proteins, signaling the autophagosome to encapsulate the dysfunctional mitochondrion. Adaptor proteins including p62, Optineurin (OPTN), calcium binding and coiled-coil domain-containing protein 2 (NDP52), tax1-binding protein 1 (TAX1BP1), and next to BRCA1 gene 1 protein (NBR1) play a role in linking the ubiquitin chains to microtubule-associated protein 1 light chain 3 (LC3) on phagophores. On the other hand, some mitochondrial receptor proteins (or lipids) such as FUN14 domain containing 1 (FUNDC1), prohibitin (PHB), BCL2 interacting protein3 (BNIP3), Nip3-like protein X (NIX), cardiolipin, and syntaxin 17 (STX17) can recruit phagophore membranes independent of ubiquitin. The autophagosome finally fuses with a lysosome for the degradation and recycling of mitochondria. b Mitochondrial dynamics is regulated by several dynamin-related GTPases, including Mfn1/2, OPA1, Drp1, Fis1, MiD49/51, and Mff. Mfn1/2 facilitate the fusion of the OMM, while OPA1 is responsible for the fusion of the IMM. The fission process is initiated by the endoplasmic reticulum (ER)-mediated pre-constriction of mitochondria. Drp1 is recruited to the pre-constricted sites by receptors (Mff, Fis1, and MiD49/51). After binding to OMM, Drp1 oligomerizes into ring-shaped filaments. Hydrolysis of GTP by Drp1 results in constriction and closure of the ring. Dnm2 is finally recruited to the constricting site to complete the fission. In addition to the ER, lysosome and Golgi-derived vesicles have also been reported to regulate mitochondrial fission

Fig. 3

Mechanisms of mitochondrial membrane permeabilization in sepsis. Three principal mechanisms are implicated in sepsis-related mitochondrial membrane pore formation. Mitochondrial outer membrane permeabilization (MOMP) is mediated by Bcl-2 family proteins Bax/Bak and regulated tBid. Large BAK/BAX pores allow the protrusion of IMM into the cytosol, therefore, enabling the escape of mitochondrial matrix contents. Mitochondrial permeability transition pore (MPTP) represents another type of mitochondrial pore in sepsis. Despite the opening mechanism of MPTP is still elusive, mitochondrial components such as F₁F_O (F)-ATP synthase, ANT, and Cyp-D have been confirmed to play pivotal roles in this process. Gasdermins (GSDMs) are well-known to form pores on plasma membrane during immune response. Recent advances have demonstrated that GSDMs target both the inner and outer mitochondrial membranes via their strong binding preference to cardiolipin. ROS promote the externalization of cardiolipin from IMM to OMM, thus, positively regulate GSDMs-mediate pore formation. Overall, mitochondrial membrane permeabilization leads to mitochondrial swelling, content loss, and dissipation of membrane potential during sepsis

Fig. 4

Mitochondria-regulated inflammatory pathways in sepsis. Pattern recognition receptors (PRRs) of immune cells recognize pathogen-associated molecular patterns (PAMPs) from microbes or damage-associated molecular patterns (DAMPs) released by damaged host cells. a Mitochondria orchestrate the activation of the NLRP3 inflammasome. mtROS and ox-mtDNA promote the NLRP3 inflammasome activation after their release from the damaged mitochondria. Additionally, mitochondrial antiviral-signaling protein (MAVS) and cardiolipin mediate the spatial association between mitochondria and NLRP3, which may facilitate a rapid and efficient sensing of the inflammatory signals from the damaged mitochondria by NLRP3. Early studies posited mitochondria or mitochondria-associated membrane (MAM) as the docking sites of NLRP3, while more recent publications have indicated the involvement of Golgi and microtubule-organizing center (MTOC). It could be plausible that NLRP3 proteins are first transported to meet mitochondria, after which NLRP3 redistributes to the adjacent Golgi apparatus as oligomeric cages. Then, the NLRP3 cages are transported to MTOC and reorganized into a single inflammasome speck. Activated NLRP3 inflammasome mediates the activation of pro-caspase-1, which proteolytically processes GSDMs and pro-inflammatory cytokines. The matured cytokines are released from the GSDMs pores to transmit inflammatory signals. b Mitochondria regulate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. cGAS is activated upon mtDNA binding, leading to the synthesis of cyclic GMP-AMP (cGAMP). cGAMP then induces a conformational change in STING, leading to its activation at ER. Activated STING translocates to Golgi, where it activates transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) to initiate the production of type I interferons and other pro-inflammatory cytokines that are required for effective immune response against pathogens. c Mitochondria regulate the TLR9 pathway. mtDNA shares similarities with bacterial DNA, thus can be recognized by TLR9. As with other TLRs and cGAS-STING axis, TLR9 pathway activates IRF3 and NF-κB to regulate the inflammatory response

Fig. 5

Mitochondria-based therapeutic interventions. Mitochondria-targeted antioxidants such as MitoQ, MitoVitE, and MitoTempol are selectively targeted to mitochondria by conjugating to a lipophilic cation decyl-triphenylphosphonium (TPP⁺). The positive charge of cation enables the molecules to accumulate in mitochondrial matrix, therefore, specifically quench the mitochondrial ROS. Non-antioxidants Urolithin A, Mdivi-1, and Cyclosporin A improve mitochondrial quality by promoting mitophagy, inhibiting mitochondrial fission, and blocking MPTP, respectively. Metformin plays multiple roles on mitochondria, including enhancing mitophagy, reducing mtROS, preventing ox-mtDNA production, and inhibiting mitochondrial protein translation. These compounds target different aspects of mitochondria and exhibit great potential in reducing sepsis-induced mitochondrial damage, excessive inflammation, and organ dysfunction