Mitochondrial division predominantly occurs during the S, G2, and M phases of the cell cycle (30). This process is initiated by stress stimuli and is aimed at eliminating damaged mitochondria from the cell through mitophagy. Therefore, mitochondrial division prevents the buildup of damaged mitochondria, alleviating the excessive production of ROS and the subsequent cellular stress (31).

On the other hand, mitochondrial fission is driven by the dynamin-related protein 1 (Drp1), which functions at the contractile site established by the interaction of actin and the endoplasmic reticulum (ER) (32). Phosphorylation-activated Drp1 translocates to the outer mitochondrial membrane (OMM) where it oligomerizes to form helices that drive OMM contraction and cleavage, thereby facilitating mitochondrial fission (33, 34). Given the Drp1 lacks the pleckstrin homology (PH) structural domain required for the direct interaction with the phospholipid membrane, its activity requires adaptor proteins. In mammals, four proteins regulate the recruitment of Drp1 to the OMM: fission protein 1 (Fis1), mitochondrial fission factor (Mff), mitochondrial elongation factor 1 (MIEF1), and mitochondrial elongation factor 2 (MIEF2), that serve as Drp1 receptors to improve the fission process (35). activation of fission following the enclosement of mitochondria by the ER leads to the Mff-dependent assembly of Drp1 (36). Inactivation of the Mff gene then inhibits mitochondrial recruitment of Drp1, mitochondrial and peroxisomal elongation, while Mff overexpression can fragment the network (37, 38). It has been shown that MIEF1 binds to the adenosine diphosphate (ADP) cofactor, whereas MIEF2 recruits Drp1 to the mitochondrial surface (39). Mff and MIEF1/MIEF2 function are important receptors of Drp1, which mediate it role on mitochondrial fission. Researchers have demonstrated that overexpression of Mff or MIEF is overexpressed, they significantly attract cytoplasmic Drp1 to the mitochondria, independent of hFis1, which enhances the process of mitochondrial fission (40). These receptors work together to help Drp1 divide mitochondria. In mammals, Fis1 usually plays a minor role in recruiting Drp1. However, during cell death or autophagy, Fis1 becomes more important, significantly boosting mitochondrial division. The role of Fis1 in humans is still unclear (41). Finally, the GTPase dynamin 2 (Dnm2) is transiently recruited to the ER contact site downstream of Drp1 where it facilitates the fission process (42, 43). Subsequently, Drp1 is transported back to the cytoplasm, creating a dynamic cycle between the cytoplasmic space and the mitochondrial membrane. The Drp1’s activation, movement, and oscillation between cellular compartments are tightly regulated by several post-translational modifications. These include phosphorylation, ubiquitination, sumoylation, and glycosylation. The mechanisms by which these modifications alter the functionality of Drp1 are described in details in later sections of this review (44–47).

Mitochondrial fusion is commonly detected in the early S and G1 phases, and is essential to the generation of sufficient ATP needed to sustain respiration and protein synthesis (48). Moreover, the fusion modulates the exchange of materials such as mtDNA, proteins, and metabolites, enhancing the repair of damaged molecules, inhibiting phagocytosis of elongated mitochondria, which may result from site-blocking during nutrient deprivation and the induction of autophagy (48, 49).

The process of mitochondrial fusion involves the fusion of the inner mitochondrial membrane (IMM) and the OMM, occurring in multiple steps beginning with the activation of dynamin-associated GTPases, including mitofusins (MFN1 and MFN2) on the OMM, and optic atrophic protein 1 (Opa1) on the IMM. This is followed by the GTP hydrolysis-induced fusion of the OMM (50). Structurally, the MFNs are embedded in the OMM via two transmembrane regions, divided by a short loop. This structure allows the N-terminal region, containing the GTPase domain, the coiled-coil heptad repeat 1 (HR1), and the C-terminal region that harbors the HR2 domain, to orient towards the cytoplasmic side (51). This is followed by the IMM fusion, orchestrated by Opa1 in the IMM and endosomal lipid components (52). During fusion, two Opa1 proteins in the IMM interact to form oligomers that assemble into flexible helices, causing membrane swelling and bringing the two IMMs into close proximity. The nucleotide binding organizes and tightens the helix assembly, pulling the IMM closer together to initiate fusion. At the end of the fusion, the helical structure of the Opa1 oligomerization is uncoiled (53). This mechanism is crucial for Opa1 to form a helical structure by dimerizing the GTPase domain. Furthermore, the membrane-bending oligomers of Opa1 undergoes conformational changes, which retract the membrane insertion loop from the outer leaflet, causing remodeling (54). OMM fusion is usually coordinated with inner membrane fusion, but can sometimes occur independently. This phenomenon may be triggered by occurrence of mutations or reduced membrane potential which impairs the fusion of the IMM, but the OMM fusion is not affected (55).

Autophagy receptors involved in the mitochondrial protein ubiquitination function through the ubiquitin-dependent mitophagy pathway, specifically the serine/threonine kinase Pink1/Parkin pathway (81). Once Pink1 is exposed on damaged mitochondria, it initiates Pink1/Parkin-dependent ubiquitination, which is often triggered by a loss of mitochondrial membrane potential (82). The expression of Pink1 is kept at low levels under physiological conditions, however, during mitochondrial damage, including mtDNA mutations, elevated mitochondria ROS (mtROS), and the buildup of misfolded proteins, the Pink1 accumulates at the OMM. This is followed by autophosphorylation and activation, as well as phosphorylation of ubiquitin on serine 65, promoting the recruiting Parkin from the cytoplasm to the mitochondrial membrane (83). Next, the Parkin is activated inducing the ubiquitination of mitochondrial proteins and triggering mitophagy (84). Even being absence in Pink1, Parkin could still be attracted to depolarized mitochondria, aiding in mitophagy. For example, HtrA2/Omi or LRRK2 can phosphorylate mitochondrial proteins or parkin itself to promote mitophagy under conditions of pink1 deficiency (85, 86). Alternatively, overexpressed or hyperactive FUNDC1 can recruit parkin to initiate autophagy (87). Among the known targets of Parkin ligase on the OMM are MFN1/2, voltage-dependent anion channel protein 1 (VDAC1), and mitochondrial GTPases (88–90). Proteomics analyses on the degradation of OMM components and the reorganization of the OMM proteome are highly advocated to increase our understanding of the process of mitophagy. Being the most abundant OMM protein, VDAC1 forms the mitochondrial pore and is a key modulator of metabolites, ions, and water transport under physiological conditions and influences mitochondrial homeostasis (91–93). The VDAC1 participates in the regulation of mitophagy, interacting with Parkin to facilitate polyubiquitination and recruitment of Parkin to induce mitophagy (94). By energizing the Pink1/Parkin mitophagy pathway, VDAC1 in conjunction with BNIP3 alters the mitophagic flux process (95). Hypoxia-induced GPCPD1 depalmitoylation has been reported to initiate mitophagy by regulating the PRKN-mediated VDAC1 ubiquitination (96). Application of the antidepressant drug sertraline was found to alter the VDAC1 protein, decrease ATP levels, activate AMPK, and inhibit the MTOR signaling pathway to induce autophagy (97).

NIX and BNIP3 belong to the Bcl-2 protein family which is located on the OMM. The Bcl-2 family members on the OMM participate in the initiation of cell apoptosis, influencing the mitophagy process (98, 99). One of the mechanisms by which autophagy activates mitophagy is through the direct binding to the light chain 3 (LC3) via the BH3 structural motif. This motif functions as a molecular effector of mitochondrial membrane depolarization-induced hypoxia which promotes occurrence of mitophagy (100). NIX was reported to act as an adaptor protein that transports the components of the autophagy machinery to the mitochondria to trigger mitophagy. Another proposed model suggests that BNIP3 or NIX competes with Beclin-1 for binding to Bcl-xl. During erythropoiesis, the expression of NIX is upregulated, disrupting the Bcl-xl-Beclin-1 interaction and freeing Beclin-1 to trigger autophagy (101). Notably, the BNIP3 was demonstrated to lower the mTOR activity and regulate autophagy by increasing LC3 expression. Similar to BNIP3 and NIX, FUNDC1 is a mitochondrial junction protein induced by hypoxia that bind with LC3 via its LIR motif. Under hypoxic environments, the ULK1 kinase relocates to mitochondria, phosphorylating FUNDC1, enhancing its binding with LC3 to promote mitophagy (102).

Most researchers agree that mitophagy is closely linked to mitochondrial dynamics. Inhibiting fission with DRP1K38A or FIS1 RNAi reduces mitophagy, while overexpressing Opa1 also inhibits autophagy (103). Impaired fusion results in a reduction in IMM potential, triggering pink1 accumulation and parkin activation. However, the inverse dependence of fusion and autophagy on membrane potential makes them complementary rather than competing processes for daughter mitochondria after a fission event (104). Therefore, we suggest that mitochondrial fission is a prerequisite for mitophagy and that fusion will inhibit autophagy. However, inhibiting mitochondrial hyperfusion by silencing Drp1 or Mff does not affect mitophagy induced by Fis1 loss (105). In future, researchers should aim to explore the crosstalk between mitochondrial dynamics and mitochondrial autophagy. Moreover, several proteins involved in mitochondrial dynamics also participate in mitochondrial autophagy process. MFN1/2 is extracted from the OMM using ubiquitin-dependent chaperones and is subsequently degraded by the proteasome (106). The deletion of ubiquitination of MFN1/2 prevents the fusion of damaged mitochondria, while enhancing the fission, thereby promoting mitophagy (107). Additionally, Pink1 phosphorylates MFN2, which acts as a Parkin receptor to eliminate impaired mitochondria (108). However, it is unclear whether the OMM proteins coordinate both mitochondrial fission and mitophagy. The precise interplay between mitochondrial dynamics and autophagy requires further investigation.

As early as 1980, Roediger et al. postulated that IBD, particularly UC, may be an energy-deficient disease (19). Since then, several studies have demonstrated that patients with UC exhibited reduced mitochondrial function, including structural abnormalities, mtDNA mutations, reduced electron transport chain activity, decreased oxidative phosphorylation, and lower ATP concentrations (110–113). Mitochondrial dysfunction and imbalance in dynamics are often accompanied with impaired energy metabolism, which triggers inflammation and gastrointestinal symptoms (114). The colonic epithelial cells consume a high amount of energy to execute various processes, including the electrolyte exchange in the intestinal epithelium, glycoprotein synthesis in the mucus layer, lipid synthesis in cell membranes, structural protein synthesis, and detoxification. Therefore, energy deprivation may impair these processes, causing epithelial cell atrophy in the short term and colonic mucosal barrier damage in the long-run, leading to the development of UC (115, 116). Compared to healthy donors, oxidative phosphorylation metabolism in UC patients shifts towards glycolysis as a strategy to compensate for ATP production defects. This increases the cellular levels of lactate acid within colonic cells, whereas bacteria in the intestinal lumen consume epithelial oxygen, inducing ecological dysregulation which promotes inflammation (117). Cells with inflammatory colitis may use glycolysis to produce ATP as an adaptive response to butyrate transport and oxidative stress. A reduction in ATP levels induce detrimental effects on the actin cytoskeleton, whereas actin irregularities may impair the localization and function of cellular junctions, increased gaps between cells (118, 119). Lan A et al. demonstrated that in DSS-induced enterocolitis mouse model, the ATP activity was enhanced, and the expression of energy-dependent differentiation markers was upregulated. This was accompanied by enhanced epithelial repair, requiring large amounts of energy to enhance the structural and functional recovery of the colonic mucosa. This process has been linked to the increase in expression levels of regulators of mitochondrial mass and biogenesis, such as Sirt3, FoxO3, and PGCα. It is also characterized by enhanced fusion, as evidenced by the upregulated Mfn2 gene expression and good mitochondrial morphology (120). In previous studies, creatine supplementation or administration of energy sensors improved intestinal epithelial repair. Therefore, strategies for promoting cellular energy metabolism via modulating mitochondrial dynamics and intestinal barrier are potential treatments for UC (121, 122).

Impaired mitochondrial dynamics have been linked to the development of oxidative stress in UC patients. Mitochondrial aerobic metabolism promotes the proliferation and differentiation of intestinal stem cells within colonic crypts and supports the synthesis of intestinal epithelial cells (123). However, excessive production of ROS may occur in damaged mitochondria. Under normal conditions, mitochondria exhibit a well-coordinated self-repair mechanism. However, in cases of a dynamics imbalance, oxidative stress levels increase within the cells, triggering an inflammatory response (124). Excessive mitochondrial fission reduces energy production and leads to the generation of oxidative stress, increasing mitochondrial fission, and reducing cell viability (125). Mitochondrial fusion may trigger the mixing of mitochondrial contents, including DNA and respiratory chain complexes, which are involved in the repair of damaged mitochondria and reduce localized oxidative stress levels. However, a decrease in mitochondrial fusion may increase the development of oxidative stress (126). Studies have shown that gut microbiota and their metabolites participate in this process. Colic acid, a major biofilm component of Escherichia coli (E. coli), increases mitochondrial fission in enterocytes in a Drp1-dependent manner, enhancing the stress-activated transcription factor-mediated unfolded protein response (UPR) in response to mitochondrial stress (127). DSS can cause damage to the intestinal epithelial respiration and stimulate the mitochondrial complexes I, II, and IV, leading to the accumulation of damaged mitochondria and ROS, both of which cause cellular damage (128).

The mitochondrial chaperone protein Prohibitin 1 (PHB1), an endomembrane protein, regulates Opa1-mediated fusion within the IMM (129). Mitochondrial dysfunction in intestinal epithelial cells, induced by PHB1 deletion was found to trigger spontaneous ileitis in mice (130, 131). In the study, it was observed that epithelial cells showed mitochondrial dysfunction, crypt cell death, and Paneth cell abnormalities, which are also observed in the intestinal epithelium of patients with IBD. Treatment with the mitochondria-targeted antioxidant Mito-Tempo ameliorated the Paneth cell defects and reduced intestinal epithelial inflammation in mice lacking PHB1. The role of Paneth cell mitochondrial impairment in the development of ileitis has been documented in multiple studies on PHB1-deficient mice (131).

The mitochondrial dynamics have been implicated in the regulation of apoptosis. Excessive mitochondrial fission can induce morpho-functional changes in mitochondria, which triggers the production of intrinsic apoptotic signals. Studies have demonstrated that inhibition of mitochondrial fusion stimulates that intracellular stress response and enhances apoptosis (132). The pathogenic E. coli secreted effector proteins, mitochondria-associated protein(Map), and E. coli secreted protein (EapF) are within the mitochondrial matrix. Map induces mitochondrial fission, while EspF promotes the permeabilization of the mitochondrial outer membrane (MOMP) in the OMM (133). Changes in mitochondrial membrane permeabilization may be accompanied by the release of pro-apoptotic factors, such as cytochrome c, which activate the apoptotic signaling pathways (134). Mitochondrial fission resulting from MFN deficiency in HeLa cells protects against Lactobacillus monocytogenes, suggesting that Listeria hemolysin O can disrupt mitochondrial dynamics and promote apoptosis via disrupting calcium influx. In multiple cell types, enhanced mitochondrial fusion inhibits the propagation of apoptotic signals, delaying cellular apoptosis (135). This phenomenon provides a potential alternative approach for treating UC.

In neurological diseases, dysregulation of Drp1 disrupts mitochondrial dynamics, stimulating inflammation and exacerbating disease severity (136). In pancreatic islet inflammatory cells, NF-κB activation was reported to increase Opa1 expression, while interleukin-6 (IL-6) was found to increase Fis1 and downregulate MFN2, enhancing disease progression (137). In colitis, abnormal mitochondrial dynamics stimulate multiple inflammatory pathways, such as the NF-κB pathway, which activated the inflammatory response. Mitochondrial fission can also trigger apoptosis, compromising intestinal barrier function and promoting cellular inflammation. In future, researchers should explore the role of mitochondrial dynamics in UC to identify robust therapeutic disease.

Genome-wide association studies (GWAS) have identified several autophagy genes, including Atg16L1, Lrrk2, and Irgm, which influence the genetic susceptibility of IBD (140–142). Atg16L1 is a critical component of the mitophagy machinery involved in the regulation of immune responses and inflammation. It is part of the complex that cleaves the ubiquitin-like protein LC3 via a lipolytic mechanism, promoting autophagosome formation and activity. The Atg16L1 risk variant (Atg16L1T300A), was found to influence the risk of IBD, creating a caspase cleavage site that weakens the stability of the protein, thereby diminishing autophagy, particularly in the presence of TNF-α (143). Irgm, a human immune-associated GTPase, translocates to mitochondria, where it regulates mitochondrial division and induces mitophagy (144). Irgm1, a homologue of Irgm, participated in the development of intestinal inflammation in mice. Irgm1 knockout mice exhibited increased severity of inflammation following exposure to DSS. Mice with DSS knockout exhibited significant disruptions in Paneth cell positioning and granule structure, which contributed to mitophagy and autophagy impairment within the Irgm1-deficient enterocytes, including Paneth cells. These findings demonstrate that Irgm1 regulates acute inflammatory response in mouse intestines, probably by regulating autophagy, which modulates the normal Paneth cell function (145). Lrrk2 is a multifunctional protein with kinase and GTPase activity; with mutations in the Lrrk2 gene found to decrease mitochondrial numbers, impaired mitochondrial dynamics, and inhibition of the mitophagy pathway (146). In individuals with UC, the expression level of Lrrk2 were upregulated in peripheral blood samples. In preclinical animal models of UC, Lrrk2 knockout ameliorated the progression of DSS-induced enterocolitis, which was accompanied with the transition of the intestinal macrophages (MФs) to alternatively activated macrophages, promoting probiotic colonization and attenuating the onset and progression of colitis (147). This indicates that Lrrk2 plays a crucial role in the development of UC.

Mitophagy influences the innate and adaptive immune responses, thereby maintaining intestinal homeostasis (148). In previous studies, most studies focused on the intestinal immunity of macrophages and T cells. In UC patients and mice with DSS-induced colitis, the mitophagy of intestinal macrophages was significantly decreased. It was found that the expression of proteins associated with the Pink1/Parkin and NIX-mediated autophagy pathways was decreased. This was accompanied by the accumulation of mtROS and mtDNA, which were then released into the cytoplasm, activating the NLRP3 inflammasome and enhancing the maturation of IL-18 and IL-1β (149, 150). In a mouse model of T-cell metastatic colitis, the expression the Th1 transcription factor TBX21 and Th1 cells in the lamina propria of Pink1 knockout (Pink1KO) mice was higher compared to the levels of naïve T cells. Treatment with the Urolithin A (UA), a mitophagy agonist, inhibited the Th1 differentiation, reducing the formation of IFN-γ and IL-17, which suppresses the levels of the associated inflammatory response (151). This finding suggests that inhibiting inflammation via enhancing mitophagy may be an attractive strategy for alleviating enteritis symptoms. Several cytokines have been reported to modulate mitophagy. IL-10, a key anti-inflammatory factor, inhibits the metabolic shifts associated with inflammatory stimuli in macrophages, while maintaining mitochondrial integrity and function by inhibiting mTOR (152).

Mitochondria are important regulators of the innate immune signaling, with several immune effectors clustered on the OMM (153). Among then, MAVS which targets the OMM through its C-terminal transmembrane domain was demonstrated to activate the downstream signaling pathways via NF-κB to regulate IFN production, and its activation is modulated by mitochondrial dynamics (154, 155). Furthermore, studies have shown that depletion of autophagy proteins, such as LC3B and Beclin 1, results in the accumulation of damaged mitochondria and the translocation of mtDNA into the cytoplasm, activating inflammatory gene transcription. The activities of TOMM20 and HSP60, proteins forming part of the OMM and mitochondrial matrix, respectively, negatively correlate with autophagy. In LPS-treated UC mouse models, MODE-K cells and colonic tissues displayed increased expression of p62, TOMM20, and HSP60, causing autophagy inhibition and enhancing inflammation (156). The absence of Nix/BNIP3L-mediated mitophagy during PHB1 protein deficiency causing excessive production of ROS and activation of inflammation, which suggests that mitochondrial dysfunction may impair mitophagy (157). Studies investigating the effect of polystyrene nanoplastics (PS-NPs) on enterocolitis development revealed that the buildup of these plastics in mitochondria induced mitochondrial stress, initiating Pink1/Parkin-mediated mitophagy. Additionally, LC3 dots in Caco-2 cells co-localized with mitotracker-labeled mitochondria, indicating the initiation of mitophagy (158).

Suppressing excessive mitochondrial fission has been shown to accelerate mucosal healing in mice. Patients with UC exhibit increased mitochondrial fission, along with higher butyrate exposure in the environment surrounding colonic stem cells. Excessive mitochondrial fission inhibits stem cell proliferation by disrupting butyrate metabolism in colonic organoids. Mechanistically, results from various enzyme activity assays in colonoids have shown that excessive fission delays mucosal repair by increasing ROS leading to the inhibition of mitochondrial acetoacetyl CoA thiolase activity, which impairs butyrate metabolism. Therefore, the failure of antibiotics to promote mucosal healing in mice was reversed following the treatment of the mitochondrial fission antagonist P110 and exogenous butyrate (165). Further findings show that P110 suppresses excessive fission by blocking Drp1 binding to Fis1, significantly alleviating intestinal inflammation and reducing UC symptoms (18). Unfortunately, few drugs effectively inhibit mitochondrial fission in vivo. Mdivi-1 is one such drug, targeting Drp1, but it may induce unintended side effects on oxidative phosphorylation and ROS levels (23). Leflunomide, an antirheumatic drug that inhibits pyrimidine synthesis has been found to mitigate mitochondrial fission by enhancing fusion to alleviate the associated symptoms (166). In addition, Chen W and colleagues described several chemotherapeutic agents that target different mechanisms of mitochondrial fission and fusion. However, evidence-based data to support the therapeutic benefits of these agents in the treatment of UC (50).

Natural products, such as curcumin, can treat diseases by targeting mitochondrial function. For instance, curcumin protects cartilage in osteoarthritis by stimulating AMPK/PINK1/Parkin-mediated mitophagy (167). Berberine protects glomerular podocytes by inhibiting Drp1-mediated mitochondrial fission and dysfunction (168). Natural products can regulate mitophagy making them potential treatments for UC-associated mitochondrial dysfunction ( Table 1 ). To assess the therapeutic efficacy of these natural products and their potential side effects on tissues or cells, UC-associated models and in vitro experiments need to be performed to accelerate the clinical translation of these findings. Dipak Kumar Sahoodeng et al. described the effects of various natural antioxidant components on IBD (169). In the following section, we provide a summary of natural products that regulate UC by modulating mitochondrial dynamics and mitophagy.