Not only do mitochondria produce ROS in large quantities, but they are also a primary target for ROS attacks ^[1][2][53,54]. Physiological ROS is important for cellular function and survival signaling, yet excess ROS-elicited oxidative stress leads to cell death ^[3][4][55,56]. There is a vicious cycle in which initial mitochondrial damage leads to ROS production, which creates further mitochondrial damage and eventually leads to massive intestinal cell death. To protect cells from oxidative damage, cells have developed an elaborate self-protective mechanism for selective degradation of the dysfunctional mitochondrion before it hurts the cell, called mitochondrial autophagy, or mitophagy ^[5][57]. Mitophagy is a term that was introduced by Lemasters in 2005 and designates the removal of dysfunctional mitochondria and their harmful byproducts and oxidative species to help maintain homeostasis ^[6][7][58,59]. Specifically, under the stimulation of starvation, hypoxia, energy deficiency, hormones, and exogenous infection, the bilayer membrane structures recognize and specifically wrap the mitochondria that are depolarized, dysfunctional, or produce high levels of ROS, and fuse with lysosomes to degrade these mitochondria, reducing the release of ROS and some pro-apoptotic factors from mitochondria. In mitophagy, the regulatory pathways can be classified as ubiquitin-dependent or ubiquitin-independent (receptor-dependent), respectively, based on whether the ubiquitin of the receptor recruit is required or not ^[8][9][60,61].

PTEN-induced putative kinase 1 (PINK1)-cytosolic E3 ubiquitin ligase Parkin pathway represents one of the most studied ubiquitin-dependent mechanisms of mitophagy ^[7][10][59,62]. PINK1–Parkin has multiple roles in mitochondrial physiology, including mitochondrial dynamics, biogenesis, transport, and recruitment of autophagic machinery, to ensure the elimination of defective organelles ^[9][61]. PINK1 is an outer mitochondrial membrane (OMM) protein with Ser/Thr protein kinase activity ^[7][59]. Parkin (PARK2) is an E3 ubiquitin-protein ligase that mediates protein degradation and signal transduction in the cell ^[11][63]. In mammals, PINK1 and Parkin are expressed in many organs and tissues, such as the brain, skeletal muscles, heart, gut, and liver. In the inner mitochondrial membrane (IMM), PINK1 is continuously imported through translocase complexes between the outer and inner membranes, and is then degraded by various proteases, such as mitochondria-processing protease (MPP) and the inner membrane presenilin-related rhomboid-like protease (PARL) ^[10][12][62,64]. As a result, PINK1 is maintained at a low level in normal mitochondria, keeping its autophagy capacity at normal levels. When mitochondria are damaged or the membrane potential (ΔΨm) is depolarized, the inward transport and degradation of PINK1 will be inhibited, resulting in the accumulation of PINK1 in the OMM. This means that PINK1 likely acts as a mitochondrial damage sensor, activating Parkin to translocate from the cytoplasm to mitochondria ^[7][59]. In addition, the disruption of PINK1 phosphorylation blocks the Parkin’s translocation, while the deficiency of Parkin phosphorylation abolishes PINK1–Parkin-induced cell death ^[13][65]. As a consequence of its translocation, PINK1-dependent phosphorylation alters Parkin conformation, causing it to bind mitochondrial surfaces and trigger E3 ligase activity ^[9][14][15][61,66,67]. PINK1 also phosphorylates ubiquitin (Ub) and poly-Ub chains on dysfunctional mitochondria ^[9][61]. The inactivated Parkin binds to phospho-Ub and promotes its activation by PINK1. Parkin mediates the feedforward mechanism to generate poly-Ub chains, which is the substrate of PINK1, thus amplifying the autophagy signals ^[9][14][16][61,66,68]. Therefore, the significance of PINK1 in the mitochondria is needed in cell-protective characteristics for combating oxidative stress ^[17][69]. As a result of poly-Ub chains being phosphorylated by PINK1 and serving as an “eat me” signal for the autophagic machinery, the adaptor proteins recognize phosphorylated poly-Ub chains on mitochondrial proteins (p62, OPTN, NDP52, TAXBP1) and bind with the LC3 receptor to begin autophagosome formation ^[9][61].

In addition to mitophagy, the PINK1–Parkin pathway plays a vital role in mitochondrial movement as well ^[18][19][70,71]. Mitochondrial fission and fusion are affected at different levels by the PINK1–Parkin pathway ^[20][72]. Mitochondrial fusion is induced by the homo- or hetero-dimerization of the mitofusins (MFNs) 1 and 2, which tether the mitochondria together, pull the mitochondria that are in close proximity, and mediate fusion ^[21][22][73,74]. On the other hand, the mitochondrial fission process is orchestrated by the GTPase dynamin-related protein 1 (DRP1) ^[20][72]. DRP1 activity is indirectly triggered by PINK1 and promotes the fission of dysfunctional mitochondria, which enables their autophagic degradation ^[20][23][72,75]. In coordination with DRP1 activation, PINK1–Parkin-mediated phosphorylation and proteasomal degradation of MFN1 also contribute to mitochondrial fragmentation and the removal of dysfunctional organelles ^[24][76]. Additionally, MFN2 may function as a scaffold protein to facilitate Parkin translocation when mitochondrial damage occurs ^[9][61]. Specifically, MFN2 mediates the recruitment of Parkin to damaged mitochondria, and PINK1 phosphorylates MFN2 and promotes its ubiquitination by Parkin ^[10][24][62,76]. In this way, PINK1–Parkin activation causes rapid ubiquitination and degradation, preventing damaged mitochondria from fusing with healthy organelles ^[10][24][62,76]. There is evidence that healthy organelles and mitochondria contacts play a critical role in mitophagy, where PINK1–Parkin activation and deubiquitylation events occur. In addition to this, mitochondrial membrane potential dissipation stimulates PINK1-dependent phosphorylation of Miro, a Rho–GTPase of the OMM that anchors mitochondria to the cytoskeleton ^[9][61]. By ubiquitinating Miro, Parkin promotes its degradation while inhibiting mitochondrial transport. This causes mitochondria to dissociate from tubulin and separate from the mitochondrial network ^[9][18][61,70]. Therefore, blocking mitochondrial transport and enhancing fission could facilitate mitophagy, possibly by reducing mitochondria’s mobility and enabling them to be sequestered by autophagosomes. In addition, Parkin can also interact with Ambra1 to activate class III PI3K complexes (Vps34) around mitochondria to promote mitochondrial autophagy ^[25][26][77,78].

In addition to Parkin, a number of other ubiquitin E3 ligases are involved in the regulation of mitophagy, including Gp78, SMURF1, SIAH1, MUL1, and ARIH1 ^{[9][10][27][28][29]}[61,62,79,80,81]. Their presence on the mitochondrial surface triggers the recruitment of autophagy adaptors, including optineurin (OPTN), nuclear dot protein 52 (NDP52), and p62, among others, by generating ubiquitin chains. In autophagy, autophagic components, like unc-51-like autophagy activating kinase 1 (ULK1), double FYVE-domain-containing protein 1 (DFCP1), and WD repeat domain, phosphoinositide interacting 1 (WIPI1), are recruited for the biogenesis of phagophores and expansion of autophagosome membranes ^[9][27][30][61,79,82].

Apart from ubiquitin-dependent mitophagy, mitochondrial proteins serve as mitophagy receptors, mediating ubiquitin-independent mitophagy, also known as receptor-dependent mitophagy ^[9][29][61,81]. The OMM proteins BNIP3 (BCL2 interacting protein 3), NIX (NIP3-like protein X), and FUNDC1 (FUN14 domain-containing protein 1) are mitophagy receptors that fine-tune mitochondrial populations in response to various stimuli ^[9][61]. These mitophagy receptors directly or indirectly interact with the LC3 protein and lead to the selective degradation of mitochondria ^[31][83]. In addition, the activities of these mitophagy receptors are regulated by the phosphorylation status of their LIR ^[32][84]. During hypoxic conditions, BNIP3 and NIX, which belongs to the subfamily of BH3-only proteins, are induced and localized to the OMM through its carboxy-terminal transmembrane domain ^[31][83]. BNIP3 and NIX share the same LIR domains, and these LIR domains help BNIP3 and NIX bind to LC3 on autophagosomes. BNIP3 interferes with mitochondrial dynamics, promoting the fission of damaged organelles through the disassembly and release of OPA1, and recruitment of DRP1 to the mitochondrial surface ^[33][34][85,86]. In addition, BNIP3 increases mitophagy by suppressing the cleavage of PINK1. BNIP3 and its homolog NIX can not only promote apoptosis through the BH3 domains, but also induce mitophagy through the LIR motifs ^[35][87]. During reticulocyte development, NIX was shown to be required for mitochondrial clearance, while BNIP3 was identified to mediate mitophagy in cardiomyocytes and liver cells ^[33][34][85,86]. In addition to participating in ubiquitin-independent mitophagy, NIX also acts as a substrate of Parkin, recruiting NBR1 and ultimately triggering mitophagy ^[10][62]. FUNDC1 is located in the OMM and is associated with mitophagy under hypoxia or mitochondrial membrane potential dissipation ^[31][83]. FUNDC1 binds to LC3 via a conserved LIR motif and this interaction is enhanced under hypoxic conditions, facilitating mitochondrial engulfment by autophagosomes ^[20][72]. Phosphorylation of FUNDC1 and the consequent inhibition of FUNCD1-mediated mitophagy leads to excessive ROS accumulation ^[20][36][72,88]. Knockout of endogenous FUNDC1 significantly inhibited hypoxia-induced mitophagy ^[37][89]. It is attractive to hypothesize that NIX, BNIP3, and FUNDC1 act synergistically during hypoxia, with the results that FUNDC1 selectively targets mitochondria to autophagosomes formation via NIX- and BNIP3-mediated Beclin 1 activation ^[18][70]. Apart from the above, other mitophagy protein receptors of OMM include autophagy and Beclin 1 regulator 1 (AMBRA1), FKBP prolyl isomerase 8 (FKBP8), BCL2 like 13 (BCL2L13), and Prohibitins (PHB) ^[10][38][62,90].

ROS regulates mitophagy by mediating the PINK1–Parkin pathway through its receptors or effector proteins. PINK1–Parkin pathway regulation of mitophagy also plays an important role in different oxidative damage diseases. The continuous differentiation and renewal of intestinal cells require a large amount of energy, which is accompanied by the production of ROS in the oxidative respiration chain of mitochondria ^[20][39][72,91]. Therefore, ROS is extremely active in intestinal epithelial cells, and its excessive accumulation can easily induce oxidative damage and lead to mitophagy, which is an important factor in the occurrence of various intestinal diseases.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with inflammation and ulceration of the colonic mucosa ^[40][92]. Oxidative stress and mitochondrial dysfunction are related to the pathogenesis of UC, and the incidence and severity of UC are correlated with the increase in ROS. Studies have found that high concentrations of oxidative molecules can be detected in plasma, serum, and even exhaled gas and saliva of UC patients, and the severity of UC is positively correlated with oxidative stress ^[41][93]. It has been confirmed that MnSOD and CAT expressions are decreased in UC, while MDA and GPX2 expressions are increased ^[42][43][44][94,95,96]. The antioxidant appearances were the same in the DSS-induced colitis mouse model, and the expression levels of ROS, IL-1β, and IL-18 in mitochondria decreased after treatment with the mitochondrial-targeted antioxidant MitQ ^[45][97]. Therefore, oxidative stress plays a critical role in UC pathogenesis and can be used as a therapeutic target and evaluation indicator. DSS-induced mitochondria in the rat model were in ridge collapse, expansion, and fragmentation states, and the membrane potential changes were reduced by 70% as compared with those in the normal mice ^[46][98]. Oxidative stress results in mitochondrial damage in UC patients, PINK1 and Parkin expressions are increased in UC, and mitophagy is activated as a protective mechanism ^[47][99]. Mitochondria can regulate the pro-inflammatory response of cells by activating molecular complexes of inflammasomes. ROS can cause NLRP3 to form a complex with apoptosis-associated speck-like protein that further enforces the precursor Caspase-1 to form the active NLRP3 inflammasome, which stimulates caspase-1 cleavage and releases activated IL-1β and IL-18 ^[48][100]. Mitochondria can also induce intestinal inflammation by signal transduction through pattern recognition receptors ^[49][101]. In conclusion, in ulcerative colitis, cells clear damaged mitochondria and overloaded ROS through mitophagy, thus protecting the colonic mucosa from damage. However, the exact route is still unclear, and further research is required in the future.

Crohn’s disease (CD) is referred to as regional enteritis due to the typical pattern of multifocal involvement with intervening normal tissue, “skip lesions”, which can involve any area of the gastrointestinal tract ^[50][102]. In patients with CD, oxidative stress and the accumulation of damaged intracellular macromolecules are important contributors to mucosal deterioration and increased intestinal permeability ^{[51][52][53][54]}[103,104,105,106]. The ROS levels in CD patients are imbalanced with the antioxidant defenses. Moreover, the impaired and reduced Paneth cell is an important mechanism for the development of intestinal pathology in CD. Khaloian et al. reported that CD-like inflammation was negatively correlated with reduced Paneth cell function and LGR5-expression, and mitochondrial metabolic disorders can be induced by the absence of HSP60 in intestinal stem cells ^[55][107]. Jackson et al. also identified Paneth cells as highly susceptible to mitochondrial dysfunction and play a key role in ileitis pathogenesis, with translational implications for the subset of Crohn’s disease patients exhibiting Paneth cell defects ^[56][108]. Mitochondrial protein abundance in the ileum and colon of CD patients was significantly lower than that in the normal population, and CD patients show high mitochondrial activity of electrical signals in the ileum ^[57][58][109,110]. OPTN is a primary receptor required for the selective autophagy of damaged mitochondria ^[59][111]. Studies have found that OPTN is closely related to CD ^[60][112]. At present, there are few studies on CD and mitophagy. However, autophagy-related gene polymorphism is indeed associated with the pathogenesis of CD.

While the role of mitophagy in the development of IBD is now beginning to be understood, there is still a lot to be discovered. Additionally, some researchers have conducted many experiments using a model simulating intestinal oxidative damage. H₂O₂ is both an exogenous and endogenous pro-oxidative mediator that can lead to lipid peroxidation within the cell membranes and destroy the structure and function of the cell membrane, so it has been utilized in establishing an oxidative stress model in vitro ^{[61][62][63][64][65]}[113,114,115,116,117]. A recent study reported that curcumin can effectively ameliorate H₂O₂-induced oxidative stress, intestinal epithelial barrier injury, and mitochondrial damage in IPEC-J2 cells in a PINK1–Parkin mitophagy-dependent way, and the authors also found depletion of Parkin abolished curcumin’s protective action on anti-oxidative stress ^[66][118]. Moreover, the same results were obtained with other drugs, such as sodium butyrate ^[67][119], selenium nanoparticles (SeNPs) ^[68][120], and resveratrol ^[69][121]. Consistent with in vitro data, dietary curcumin protected intestinal barrier function, improved redox status, alleviated mitochondrial damage, and triggered mitophagy in a well-established pig oxidative stress model by challenging with diquat ^[66][70][71][118,122,123]. Similarly, resveratrol can induce mitophagy in the intestine to alleviate the intestinal barrier dysfunction induced by oxidative stress ^[70][122].