From macroautophagy to mitophagy: Unveiling the hidden role of mitophagy in gastrointestinal disorders

Table 1 Research progress of mitophagy in gastrointestinal diseases

Year of publication	Diseases of concern	Problem solved	Ref.
2017	SRMD	SRMD leads to intestinal mucosal injury: Defective mitochondria with excess O2- production inhibit mitophagy, ultimately triggering Bax-dependent apoptosis and NF-κB-intervened proinflammatory mucosal injury	[15]
2020	H. pylori associated gastritis	There was a link between H. pylori infection-promoted mitophagy and inflammation	[16]
2022-2024	Functional dyspepsia	Traditional Chinese medicine can improve gastrointestinal motility disorders, and the mechanism may be related to the inhibition of mitophagy and mitochondria fission	[17-19]
2023	I/R injury	Increased NET formation induces inhibition of mitophagy and lipid peroxidation in IECs, leading to ferroptosis of endothelial cells and microvascular dysfunction	[20]
2023	Malnutrition enteropathy	Dysregulation of SIRT1 and mTORC1 pathways leads to disruption of autophagy, mitochondrial homeostasis, which triggers intestinal barrier dysfunction and nutrient malabsorption	[21]
2023	IBD	Bergapten treatment alleviated NLRP3 inflammasome activation and pyroptosis by promoting mitophagy, suggesting BeG as a potential anti-inflammatory drug for the treatment of inflammatory diseases	[93]
2021-2023	IBD	Polystyrene nanoplastic induced Crohn’s ileitis-like features are related to mitophagy, while Biogenic selenium nanoparticles can alleviate intestinal epithelial barrier damage by regulating mitophagy, which provides new insights for further evaluating the safety of nanoparticles	[22-24]
2023	IBD	NSAIDs induce mitochondrial stress and mitophagy in IECs, which are related to the pathophysiology of Crohn’s disease	[89]
2021	CRC	Mitophagy suppresses CRC growth: PINK1 inhibits CRC growth by reducing acetyl-CoA production and activating P53	[70]
2023	CRC	Mitophagy promotes CRC growth: GPR176 activates cAMP/PKA signaling pathway and regulate mitophagy to promote the tumorigenesis and progression of CRC	[74]
2018	Gastric cancer	Mitophagy promotes gastric cancer growth: Hippo-Yap promotes tumor progression by activating SIRT1/Mfn2/ mitophagy	[63]
2023	Gastric cancer	Mitophagy suppresses gastric cancer growth: 8-paradol promoted PINK1/Parkin-associated mitophagy, mediating cell apoptosis	[67]

SRMD: Stress-related mucosal disease; H. pylori: Helicobacter pylori; I/R injury: Ischemia-reperfusion injury; NET: Neutrophil extracellular traps; IECs: Intestinal epithelial cells; SIRT1: Sirtuin 1; mTORC1: Mechanistic target of rapamycin complex 1; IBD: Inflammatory bowel diseases; NLRP3 inflammasome: NOD-like receptor thermal protein domain associated protein 3 inflammasome; CRC: Colorectal cancer; GPR176: G protein-coupled receptors 176; Mfn2: Mitofusin 2.

Table 2 Pathways regulating mitophagy in gastric cancer, colorectal cancer, and inflammatory bowel diseases

Diseases	Molecules	Effects/mechanisms	Significance	Ref.
Gastric cancer	Yap	Activates the SIRT1/Mfn2/mitophagy axis. Knockdown of Yap impairs the expression of adhesive proteins, reduces F-actin expression, and inhibits lamellipodium formation	Tumor-promoting effects: It contributes to the migration and survival of gastric cancer cells	[63]
	GGT7	Binds with the mitophagy regulator RAB7 to induce mitophagy. GGT7 inhibits ROS production and MAPK cascades	Tumor-suppressing effect: It inhibits the growth, G1-S phase transition and migration of gastric cancer cells	[64]
CRC	piR823	Promotes ubiquitination and proteasome-dependent degradation of PINK1, thereby inhibiting mitophagy	Tumor-promoting effects: It is involved in CRC tumorigenesis	[71]
	MST1	Inhibits mitophagy through the JNK/p53/BNIP3 pathway, leading to oxidative stress and initiating mitochondria-mediated apoptosis	Tumor-suppressing effect: It inhibits tumor proliferation	[73]
	GPR176	Inhibits mitophagy through the cAMP/PKA/BNIP3L axis	Tumor-promoting effects: It promotes the development of CRC	[74]
IBD	NR1D1	Acts as a positive regulator of BNIP3 expression, promoting mitophagy and maintaining the immune homeostasis of IECs	Inhibitory effect on colitis: It reduces the severity and progression of colitis	[88]

CRC: Colorectal cancer; IBD: Inflammatory bowel diseases; Yap: Yes-associatide protein; GGT7: Gamma-glutamyltransferase 7; SIRT1: Sirtuin 1; Mfn2: Mitofusin 2; JNK: c-Jun N-terminal kinase; BNIP3: BCL2-interacting protein 3; BNIP3L: BCL2-interacting protein 3 like; IECs: Intestinal epithelial cells; MST1: Mammalian sterile 20-like kinase 1; GPR176: G protein-coupled receptors 176; PKA: Protein kinase A; NR1D1: Nuclear receptor subfamily 1 group D member 1.

Table 3 Drugs affecting mitophagy in gastric cancer, colorectal cancer, and inflammatory bowel diseases

Diseases	Drugs	Effects/mechanisms	Significance	Ref.
Gastric cancer	TNFα	Activates Parkin-dependent mitophagy, and excessive mitophagy blocks mitochondrial apoptosis	Relates to the resistance of gastric cancer cells to TNFα	[65]
	Metformin	Activates AMPK signaling pathway and up-regulates the expression of mitophagy-related proteins PINK1, Parkin, and LC3B	Promotes the resistance of gastric cancer cells to cisplatin	[66]
CRC	Mito-CP, mito-metformin	Induces the release of ULK1, which promotes mitophagy	Tumor-suppressing effect: It inhibits tumor proliferation	[78]
	Aloe gel glucomannan	Activates PINK1/Parkin pathway to promote mitophagy; it activates the transcription factor EB to induce mitochondrial damage and ROS generation	Tumor-suppressing effect: It Inhibits tumor proliferation	[79]
	δ-valbetaine	Activates mitophagy through the PINK1/Parkin pathway	Tumor-suppressing effect: Inducing apoptosis of CRC cells	[80]
	Oxymatrine	Induces mitophagy and reduces NLRP3 inflammasome activation in CRC cells	Tumor-suppressing effect: Inhibit the growth and migration of CRC cells	[81]
	Small molecule andrographolide	Inactivates the NLRP3 inflammasome induced by mitophagy in macrophages	Alleviates colitis progression and reduces the risk of colitis-related cancers	[82]
IBD	Sodium butyrate	Activates Pink1/Parkin expression to promote mitophagy; it inhibits phosphorylation of NF-κB and activation of the NLRP3 inflammasome	Has an inhibitory effect on ulcerative colitis	[92]
	NSAIDs	Induces mitochondrial stress which leads to impaired mitophagy	Proinflammatory effects	[89]
	Bergapten	Promotes mitophagy and maintains mitochondrial homeostasis to inhibit NLRP3 inflammasome activation and pyroptosis	Anti-inflammatory activity	[93]
	Ginsenoside Rd	Activates AMPK/ULK1/p62 signaling pathway to trigger mitophagy, thereby inhibiting NLRP3 inflammasome	Anti-inflammatory activity	[94]

CRC: Colorectal cancer; IBD: Inflammatory bowel disease; LC3B: Microtubule-associated proteins light chain 3B; ULK1: UNC-51-like Kinase 1; ROS: Reactive oxygen species; NLRP3: NOD-like receptor thermal protein domain associated protein 3; NSAIDs: Non-steroidal anti-inflammatory drugs.