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

Abstract

In this editorial, we comment on an article titled "Morphological and biochemical characteristics associated with autophagy in gastrointestinal diseases", which was published in a recent issue of the World Journal of Gastroenterology. We focused on the statement that "autophagy is closely related to the digestion, secretion, and regeneration of gastrointestinal cells". With advancing research, autophagy, and particularly the pivotal role of the macroautophagy in maintaining cellular equilibrium and stress response in the gastrointestinal system, has garnered extensive study. However, the significance of mitophagy, a unique selective autophagy pathway with ubiquitin-dependent and independent variants, should not be overlooked. In recent decades, mitophagy has been shown to be closely related to the occurrence and development of gastrointestinal diseases, especially inflammatory bowel disease, gastric cancer, and colorectal cancer. The interplay between mitophagy and mitochondrial quality control is crucial for elucidating disease mechanisms, as well as for the development of novel treatment strategies. Exploring the pathogenesis behind gastrointestinal diseases and providing individualized and efficient treatment for patients are subjects we have been exploring. This article reviews the potential mechanism of mitophagy in gastrointestinal diseases with the hope of providing new ideas for diagnosis and treatment.

Keywords: Autophagic receptor; Colorectal cancer; Gastric cancer; Gastrointestinal diseases; Inflammatory bowel disease; Mitophagy; Parkin.

Figure 1

Major Signaling pathways of mitophagy. Parkin-dependent Ubiquitinated Mitophagy Pathway: Following the depolarization of the mitochondrial membrane, PINK1 recruits and activates the E3 ubiquitin ligase activity of Parkin, leading to the formation of ubiquitin chains. These chains then attract a series of autophagy receptors including P62, NDP52, and OPTN. Subsequently, these receptors bind to light chain 3 (LC3), facilitating the connection of the polyubiquitinated mitochondrial outer membrane to the autophagosome membrane, thereby mediating mitophagy. In this process, TANK-binding kinase 1 kinase enhances the affinity of the autophagy receptor for the Ub chain by phosphorylating the receptor. PTEN-L can reduce Parkin phosphorylation and inhibit its E3 ligase activity, thereby inhibiting mitophagy. Parkin-Independent Ubiquitinated Mitophagy Pathway: E3 ubiquitin ligases such as ARIH1, MUL1, and Gp78 may serve as compensatory pathways for Parkin-mediated mitophagy, although the precise mechanisms are yet to be elucidated. Furthermore, PINK1 has the ability to recruit NDP52 and OPTN to mitochondria, thereby directly initiating mitophagy in a Parkin-independent manner. Receptor-Mediated Ubiquitination-Independent Mitophagy Pathway: Proteins including FK506 binding protein 8, BCL2-interacting protein 3 like/NIP3-like protein X (BNIP3L/NIX), BNIP3, FUN14 domain containing 1 (FUNDC1), and Bcl2-L-13 directly bind to LC3, enabling the mitochondrial membrane to connect to the autophagosome membrane and mediate mitophagy. SCF-FBXL4 mediates the ubiquitination and degradation of BNIP3L/NIX and BNIP3, thereby inhibiting mitophagy. Under hypoxia conditions, phosphoglycerate mutase 5 (PGAM5) promotes the dephosphorylation of FUNDC1, enhancing FUNDC1-mediated mitophagy. Conversely, Src kinase and Casein kinase 2 phosphorylate FUNDC1, inhibiting its mitophagy-promoting activity. Although Bcl-xL positively regulates the binding of BNIP3 to LC3, it inhibits FUNDC1-mediated mitophagy by suppressing PGAM5. LC3: Light chain 3; BNIP3L/NIX: BCL2-interacting protein 3 like/NIP3-like protein X; FUNDC1: FUN14 domain containing 1; TBK1: TANK-binding kinase 1.

Figure 2

Pathways regulating mitophagy in colorectal cancer, gastric cancer, and inflammatory bowel disease. A: Colorectal cancer cells: GPR176 recruits GNAS to inhibit BCL2-interacting protein 3 like through the AC/cAMP/PKA pathway, thereby suppressing mitophagy. Additionally, MST1 activates the c-Jun N-terminal kinase (JNK) pathway, up-regulating P53 expression, which in turn inhibits BNIP3 transcription and activity, leading to mitophagy arrest; B: Gastric cancer cells: Interactions between GGT7 and Rab7 promote mitophagy. Yap activates sirtuin 1, enhancing Mfn2 expression and sustaining mitophagy. JNK upregulates Parkin to activate mitophagy; however, overexpression of NR4A1 inhibits mitophagy by suppressing JNK. Furthermore, the AMPK/ULK1/Parkin axis also supports mitophagy; C: Macrophages in inflammatory bowel disease: Damaged or stressed mitochondria in macrophages release mtDNA and reactive oxygen species, which directly contribute to NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome formation and activate NF-κB via the TLR9 pathway, triggering NLRP3 inflammasome activation and subsequent Caspase-1 activity. This results in the production of IL-1β and IL-18. Enhancing the AMPK-ULK1-P62 axis-driven mitophagy efficiently removes damaged mitochondria, inhibiting NLRP3 inflammasome activation and exerting anti-inflammatory effects. CRC: Colorectal cancer cell; NLRP3: NOD-like receptor thermal protein domain associated protein 3; SIRT1: Sirtuin 1; JNK: c-Jun N-terminal kinase.