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The role of mitochondrial biogenesis, mitochondrial dynamics and mitophagy in gastrointestinal tumors
Cancer Cell International volume 25, Article number: 46 (2025)
Abstract
Gastrointestinal tumors remain the leading causes of cancer-related deaths, and their morbidity and mortality remain high, which imposes a great socio-economic burden globally. Mitochondrial homeostasis depend on proper function and interaction of mitochondrial biogenesis, mitochondrial dynamics (fission and fusion) and mitophagy. Recent studies have demonstrated close implication of mitochondrial homeostasis in gastrointestinal tumorigenesis and development. In this review, we summarized the research progress on gastrointestinal tumors and mitochondrial quality control, as well as the underlying molecular mechanisms. It is anticipated that the comprehensive understanding of mitochondrial homeostasis in gastrointestinal carcinogenesis would benefit the application of mitochondria-targeted therapies for gastrointestinal tumors in future.
Introduction
Gastrointestinal tumors, including gastric cancer and colorectal cancer, have long been one of the leading causes of cancer-related deaths, and their morbidity and mortality remain high, which imposes a great socio-economic burden globally. According to the global cancer death statistics, colon and gastric cancers are among the top five causes of death, with approximately five million new cases of gastrointestinal cancers and three million deaths worldwide each year [1, 2]. Gastric cancer continues to occur at a high rate with more than 1 million new cases diagnosed globally each year, and more than half of all gastric cancers occur in the Asia-Pacific region [3]. The occurrence and development of gastrointestinal tumors is a multi-step process with various genetic and epigenetic factors involved. Therefore, it is urgent to understand the mechanism of gastrointestinal tumorigenesis and development, and to optimize their diagnosis and treatment to reduce the cancer burden.
Mitochondria are important double-membrane-bound organelle abundant in the cytoplasm of eukaryotic cells [4]. Unlike other organelles, mitochondria have their own genome, namely mtDNA, which is present in the mitochondrial matrix [5]. As it is involved in diverse cellular function including apoptosis activation, cell death, calcium homeostasis, and hemoglobin synthesis, mitochondrial homeostasis is critical to the homeostasis of organisms [6,7,8]. Cells respond to metabolic stress and coordinate metabolic patterns mainly by adjusting the mitochondria. On the one hand, mitochondria meet the increase in demand through mitochondrial biogenesis and mitochondrial fusion; on the other hand, mitochondria meet the decrease in demand through mitochondrial fission and mitophagy [9,10,11]. Once mitochondria fail to rapidly adapt to the bio-energetic changes caused by environmental changes, cells are prone to be affected by oncogenic factors, thus leading to the occurrence and development of tumors. Moreover, it has been proposed that the mitochondrial quality control (MQC) system includes four parts: biogenesis, fission, fusion, and autophagy, which need their complicated and accurate coordination. The disorders in any one of the four parts may lead to mitochondrial disorders, thereby resulting in the occurrence and development of tumors [12].
In recent years, a large number of studies have focused on the relationship of the MQC system with gastrointestinal tumorigenesis and progression, as well as the potential therapeutic approaches. For example, a large number of studies have demonstrated that mitochondrial biogenesis, dynamics, and mitophagy are closely related to gastrointestinal tumors and mitochondria might turn out to be novel therapeutic targets. For example, Mst1 acts as a tumor suppressor and is often down-regulated in CRC, which hinders mitophagy by regulating the JNK/P53/Bnip3 axis, thereby inducing apoptosis and impeding the proliferation and migration of CRC cells [13]. In addition, MYC regulates metabolic reprogramming of CRC cells by decreasing PGC-1α, a regulator of mitochondrial biogenesis, and TFEB, a master regulator of mitophagy [14]. NDUFA4 promotes mitochondrial fission and biogenesis, which promotes glycolysis and oxidative metabolism in gastric cancer cells [15]. Moreover, LMP2A was found to promote mitochondrial fission levels in gastric cancer by activating the Notch pathway [16].
In this review, we comprehensively summarized the latest research advances of mitochondrial quality control systems and gastrointestinal tumors. The role of mitochondrial biogenesis, mitochondrial dynamics (mitochondrial fission and fusion), and mitophagy in the occurrence, progression, treatment, and prognosis of gastrointestinal tumors and their molecular mechanisms were discussed. The understand of the pathogenesis of gastrointestinal tumors from the perspective of mitochondria would offer novel insights and provide promising therapeutic strategies in the future.
Gastrointestinal tumorigenesis
Mitochondrial biogenesis associated with gastrointestinal tumorigenesis
Mitochondrial biogenesis refers to the way in which mitochondria replicate themselves, the process by which existing mitochondria grow and divide to produce new mitochondria [17]. The process of mitochondrial biogenesis involves an increase in the amount of mitochondrial proteins encoded by the nuclear genome (nDNA) and the mitochondrial genome (mtDNA). The vast majority of proteins involved in mitochondrial biogenesis originate in the cytoplasm, where the activation of the nuclear genome allows mRNA to be translated into precursor proteins [18]. The precursor proteins are subsequently imported into the mitochondria to participate in mitochondrial biogenesis via different protein import pathways [19]. Mitochondrial biogenesis is mainly regulated by the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Activated by phosphorylation or deacetylation, PGC-1α sequentially activates nuclear respiratory factor 1 or 2 (NRF1/NRF2) or ERRα and mitochondrial transcription factor (TFAM). The activation of the PGC-1α/NRF (NRF1/NRF2)/TFAM pathway drives mitochondrial DNA for transcription and replication with the help of specific translation factors encoded by nuclear DNA [20,21,22]. Disorders of mitochondrial biogenesis are key to important oncogenic signaling pathways [23]. Impairment of the process of mitochondrial biogenesis may affect gastrointestinal tumorigenesis in different ways by affecting mitochondrial apoptosis and glycolysis.
Colorectal cancer
PGC-1α was initially discovered in brown adipose tissue, where it can interact with peroxisome proliferator-activated receptor γ (PPARγ) [24]. PGC-1α is involved in mitochondrial biogenesis, metabolism, proliferation and energy homeostasis. Significant increase of the expression of the mitochondrial biogenesis gene PGC-1α was observed in the precancerous region of colorectal cancer (CRC) patients [25]. PGC-1α can not only induce the proliferation and activation of mitochondria, but also induce metabolic shifts. In CRC, overexpressed PGC-1α triggered mitochondria-dependent apoptosis by inducing the translocation of the pro-apoptotic molecule Bax to mitochondria and promoting the accumulation of ROS, thereby suppressing tumorigenesis [26, 27].
As one of the most abundant mitochondrial-localized DNA-binding proteins [28], TFAM is encoded by nuclear genes and regulated by NRFs, which is closely related to transcription initiation and homeostasis in mammalian mitochondria. As a downstream of PGC-1α, NRF acts as a transcriptional activator in mitochondrial biogenesis [53], the disturbance of which leads to intestinal tumorigenesis. A study based on a CRC population showed that mitochondrial TFAM expression was increased in CRC tissues and was primarily regulated by NRF1 [29].
TFAM is closely involved in mitochondrial DNA replication and transcription, the regulation of ROS levels, and oxidative phosphorylation [30, 31]. Aberrant TFAM protein has been reported to affect mitochondrial biogenesis and intimately correlate with gastrointestinal tumors. TFAM knockout mice were more susceptible to colitis-associated carcinoma (CAC), however, interestingly, TFAM expression was upregulated in CAC tissues [32].
Another member of the PGC-1 family, PGC-1β, is structurally and functionally similar to PGC-1α [33]. It has been shown that high expression of PGC-1β in the intestine induces an increase in mitochondrial biogenesis and increases susceptibility to intestinal tumors [34].
In addition, deletion of the tumor suppressor GUCY2C increases mitochondrial biogenesis through activation of AKT signaling and promotes intestinal tumorigenesis [35]. In colon cancer, knockdown of the uPAR gene, which has a pro-tumorigenic effect, was discovered to decreases glycolysis and impair mitochondrial biogenesis [36].
Gastric cancer
Tumor suppressor calcium-binding protein 39-like (CAB39L) is a hypermethylated gene in gastric cancer, and its promoter methylation has been associated with poor prognosis. The mechanism by which CAB39L inhibits gastric carcinogenesis is to reverse the Warburg effect through the LKB1-STRAD/AMPK/PGC-1α axis to promote oxidative phosphorylation and inhibit the glycolysis to prevent the metabolic shifts that drive carcinogenesis [37].
Furthermore, the ATP4Ap.R703C mutation impairs the intracellular acid-base homeostasis and mitochondrial biogenesis, leading to an increase in intracellular ROS and activation of apoptosis as well as inflammatory responses, which increases the risk of gastric neuroendocrine tumors (gNETs) [38].
Mitochondrial dynamics associated with gastrointestinal tumorigenesis
Mitochondria are highly dynamic rather than discrete organelles by forming a dynamic network through the correct balance of constant fission and fusion and dynamically adjusting their position in the cell [39]. Mitochondrial dynamics involves fission and fusion of mitochondria as two opposing processes that are mediated by a variety of dynamic GTP-related enzymes.
Mitochondrial fission is mainly driven by the cytoplasmic dynamin-related protein 1 (Drp1). Drp1, encoded by the DNM1L gene, is recruited to the outer mitochondrial membrane (OMM) and forms a homodimeric helical structure [40]. Drp1 regulates mitochondrial fission via post-translational modification and other fission-associated proteins, such as mitochondrial fission factor (Mff) and mitochondrial fission protein 1 (Fis1) [41, 42]. The process of mitochondrial fission separates dysfunctional smaller mitochondria, and these fragmented mitochondria can be recruited in regions of high energy demand or energy deficiency. In addition, mitochondrial fission avoids the accumulation of massive defective mitochondria and compromises the efficiency of ATP production [43, 44]. In contrast, mitochondrial fusion is a complex process involving mitochondrial fusions 1 and 2 (Mfn1 and Mfn2) localized at the OMM and optic atrophy 1 (OPA1) localized at the inner mitochondrial membrane (IMM) [40, 45, 46]. Mfn1 and Mfn2 are responsible for outer membrane fusion followed by OPA1 for inner membrane fusion [47]. Damaged mitochondria are inclined to fuse together, which not only promotes the exchange and sharing of nutrients and mtDNA in different regions, thereby favoring the repair and energy supply of defective mitochondria, but also protects the mitochondria from removal under adverse conditions of nutrient deprivation and autophagy by diluting damaged molecules [48].
The shape, size, number, distribution location, and function of mitochondria are regulated by mitochondrial dynamics in response to a variety of stimuli both inside and outside the cell [49, 50]. Once this regulation of mitochondria is out of control, it will be detrimental to the health of the organism. It has been consistently shown that an imbalance of mitochondrial fission and fusion is prevalent in gastrointestinal tumors.
Patients with pre-cancerous CRC present a significant increase in the expression of genes related to mitochondrial dynamics, including the mitochondrial fission gene DRP1 and the mitochondrial fusion gene OAP1 [25]. A study evaluated the mitochondrial genome of patients with CRC, and the results showed that there was an abundance of mutations in the genes related to mitochondrial fission and fusion, thus speculating that mitochondrial dynamics are crucial in colorectal carcinogenesis [51]. Interestingly, another study showed that the expression level of Drp1 in human colon cancer was decreased by 75% compared to normal tissues, suggesting that a substantial loss of Drp1 expression may contribute to the development of colon cancer [52]. Future studies are still needed to elucidate the exact role of mitochondrial dynamics in gastrointestinal tumorigenesis.
In CRC, increased expression of OTUD6A stabilizes and promotes Drp1 expression by regulating its deubiquitination, thereby promoting mitochondrial fission and tumorigenesis [53]. ARF1 interacts with IQGAP1, which activates the ERK signaling pathway to regulate the phosphorylation of Drp1 and promote the occurrence of colon tumors [54]. In colon cancer, fatty acids can activate the phosphorylation of Drp1. On the one hand, p-Drp1 enhances the dimerization of Drp1 and promotes its interaction with the receptor MFF, inducing mitochondrial fission; on the other hand, Drp1-mediated mitochondrial fission in turn activates the FA-mediated wnt/β-catenin signaling pathway, thereby inducing cellular metabolic remodeling and promoting tumorigenesis and growth [55].
Another study based on a gastric cancer population showed that the expression of FIS1 involved in mitochondrial fission was increased and may be involved in gastric carcinogenesis [56].
Mitophagy associated with gastrointestinal tumorigenesis
Christian de Duve first observed lysosomal degradation in 1963 and coined the term “autophagy”, while “mitophagy” was not proposed until 2005 by John Lemasters [57]. Mitophagy is the opposite process of mitochondrial biogenesis, which can be categorized into Ub-dependent autophagy and LC3-mediated non-Ub-dependent autophagy. The process of mitophagy can be divided into four steps: (1) loss of mitochondrial membrane potential under external stimuli (nutrient deprivation, hypoxia, inflammation, DNA damage, etc. (2) formation of mitochondrial autophagosomes (3) fusion of the mitochondrial autophagosomes with the lysosome (4) degradation of the mitochondria [58,59,60].
Mitophagy, as a key cellular event, selectively induces the degradation of damaged and dysfunctional mitochondria, which is advantageous to cellular homeostasis. On the one hand, mitophagy removes defective or senescent mitochondria to prevent tumorigenesis [61]; on the other hand, mitophagy driven by oncogenic signals plays a protective role against cancer cells [62]. The role of mitophagy in tumors is gradually being emphasized, and a profound understanding of the relationship between mitophagy and gastrointestinal tumors will hopefully propel more effective diagnostic and therapeutic approaches.
The classical mitophagy pathway is most commonly mediated by PINK1/Parkin [63]. Parkin is an E3 ubiquitin ligase located in the cytoplasm, and PINK1 is a serine/threonine kinase located upstream of Parkin [64]. Phosphorylation of PINK1 at ser65 facilitates the translocation of Parkin from the cytoplasm to the mitochondria, thus triggering mitophagy [59]. Thus, either aberrant activation or inhibition of the PINK1/Parkin pathway can have an impact on gastrointestinal tumors.
PINK1 expression is decreased in CRC and acts as a tumor suppressor. PINK1 remodels CRC metabolism by activating the p53 signaling pathway to promote mitophagy and impede the production of acetyl-CoA, which ultimately suppresses CRC [65]. PiR-823 attenuates PINK1/Parkin-mediated mitophagy by promoting the degradation of PINK1, thereby contributing to colorectal tumorigenesis [66]. Mitophagy in intestinal epithelial cells may interfere with adaptive immunity in colorectal carcinogenesis [67] (Fig. 1).
Relationship between the mitochondrial quality control (MQC) system and gastrointestinal tumorigenesis
Progression of gastrointestinal tumors
Mitochondrial biogenesis associated with gastrointestinal tumor progression
Colorectal cancer
Studies also suggest significant relationship between mitochondrial biogenesis and gastrointestinal metastasis. For instance, increased Keap1 expression in metastatic CRC has been found to impact mitochondrial biogenesis [68]. Silencing or inhibiting the mitochondrial deacetylase sirtuin3 (SIRT3) result in a significant reduction of mitochondrial biogenesis-related proteins such as PGC-1α and mitochondrial transcription factor A (TAFM), which impairs the mitochondrial integrity and thus affects the viability and invasiveness of colon cancer cells [69]. In CRC, the β-catenin/c-Myc axis induced TFAM increase promotes gastro-intestinal tumor cell proliferation [32]. Imbalanced expression of PGC-1α in CRC cells regulates the proliferation and invasion of cancer cells through the AKT/GSK-3β/β-catenin signaling pathway [70]. In addition, LINC00839, a long chain non-coding RNA localized in the nucleus, is highly expressed in CRC. LINC00839 promotes CRC proliferation, invasion, and metastasis by facilitating mitochondrial biogenesis via Ruvb1/Tip60-NFR1 axis [71].
Overgrowth of tumor cells promotes tumor progression. MiR-138-5p, which is downregulated in CRC, promotes mitochondrial biogenesis by targeting the MCU/ROS axis, thereby promoting tumor cell growth and leading to unfavorable prognosis [72]. Moreover, Mitochondrial calcium uniporter (MCU), which is expressed at significantly high levels, is strongly associated with poor prognosis of CRC patients. The mechanism is that MCU inhibits the phosphorylation of TFAM at the serine-55 site and enhances its stability by inducing an increase in Ca2+ uptake, thereby promoting mitochondrial biogenesis and CRC growth via the ROS/NF-kB signaling pathway [73]. Furthermore, in contrast to other tumors in which mitochondrial biogenesis is suppressed, inflammation-induced overexpression of mitochondrial single-stranded DNA-binding protein (mtSSB) allows mitochondrial biogenesis to be increased in CRC, thereby promoting the growth of CRC. On the one hand, mtSSB promotes telomerase reverse transcriptase (TERT) expression and telomere lengthening by facilitating mitochondrial biogenesis and the ROS/Akt/mTOR signaling pathway; on the other hand, FOXP1, a transcription factor of mtSSB, is regulated by the pro-inflammatory signaling pathway IL-6/STAT3 to promote mtSSB expression [74].
Gastric cancer
TFAM binds to the D-loop of mtDNA and regulates mtDNA replication and transcription. In gastric adenocarcinoma (GAC), in addition to inducing reprogram of glucose metabolism, knockdown of TFAM resulted in a gradual decrease in mtDNA copy number that was highly correlated with tumor progression and prognosis [75].
It has also been found that PGC-1α, which is highly expressed in gastric cancer, regulates invasion, migration, and apoptosis of gastric cancer cells by targeting the SNAI1/miR-128b axis [76].
Mitochondrial dynamics associated with gastrointestinal tumor progression
Colorectal cancer
Drp1 unites mitochondrial dynamics with apoptosis, both of which exert certain influence on CRC progression. Drp1 can promote the growth and proliferation of CRC cells and inhibit apoptosis by decreasing cytochrome C release and regulating the integrity of mitochondrial membrane potential [77]. YAP, which is highly expressed in CRC, can directly interact with JNK, thereby regulating the JNK/Drp1 signaling pathway and ultimately causing mitochondrial fission blockage. Blocked mitochondrial fission will lead to a decrease in the release of HtrA2/Omi, which not only results in an anti-apoptotic effect, but also promotes tumor cell migration and invasion by affecting actin [78]. Mitochondrial fission and intrinsic apoptosis induced by the Bax-PGAM5L-Drp1 complex in response to Bax-mediated apoptotic stimuli could suppress growth and migration of CRC cells [79].
Moreover, increased expression of key upstream proteins will interact with mitochondria to modulate mitochondrial dynamics and tumor cell behavior. Sirtuin-3, which is remarkably expressed in CRC, blocks mitochondrial fission through activation of the Akt/PTEN pathway, thereby promoting tumor proliferation and migration [80]. The transcription factor HOXC10, which is highly expressed in CRC, promotes tumor cell proliferation, invasion and migration by interacting with mitochondrial fission regulator 2 (MTFR2) to activate its expression [81].
Gastric cancer
A bioinformatics study showed that MTFR2 expression is increased in gastric cancer and promotes tumor progression [82]. Nestin, whose expression level is increased in gastrointestinal stromal tumors (GISTs), regulates Drp1 recruitment and intracellular redox status by interacting with mitochondria, thereby promoting the proliferation and invasion of GISTs [83].
Excessive mitochondrial fission has been suggested to facilitate the proliferation, invasion, and metastasis of gastric cancer. In all types of gastric cancer except diffuse gastric adenocarcinoma, highly expressed Drp1 inhibits the export of its downstream protein RPL22 from the cytoplasmic to the nuclear [84]. GLI2 is overexpressed in gastric adenocarcinomas and causes an increase of CDH6 by binding directly to CDH6, and both proteins promote mitochondrial fission [85]. High expression of NDUFA4 promotes mitochondrial fission and biogenesis, which promotes glycolysis and oxidative metabolism in gastric cancer cells [15]. In addition, LMP2A was found to promote mitochondrial fission levels in gastric cancer by activating the Notch pathway [16]. Up-regulated FTO-mediated demethylation of m6A in gastric cancer regulates mitochondrial dynamics by directly targeting caveolin-1 mRNA to enhance its degradation [86].
Mitophagy associated with gastrointestinal tumor progression
Colorectal cancer
Inhibition of survival and proliferation of CRC cells incubated with their own m(hypermethylated)-DNA is associated with the activation of TLR9-dependent mitotophagy [87].
In the case of nutrient deficiency, mitophagy can initiate the recycling of mitochondrial metabolites to meet the metabolic demands of colon cancer cell proliferation and maintain cell growth [88].
BNIP3L/NIX-induced Parkin-independent mitophagy is particularly important under hypoxic conditions. BNIP3L is a member of the BCL-2 family, which participates in mitophagy along with the mitochondrial outer membrane protein Nix [63]. Up-regulated GPR176 recruits GNAS and binds to it to form a complex, and the formed complex impairs BNIP3L-induced mitophagy by activating the cAMP/PKA signaling pathway, which ultimately promotes CRC cell progression [89].
In addition to increased Keap1 expression in metastatic CRC affecting mitochondrial autophagy [68], in colon cancer liver metastases, AMPKα2 deficiency impairs mitophagy and increases its mediated ROS production and accumulation to exacerbate hepatocyte death [90].
Gastric cancer
It is well known that HIF-1α is essential for tumor cells to sense and adapt to the hypoxic environment [89]. The mechanism of HIF-1α regulation is complex, yet only a few studies have found that it is closely related to mitophagy in gastric cancer. Under hypoxic conditions, the expression of mitophagy-related BNIP3 was decreased in HIF-1α-deficient gastric cancer cells, which led to excessive accumulation of ROS and induction apoptosis [91]. In addition, mitophagy with impaired integrity increases the invasiveness of gastric cancer cells under hypoxic conditions by activating mtROS/HIF-1α interaction [92].
Under Met deficiency, the expression of lncRNA PVT1 was decreased, which led to the demethylation of the BNIP3 promoter to activate mitochondrial autophagy and ultimately inhibit the proliferation of gastric cancer cells [93].
In gastric cancer, the expression level of gamma-glutamyltransferase 7 (GGT7) is down-regulated by methylation modification. GGT7 directly binds to its downstream RAB7 to drive mitophagy, which subsequently inhibits ROS accumulation and AMPK signaling, and ultimately inhibits gastric cancer progression [94].
YAP is up-regulated in gastric cancer. On the one hand, the YAP/JNK signaling pathway is activated by targeting mitophagy [95]; on the other hand, YAP blocks the apoptotic pathway by activating the SIRT1/Mfn2/mitophagy axis and enhanced the expression of F-actin based on the reduction of cellular oxidative stress [96], and ultimately promoted the survival, proliferation, migration, and invasion of gastric cancer cells (Fig. 2).
Relationship between the mitochondrial quality control (MQC) system and the progression of gastrointestinal tumors
Treatment of gastrointestinal tumors
Mitochondrial biogenesis relevant to gastrointestinal tumor therapy
Given the inescapable role of mitochondrial biogenesis in gastrointestinal tumorigenesis and development, targeting this process will lead to new therapeutic options (Fig. 3).
Mitochondrial biogenesis and the treatment of gastrointestinal tumors
The importance of PGC-1αin disrupting tumorigenesis and development make it a promising target for the treatment of gastrointestinal tumors. For example, proton beam therapy (FBT) inhibits colon cancer metastasis by stimulating mitochondrial biogenesis. In invasive colon cancer cells, on the one hand, proton beam irradiation increases the expression of PGC-1α and its co-transcription factors NRF1α/ERRα and the mitochondrial transcription factor mtTFA; on the other hand, proton beam irradiation increases the phosphorylation of AMPK, a molecule upstream of PGC-1α, which induces an increase in mitochondrial biogenesis [97]. In addition, oil production waste products (OPWPs) and their extract, hydroxytyrosol (HTyr), can serve as an adjuvant anticancer drug to promote mitochondrial biogenesis by increasing the expression of PGC-1α and TFAM in colon cancer cells [98].
It is common for cancer cells to be insufficiently sensitive to therapeutic drugs and develop drug resistance. Emerging evidence suggested close implications of PGC-1αin drug resistance of gastrointestinal tumors. Metastatic CRC patients undergo chemotherapy demonstrated increased levels of mitochondrial biogenesis gene expression. Under the regulation of STRT1/PGC-1α signaling pathway, cancer cell metabolism changes from glycolysis to oxygen phosphorylation, which increases the resistance of intestinal cancer cells to chemotherapy [99]. In colon cancer, anti-angiogenic therapies can enhance tumor cell sensitivity to glycolysis inhibitors by inhibiting mitochondrial biogenesis, thus bringing a new light to cancer treatment [100]. In CRC cells resistant to oxaliplatin, exosomes circ_0001610 released by cancer cells increase the protein expression of PGC-1aα through the circ_0001610/miR-30e-5P/PGC-1aα axis, which facilitates cellular oxidative phosphorylation and lead to chemoresistance [101]. Some patients with gastrointestinal stromal tumors (GIST) are prone to develop resistance to imatinib, as mitochondrial biogenesis proteins such as PGC-1α, NRF2 and TFAM are inhibited in imatinib-sensitive GIST cells [102, 103]. In 5-FU-resistant CRC, increased PGC-1α not only impairs drug effects by increasing antioxidant enzyme activity and inhibiting ROS production, but also suppresses apoptosis by regulating cellular endoplasmic reticulum stress [104]. Under hypoxic conditions, CRC cells promote oxidative phosphorylation metabolism, tumorigenesis, proliferation and migratory properties of tumor cells through up-regulating PGC-1α. In addition, up-regulated PGC-1α lead to resistance of CRC cells to 5-FU by inducing an imbalance in apoptotic protein expression [105].
A study based on patients with stage III CRC found that high expression of folate-related genes such as SLC46A1/PCFT, may have an impact on the adjuvant therapy of patients [106]. These genes are partially regulated by the mitochondrial biogenesis-related factors NRF-1 or NRF-2, thus suggesting that there may be an association between folate metabolism and mitochondrial biogenesis [107, 108].
Another study showed that mtDNA expression levels and T/N mtDNA index were increased in CRC. Notably, hypoxia impairs mitochondrial biogenesis, resulting in the downregulation of TFAM and β-F1-ATPase, which leads to the decline of the T/N mtDNA index with CRC progression and would be conductive to resisting the apoptotic response of chemotherapeutic agents [109]. As the only COX-2 selective inhibitor with anticancer activity, the mechanism of celecoxib against CRC involves silencing TMEM117 to induce the decrease in the expression of proteins involved in mitochondrial biogenesis, such as TFAM, STRT1, and NRF1, which regulates mitochondrial biogenesis and then affects cell viability [110].
Plants and their active ingredients are often considered natural healing ingredients. Interestingly, high concentrations of genistein affect mitochondrial biogenesis distinctly in different colon cancer cell lines: mitochondrial biogenesis is increased in HT29 but decreased in SW620, both of which can ultimately reduce cell viability by regulating cellular oxidative stress, cell cycle and inflammation [111]. Low concentrations of xanthohumol can act as an anticancer agent by hindering the proliferation and progression of CRC cells through decreasing the expression of the pro-inflammatory genes and mitochondrial biogenesis genes [112]. Resveratrol (RSV), which has anti-colon cancer properties, can promote mitochondrial biogenesis by increasing mitochondrial biogenesis-associated proteins, thereby increasing the mass rather than the number of pre-existing mitochondria [113].
Besides, aldose reductase (AR) inhibitors can increase mitochondrial biogenesis and reduce mitochondrial DNA damage by promoting the Nrf2/HO-1/AMPK/P53 pathway, thereby inhibiting colon cancer growth and exerting anticancer effects [114].Tumor growth in plasmodium-infected mice with colon cancer is suppressed by the mechanism that plasmodium disrupts mitochondrial biogenesis and significantly decreases the level of PGC-1α protein, thereby inhibiting proliferation and promoting apoptosis of colon cancer cells [115]. Furthermore, K46 down-regulates PGC-1α and modulates mitochondrial biogenesis, which impairs mitochondrial dynamics to affect survival of colon cancer cells [91].
We regret to find that current research addressing mitochondrial biogenesis and the treatment of gastrointestinal tumors focuses on CRC, while aspects related to gastric cancer require further study.
Mitochondrial dynamics relevant to gastrointestinal tumor therapy
Colorectal cancer
Although new treatment modalities have consistently been developed, chemotherapy is still a typical and important treatment for gastrointestinal tumors. By studying the effects of chemotherapeutic agents targeting different mechanisms on mitochondria of CRC, it was found that mitochondrial fission affects the sensitivity of chemotherapeutic agents by participating in the process of chemotherapeutic agent-induced apoptosis of tumor cells [116]. Therefore, once mitochondrial fission is affected, it will lead to insufficient sensitivity of tumor cells to chemotherapeutic drugs, thus resulting in drug resistance. For example, HMGB1 released by CRC cells activates the ERK1/2 signaling pathway by binding to RAGEs, which triggers the phosphorylation of Drp1 at ser616, leading to chemotherapy resistance in CRC patients [117]. Assays in adriamycin-resistant colon cancer cells revealed that in order to resist chemotherapeutic agents, tumor cells adapted by increasing mitochondrial fission (increased DRP1) and decreasing mitochondrial fusion (decreased OPA1) [118]. Abnormal mitochondrial fusion is associated with 5-FU resistance in gastrointestinal cancer cells. In CRC, the METTL14/miR-17-5p/MFN2 axis reduces cellular sensitivity to 5-FU by decreasing mitochondrial fusion and promoting mitophagy [119].
In view of the close connection between mitochondrial fission and apoptosis of tumor cells, multiple drugs utilize mitochondrial fission to induce apoptosis of cancer cells. For example, Paris Saponin II inhibits colorectal carcinogenesis by inducing the dephosphorylation of Drp1 and its recruitment to mitochondria as well as ERK signaling, thus inhibiting the mitochondrial fission. Moreover, Drp1 inhibition further prohibits the activation of NF-KB signaling pathway, which ultimately leads to cell cycle arrest and promotes apoptosis of tumor cells [120]. In CRC, the HER2/3 heterodimerization inhibitor corosolic demonstrates an anticancer role by regulating mitochondrial dynamics. On the one hand, corosolic regulates Drp1 phosphorylation and promotes apoptosis by inhibiting the Ra1A/Ra1BP1/CDK1 axis through the inhibition of HER2 phosphorylation; on the other hand, corosolic prevents mitochondrial fission by blocking the PI3K/Akt/PKA signaling pathway through the inhibition of HER3 phosphorylation [121]. In addition, Sodium butyrate regulates mitochondrial fission and fusion by reducing the cell cycle protein B1-CDK1 complex required for DRP1 activation and down-regulating DRP1, which facilitates the induction of apoptosis in CRC cells [122]. Besides, anti-allergic drug azelastine directly targets ARF1 and acts as an anti-colon cancer drug by inhibiting mitochondrial fission [54].
Also most researches on mitochondrial fission have been focused on Drp1, the role of factors that regulate mitochondrial fission such as MFF and FIS1 should not be overlooked. The increase of MFN1 and MFN2 and the decrease of MFF indicate that OPWPs and HTyr can exert anti-proliferative and apoptosis-promoting effects on colon cancer cells by regulating mitochondrial dynamics [98]. Tanshinone IIA activates mitochondrial fission through the JNK-Mff axis, which mediates mitochondrial damage and exerts an anti-CRC effect [123]. Another study showed that in CRC, Tanshinone IIA combined with IL-2 can enhance INF2-mediated mitochondrial fission through Mst1-Hippo pathway to improve its therapeutic efficiency [124]. In addition, the mechanism of Matrine is to up-regulate MIEF1 through activating the LATS2-Hippo pathway, which activates mitochondrial fission and promotes the death of CRC cells [125].
As the opposite process of mitochondrial fission, mitochondrial fusion may also serve as an attractive target for inducing apoptosis in cancer cells. RKK-1447, a ROCK1/2 inhibitor, disrupts the association between ER and mitochondria and leads to ER stress-associated apoptosis in CRC cells through activating the cleavage of OPA1 [126]. In colon cancer, celecoxib reduces the expression of the mitochondria-associated membrane (MAM) and MFN2, which may be involved in inducing apoptosis [110]. Colon cancer cells shift mitochondrial dynamics toward fusion in response to 2-DG treatment, including decreased expression of Drp1 and increased expression of Mfn1 and Mfn2 [127]. In CRC, different co-stimulatory signals have different effects on the mitochondrial dynamics of CAR-T cells, whereas CEA28BB27Z signaling contributes to the fact that CAR-T cells can maintain more fused mitochondria thus enhancing their anti-tumor efficacy [128].
Studies on vesicle and mitochondrial dynamics in gastrointestinal tumors are relatively rare. The mechanism by which Paris polyphylla and its active ingredients exert anti-CRC activity is by inhibiting the extracellular vesicles (EV) released by fusobacterium nucleatum to inhibit the mitochondrial fusion that it promotes, thus inhibiting the growth and invasion of tumor cells [129]. In addition, the anti-CRC efficacy of YQ456 is related to its targeting of MYFO to interfere with Rab32-dependent mitochondrial dynamics, thereby disrupting the vesicle transport process [130].
The therapeutic mechanism of the Drp1 inhibitor mdivi-1 in tumors is to inhibit cell proliferation by modulating mitochondrial dynamics and cellular oxygen consumption [131]. In invasive colon cancer, proton beam irradiation modulates the mitochondrial dynamics imbalance in colon cancer by regulating the expression of DRP1 and OPA1 [97]. Lycorine exerts anticancer activity by targeting IDH1 to promote its acetylation modification, which damages the balance of mitochondrial dynamics by triggering oxidative stress in CRC cells [132].
Metformin targets mitochondria in CAC to protect the normal structure of mitochondria in colorectal cells by preventing H2O2-induced mitochondrial fission damage and activating the LKB1/AMPK signaling pathway [133]. Similarly, the heterozygous knockdown of IGF-1R could prevent oxidative stress-induced mitochondrial fission and activate mitochondrial fusion through activation of the LKM1/AMPK pathway, thus preventing CAC by protecting mitochondrial dynamics [134].
Gastric cancer
Based on the analysis of cisplatin-resistant gastric cancer patients, miR-148a-3p down-regulation was found in gastric cancer. MiR-148a-3p hinders mitochondrial fission by targeting the AKAP1/P53/Drp1 axis, which ultimately leads to drug resistance [135]. Research on gastric cancer cells stimulated by cisplatin revealed that HACE1 catalyzes ubiquitination of cyclin C and regulates its nuclear-mitochondrial translocation, ultimately leading to enhanced mitochondrial fission. Therefore, it is hypothesized that cisplatin resistance in gastric cancer cells may be related to mitochondrial fission alterations caused by mutations in the modification site of Cylin C or deletion of HACE1 [136]. Phosphorylation of ARC at the T149 is essential for mitochondrial fission and gastric cancer chemoresistance [137]. Its direct combination with PUMA inhibits Drp1 accumulation in mitochondria and mitochondrial fission, which attenuates apoptosis and leads to adriamycin chemoresistance in gastric cancer cells [138]. FTO targets CDKAL1 to regulate its methylation and induce sequential mitochondrial fusion, which ultimately leads to 5-FU resistance in gastric cancer cells [139].
Notably, in addition to mitochondrial fission inhibition, mitochondrial fission promotion can also induce apoptosis in tumor cells. In gastric cancer, sodium selenite combined with PAMD can amplify the inhibition of PAMD on tumor cells by promoting mitochondrial fission and apoptosis [140]. The mechanism by which the NASID drug indomethacin induces apoptosis in gastric cancer cells is to induce excessive mitochondrial fission and inhibit mitochondrial fusion through activation of the PKCζ-p38MAPK-DRP1 signaling pathway [141].
Lowly expressed in gastric cancer, Mnf2 can exert anticancer effects by affecting apoptosis, invasion, and migration of gastric cancer cells [142].
Gastric cancer cells with opa-interacting protein 5 (OIP5) deletion exhibited increased Drp1 phosphorylation and decreased expression of MFN2 after docetaxel treatment, revealing that OPI5 affects the efficacy of docetaxel by regulating mitochondrial dynamics [143]. In addition, the mechanism of Sanggenon C in gastric cancer is related to the blockade of the ERK signaling pathway and the inhibition of mitochondrial fission [144] (Fig. 4).
Mitochondrial dynamics and the treatment of gastrointestinal tumors
Mitophagy relevant to gastrointestinal tumor therapy
Colorectal cancer
Targeting mitophagy is a potential therapeutic strategy for gastrointestinal tumors. On the one hand, CRC can be inhibited by promoting mitophagy. δ-Valerobetaine (δVB) inhibits colon cancer by activating PINK1/Parkin/LC3B-mediated mitophagy to promote cancer cell death [145]. Bacterial-extracellular-vesicles (BEVs) induce PINK1-dependent mitophagy and oxidative stress, thus leading to colon cancer cell death through the Akt/ PI3K-AMPK/mTOR pathway [146]. Oleanolic acid (OA) induces PINK1-dependent mitophagy via the p38/FOXO3a/Sirt6 pathway and thereby exerts anti-colon cancer potential [147]. The anti-colon cancer activity of Aloe gel glucomannan (AGP) is associated with TFEB signaling activated by ROS overproduction and mitophagy mediated by PINK1/Parkin [148]. The mechanism by which Berberine (BBR) acts against gastrointestinal tumors depends on the induced Parkin/PINK1-related mitophagy [149]. Metformin is a mitochondria-targeted drug, which is often used adjunctively in the treatment of tumors. Metformin induces mitophagy by regulating the AMPK/MTORC1/ULK1 axis, thus exerting anti-proliferative effects on CRC cells [150]. In radiotherapy for CRC, adjuvant use of metformin not only reduces treatment-induced intestinal toxicity by activating the AMPK2-NRF2 pathway to enhance mitophagy, but also increases the therapeutic sensitivity of p53-mutant colorectal tumors [151]. In addition, high expression of SIRT3 leads to over-activation of PINK1/Parkin-mediated mitophagy, which enhances the radiation resistance of CRC cells [152]. The combination of FO + CO (2.5:1) + DMEM can activate mitophagy to inhibit the proliferation of tumor cells and thus play a preventive role against CRC [153]. The supramolecular complex of Ad-HA/FA-M-β-CyD targets colon cancer cells to induce cell death by activating mitophagy [154]. In colon cancer, FA relies on the Drp1/p62/LC3 pathway to induce mitophagy to protect mitochondrial integrity and facilitate cell survival [55].
The chemotherapeutic agent KP46 targets mitochondria to exert anti-colon cancer activity, and the specific mechanism is related to its triggering of p53/BNIP3-Parkin-mediated mitophagy. In addition, drug resistance in CRC stem cells induced by doxorubicin is associated with its promotion of BNIP3L-dependent mitophagy [92]. The anti-CRC activity of oxymatrine is associated with its inhibition of LRPPRC expression to promote Parkin-mediated mitophagy, which induces the inactivation of the NLPR3 inflammasome [155]. Andro drives mitophagy of macrophages through the PK3CA-AKT1-MTOR-RPS6KB1 signaling pathway, which mediates the inactivation of NLRP3, thereby suppressing the progression of CAC [156]. It is promising that mitophagy negatively regulates the activity of NLPR3 can be considered as a therapeutic target for tumors.
On the other hand, inhibition of mitophagy likewise offers the possibility of treating CRC. The decreased PINK1 and Parkin in Plasmodium infected mice with CRC reveals that Plasmodium can inhibit colon cancer by inhibiting mitophagy [115]. The mechanism by which YQ456 induces CRC cell death is related to its ability to target MYFO to inhibit Rab7-mediated lysosomal degradation, thereby disrupting the PINK1/Parkin-mediated mitophagy [130]. Single-nucleotide variants (SNVs) in PINK1 gene were found to be associated with a low relapse rate in patients treated with adjuvant 5-FU chemotherapy for CRC, which suggests that SNVs in PINK1 enhance the efficacy of chemotherapeutic agents by inhibiting mitophagy [157]. In addition, Mefloquine inhibits PINK1/Parkin-dependent mitophagy by targeting endolysosomal RAB5/7, thereby inducing the elimination of colon cancer stem cells (CSCs) [158]. Ionizing radiation can significantly increase Parkin expression in CRC cells, and inhibition of mitophagy combined with ionizing radiation treatment can induce ROS accumulation and enhanced DNA damage, thus improving radiation sensitivity of CRC cells [159]. Moreover, the anti-CRC efficacy of gossypol derivative and BH3 mimetic ch282-5 is correlated with the disruption of mitophagy [160].
Gastric cancer
The therapeutic efficacy of Huazhuojiedu decoction (HZJD) in gastric cancer precancerous lesions was associated with its reversal of Parkin-dependent mitophagic activity [161]. 8-paradol from ginger induced apoptosis in gastric adenocarcinoma cells by activating PINK1/Parkin-mediated mitophagy, and chloroquine (CQ) can reverse this effect by inhibiting mitophagy [162]. The overexpression of OIP5 activated PINK1-mediated mitophagy, which prevented docetaxel-induced mitochondrial damage in gastric cancer cells [143].
Whereas, increased mitophagy during indomethacin treatment of gastric cancer prevents cellular damage induced by excessive mitochondrial debris [141].
As for gastric cancer, TRPM2 deletion could inhibit BNIP3-mediated mitophagy by down-regulating the JNK signaling pathway, thereby enhancing apoptosis of gastric cancer cells, and enhance the efficacy of paclitaxel and doxorubicin in gastric cancer [163] (Fig. 5).
Mitophagy and the treatment of gastrointestinal tumors
Others
The expression of mitochondrial dynamics-related proteins such as p-DRP1, MFN1, and OPA1 were significantly increased in CRC cells under hypoxic conditions [105]. In CRC, MCU-mediated mitochondrial Ca2 + uptake exerts an impact on the expression of proteins related to mitochondrial dynamics, including enhancement of mitochondrial fission (increased expression of Drp1) and inhibition of mitochondrial fusion (decreased expression of OPA1) [73]. In addition, inhibition of piR-823 will impair mitochondrial dynamics in CRC cells, including increased expression of DRP1 and decreased expression of MFN2 [66].
In CRC, PINK1-mediated mitophagy is critical for the balance of intracellular iron distribution [164]. Furthermore, altered expression of PINK1 in metastatic CRC to the liver is associated with poor patient prognosis [165].
In CRC, Aflatoxin B1 (AFB1)-induced mitophagy is associated with its enhanced m6A methylation modification [166]. A bioinformatic analysis suggested that four mitophagy-related genes were associated with the prognosis of colon adenocarcinoma, including PPARGC1A, SLC6A1, EPHB2 and PPP1R17 [167].
Another study showed that GABARAPL2 and CDC37 are mitophagy-related genes associated with the prognosis of gastric cancer [168]. The exact mechanism of certain mitophagy-related genes in gastrointestinal carcinogenesis remains to be investigated. In order to maintain homeostasis, gastric cancer cells require the combined action of NR4A1 and TNF-α to activate Parkin-dependent mitophagy. In addition, overexpression of NR4A1 could enhance TNF-α-induced apoptosis in gastric cancer cells by inhibiting JNK/Parkin-dependent mitophagy [169, 170]. In skeletal muscle and related cell models of gastrointestinal cancer-associated cachexia (CC) patients, it was found that Drp1 phosphorylation was abnormally activated and led to an increase in its expression level in CC patients, and the overexpression of DRP1 would exacerbate cachexia in patients, whereas the expression of Mfn2 was decreased [171,172,173]. It is therefore hypothesized that mitochondrial dynamics are involved in muscle loss associated with cancer cachexia. Studies in gastric cancer patients accompanied by CC revealed decreased protein expression of PINK1 and Parkin, and it was hypothesized that mitophagy signaling is a disordered checkpoint for muscle MQC in gastric cancer malignancy [172].
Summary and future directions
Mitochondrial adaptive cellular processes are important for cell survival, and once this adaptation is lost, it predisposes to the development of mitochondria-associated diseases such as cancers. Mitochondria have been proved to be closely related with the occurrence and development of gastrointestinal tumors. Early investigations mainly focused on the relationship between mitochondria and aberrant energy metabolism of gastrointestinal tumors. Recent advances indicated that mitophagy as well as quality and quantity of mitochondria might significantly contribute to the carcinogenesis and progression of gastrointestinal tumors. According to this review, different aspects of mitochondrial processes including mitochondrial biogenesis, dynamics, and mitophagy are all implicated in gastrointestinal tumorigenesis, progression, inflammation, metabolism and drug resistance.
Importantly, the three mitochondrial processes are not split or isolated, therefore their dynamic interplay might implicit potential mechanisms. Multiple studies have shown that mitophagy and mitochondrial dynamics are closely linked. For example, MFN2 in mitochondrial dynamics is also involved in mediating and controlling the process of mitophagy [174]. BNIP3L is associated with DRP1 and OPA1, which can participate in the regulatory process of mitochondrial dynamics [175]. Mitochondrial biogenesis and mitophagy “cooperate” to ensure a sufficient number of functional and active “healthy” mitochondria. Mitophagy selectively removes aging and defective mitochondria, and mitochondrial biogenesis compensates for this loss by promoting the production of fresh mitochondria [176]. So that different mitochondrial processes often occur in tandem, imbalance of which might inevitably lead lead to gastrointestinal tumorigenesis.
Moreover, a large number of studies have focused on the therapeutic potential of targeting mitochondria in gastrointestinal tumors, and a series of novel therapeutic methods have been recommended in cell and animal models. Treatment targeting mitochondrial dynamics, usually promotion of mitochondrial fission and inhibition of mitochondrial fusion, for drug-resistant colorectal cancer and gastric cancer demonstrated different outcomes. Promotion of mitochondrial fusion lead to 5-FU resistance in gastric cancer cells while inhibition of mitochondrial fusion resulted in 5-FU resistance colorectal cancer. Moreover, adriamycin-resistant gastric cancer cells showed inhibition of mitochondrial fission, whereas casplatin-resistant colorectal cancer showed increased mitochondrial fission. The underlying mechanisms of this difference remain to be further investigated. It is worth noting that recent investigations also suggested that combination of traditional therapy and mitochondria-targeted therapies might generate favorable outcome by cooperation effect. Future molecular mechanism studies and clinical trials are still required to expand the application of mitochondria-targeted therapies for gastrointestinal tumors.
Data availability
No datasets were generated or analysed during the current study.
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This work was supported by the National Natural Science Foundation (82102740).
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This work was supported by the National Natural Science Foundation (82102740).
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YH Liu, H Wang, N Peng and SS Hai wrote the manuscript. S Zhang and Haibo Zhao prepared the figures. JW Liu and WX Liu revised the paper. All authors read and approved the final manuscript.
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Liu, Y., Wang, H., Zhang, S. et al. The role of mitochondrial biogenesis, mitochondrial dynamics and mitophagy in gastrointestinal tumors. Cancer Cell Int 25, 46 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12935-025-03685-2
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DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12935-025-03685-2