Abnormal lipid metabolism has been commonly observed in various human cancers, including colorectal cancer (CRC). The mitochondrial citrate carrier SLC25A1 (also known as mitochondrial citrate/isocitrate carrier, CIC), has been shown to play an important role in lipid metabolism regulation. Our bioinformatics analysis indicated that SLC25A1 was markedly upregulated in CRC. However, the role of SLC25A1 in the pathogenesis and aberrant lipid metabolism in CRC remain unexplored. Here, we found that SLC25A1 expression was significantly increased in tumor samples of CRC as compared with paired normal samples, which is associated with poor survival in patients with CRC. Knockdown of SLC25A1 significantly inhibited the growth of CRC cells by suppressing the progression of the G1/S cell cycle and inducing cell apoptosis both in vitro and in vivo, whereas SLC25A1 overexpression suppressed the malignant phenotype. Additionally, we demonstrated that SLC25A1 reprogrammed energy metabolism to promote CRC progression through two mechanisms. Under normal conditions, SLC25A1 increased de novo lipid synthesis to promote CRC growth. During metabolic stress, SLC25A1 increased oxidative phosphorylation (OXPHOS) to protect protects CRC cells from energy stress-induced cell apoptosis. Collectively, SLC25A1 plays a pivotal role in the promotion of CRC growth and survival by reprogramming energy metabolism. It could be exploited as a novel diagnostic marker and therapeutic target in CRC.

Growing evidence indicates that the dysregulation of mitochondrial calcium (Ca²⁺) plays a critical role in the growth of tumor cells, including colorectal cancer (CRC). However, the underling mechanism is not fully elucidated. In this study, the regulatory effects of mitochondrial Ca²⁺ on phosphodiesterase 2 (PDE2)/cAMP/PKA axis and the phosphorylation of mitochondrial transcription factor A (TFAM) as well as the growth of CRC cells were systematically investigated both in vitro and in vivo. Our findings demonstrated that MCU-induced mitochondrial Ca²⁺ uptake activated mitochondrial PDE2 in CRC cells. Moreover, overexpression MCU in CRC led to a 1.9-fold increase in Ca²⁺ uptake compared to control cells. However, knockdown of MCU resulted in 1.5-fould decrease in Ca²⁺ uptake in mitochondria compared to the controls. Activation of mitochondrial PDE2 significantly inhibited the activity of mitochondrial protein kinase A (PKA), which subsequently leads to decreased phosphorylation of TFAM. Our data further revealed that PKA regulates the phosphorylation of TFAM and promotes the degradation of phosphorylated TFAM. Thus, TFAM protein levels accumulated in mitochondria when the activity of PKA was inhibited. Overall, this study showed that the overexpression of MCU enhanced CRC growth through promoting the accumulation of TFAM proteins in mitochondria. Conversely, knockdown of MCU in CRC cells resulted in decreased CRC growth. Collectively, these data suggest that the mitochondrial Ca²⁺-activated PDE2/cAMP/PKA axis plays a key role in regulating TFAM stability and the growth of CRC cells.

Epididymal protein 3A (EDDM3A) is a protein involved in sperm maturation. It has been demonstrated that EDDM3A expression is upregulated and promotes cell proliferation in non-small cell lung cancer (NSCLC). However, the role of EDDM3A in other types of human cancers, including gastric cancer (GC), is still unexplored. Here, we show that the expression of EDDM3A is significantly upregulated in gastric cancer (GC) tissues and its upregulation correlates with poorer survival in patients with gastric cancer. Knockdown of EDDM3A inhibited growth and metastasis of GC cells, whereas overexpression of EDDM3A exhibited the opposite effect. Mechanistically, enhanced aerobic glycolysis mediated by upregulation of HIF-1α and subsequently increased target glycolytic genes and decreased mitochondrial biogenesis was found to contribute to the promotion of tumor growth and metastasis by EDDM3A in GC cells. Additionally, upregulation of EDDM3A in GC is at least partially mediated by downregulation of miR-618. In conclusion, elevated EDDM3A plays a pivotal oncogenic role in gastric carcinogenesis, suggesting it as a potential therapeutic target for treatment of GC.

Accumulating evidence has shown that the dysfunction of mitochondria, the multifunctional organelles in various cellular processes, is a pivotal event in the development of various diseases, including human cancers. Solute Carrier Family 25 Member 42 (SLC25A42) is a mitochondrial protein governing the transport of coenzyme A (CoA). However, the biological roles of SLC25A42 in human cancers are still unexplored. Here we uncovered that SLC25A42 is upregulated and correlated with a worse prognosis in GC patients. SLC25A42 promotes the proliferation of gastric cancer (GC) cells while suppresses apoptosis in vitro and in vivo. Mechanistically, SLC25A42 promotes the growth and inhibits apoptosis of GC cells by reprograming lipid metabolism. On the one hand, SLC25A42 enhances fatty acid oxidation-mediated mitochondrial respiration to provide energy for cell survival. On the other hand, SLC25A42 decreases the levels of free fatty acids and ROS to inhibit ferroptosis. Moreover, we found that SLC25A42 reprograms lipid metabolism in GC cells by upregulating the acetylation and thus the expression of CPT2. Collectively, our data reveal a critical oncogenic role of SLC25A42 in GCs and suggest that SLC25A42 represent a promising therapeutic target for GC.

The dependence of cancer cells on mitochondrial metabolism has been revealed in various cancer types. However, the mechanisms underlying this metabolic remodeling remain largely unclear. Solute carrier family 44 member 4 (SLC44A2) is a mitochondrial membrane-localized transmembrane protein belonging to the choline transporter-like protein family. Recently, it was reported that deletion of SLC44A2 impairs adhesion and increases proliferation in cultured lung mesenchymal cells. This finding implies that SLC44A2 may play a role in the malignant phenotypes of human cancers. However, the effects of SLC44A2 on malignant phenotypes and mitochondrial metabolism in human cancers remain unexplored. In the present investigation, we observed a significant reduction in SLC44A2 expression in colorectal cancer (CRC), and low SLC44A2 expression was closely associated with poorer survival of CRC patients. Functional assays demonstrated that SLC44A2 suppressed CRC growth and metastasis both in vitro and in vivo. Mechanistically, SLC44A2 inhibits mitochondrial fatty acid oxidation, thereby reducing energy supply and increase ROS stress. This effect is achieved by promoting mitochondrial E3 ubiquitin ligase 1 (MUL1)-regulated degradation of carnitine palmitoyltransferase 2 (CPT2) via enhancing the interaction between MUL1 and CPT2, without increasing MUL1 expression, which ultimately contributes to the proliferation and metastasis of CRC. Together, SLC44A2 functions as a critical tumor suppressor in CRC and potential therapeutic target in the treatment of this malignancy.

Mycoplasma is widespread in various hosts and may cause various diseases in animals. Interestingly, the occurrence of mycoplasma infection was observed in many tumor types. However, the mechanism regulating its infection is far from clear. We unexpectedly found that the knockdown of mitochondrial transcription factor A (TFAM) remarkably enhanced mycoplasma infection in hepatocellular carcinoma (HCC) cells. More importantly, we found that mycoplasma infection facilitated by TFAM knockdown significantly promoted HCC cell metastasis. Mycoplasma infection was further found to be positively correlated with poor prognosis in patients with HCC. Mechanistically, the decreased TFAM expression upregulated the transcription factor Sp1 to increase the expression level of Annexin A2 (ANXA2), which was reported to interact with membrane protein of mycoplasma. Moreover, we found that mycoplasma infection enhanced by the TFAM downregulation promoted HCC migration and invasion by activating the nuclear factor-kappa B signaling pathway. The downregulation of TFAM enhanced mycoplasma infection in HCC cells and promoted HCC cell metastasis. Our study contributes to the understanding of the pathological role of mycoplasma infection and provides supporting evidence that targeting TFAM could be a potential strategy for the treatment of HCC with mycoplasma infection.