The mitochondrial S-adenosylmethionine carrier (mSAMC), a member of the mitochondrial carrier family (MCF), widely exists in all eukaryotes and is located in the mitochondrial inner membrane [1–3]. The mSAMC catalyzes the import of S-adenosylmethionine (SAM) from the cytosol into the mitochondria and the export of S-adenosylhomocysteine (SAH) from the mitochondria into the cytosol [4–11]. In the cytoplasm, SAM participates in the methionine cycle and polyamine biosynthesis (Figure 1) [12–18]. In the mitochondria, SAM provides the methyl for methylation of DNA, RNA, proteins, and amino acids (Figure 1). Therefore, SAM has a great influence on sustained epigenetic modifications and has been implicated in several diseases and potential pathogenesis of cancer development [19]. For example, high or extremely high activity of methionine cycle metabolism was observed in cancer cells, especially tumor-initiating cells or tumor stem cells. Moreover, the proliferation of tumor cells is significantly inhibited by drug intervention of methionine cycle metabolism [20]. Schober et al. reported that mSAMC is the only carrier for transporting SAM from cytoplasm to mitochondria, and mitochondrial SAM levels in flies, mice, and humans are directly dependent on cytosolic SAM generated in the methionine cycle. Therefore, SLC25A26 abnormal expression or mSAMC dysfunction can be associated with multiple disease states, including cancer, nutrient deficiencies, and cardiovascular diseases [21]. The mitochondrial carrier family in humans, called solute carrier family 25 (SLC25), has been identified for 53 members which are widely distributed in eukaryotes with similar structure and are mainly embedded in the inner membrane of mitochondria. They are involved in the transmembrane transport of various substrates including amino acids and their derivatives, cofactors, inorganic ions, nucleotides, and so on, which is further associated with mitochondrial metabolism and cell function [3, 22, 23]. Human mSAMC was encoded by solute carrier family 25 member 26 (SLC25A26) gene [9]. Growing studies showed that aberrant expression of SLC25A26 may be involved in the occurrence and development of some cancers [24–32].

Therefore, we will briefly review mSAMC in different species and its encoding gene, focusing on the association of SLC25A26 gene aberrant expression and some cancers as well as potential mechanisms, and characteristics of mitochondrial diseases caused by SLC25A26 mutation. Finally, we provide a brief expectation that needs to be further investigated.

To date, mSAMC was identified in saccharomyces cerevisiae in 2003, human in 2004 and Arabidopsis in 2006 [5, 9, 10]. In Saccharomyces cerevisiae, it was named Sam5p (Pet8p is used now) and encoded by PET8 gene [5, 33–37]. In human, it was named SAMC and encoded by SLC25A26 gene which is located on chromosome 3p14.1 as an autosomal recessive hereditary double allele gene with a highly conserved exon similar to the other mitochondrial carrier genes [38]. In Arabidopsis, it has two isoforms, named SAMC1 and SAMC2 which were encoded by At4g39460 and At1g34065 gene, respectively. Sam5p (Pet8p), SAMC, SAMC1, and SAMC2 have the characteristics of the MCF and are located at mitochondria [3, 39]. However, later research proved that SAMC1 also exists on the chloroplast envelope membrane [24, 40–42]. SAMC1, SAMC2, and Sam5p (Pet8p) catalyze countertransport between SAM and mitochondrial SAH (mainly), S-adenosylcysteine (SAC), or adenosylornithine [5]. SAMC catalyzes countertransport between SAM and mitochondrial SAH [9]. SAMC1 and SAMC2 catalyze countertransport between SAM and mitochondrial SAH (mainly) or SAC [10]. Table 1 showed the differences and function of the mitochondrial S-adenosylmethionine carrier in yeast, human, and Arabidopsis, respectively.

Additionally, the 2004 in vitro study on human recombinant SAMC identified several potent inhibitors [9]. These include pyridoxal 5′-phosphate, p-hydroxymercuribenzoate, mersalyl, and mercuric chloride, which are general inhibitors of mitochondrial carriers, and tannic acid and Bromocresol Purple, which specifically inhibit glutamate carriers. Notably, inhibitors characteristic of other mitochondrial carriers showed minimal impact on the activity of recombinant SAMC.

Regarding the regulation of the SLC25A26 gene, FOXD3 has been identified as a repressor in the CaSki cell line [25], while CTB enhances senescence in HCC cells by inducing the upregulation of SLC25A26 expression, potentially influencing its activation [28].

In some cancers, SLC25A26 expression is aberrant (Table 2). Patients with invasive cervical cancer have recurrent chromosome 3p12-p14 loss. In 2013, Lando et al. reported that 8 genes including SLC25A26 were highly downregulated in invasive cervical cancer patients with recurrent chromosome 3p12-p14 loss, which may be associated with cancer invasiveness [43]. In cervical cancer line CaSki and HeLa cells, SLC25A26 gene is also downregulated [26]. A large-scale genome-wide association study of low-grade glioma revealed 2 causal single nucleotide polymorphisms at rs11706832 site. One is rs11706832 reference allele: A, which may generate a binding site for a transcriptional repressor named LEF1 to inhibit SLC25A26 expression. The other is rs11706832 alternative allele: C, a risk alternative allele, which promotes SLC25A26 expression [27]. In human liver cancer tissues, SLC25A26 expression was low compared to adjacent tissues. A novel copper complex [Cu(ttpy-tpp)Br₂]Br (Referred to as CTB) exerted an anti-hepatocellular carcinoma effect by up-regulating SLC25A26 expression level in mice [28]. In non-small cell lung cancer, expression of SLC25A26 and the 10-year survival rate of the patients were negatively correlated [31]. In most colorectal cancer patients, SLC25A26 gene was highly expressed. Moreover, in a subcutaneous transplanted tumor model with MC38 cells, a mouse colon cancer cell lines, knockdown of SLC25A26 caused tumor volume to begin to decrease by day 9 and completely disappear by day 30, whereas control tumor volume continued to increase [32]. The expression of SLC25A26 in different cancers is shown in Table 2. These studies suggest that aberrant expression of SLC25A26 may be associated with the occurrence and development of some cancers.

Studies from clinical trials, and animal and cell models indicate that SLC25A26 abnormal expression can regulate the occurrence and development of cancers. Its potential mechanisms are as follows (Figure 2).

The low expression levels of eight genes located on chromosome 3p12-14, including SLC25A26, have been verified to be associated with poor prognosis in patients with cervical squamous cell carcinomas (SCC). In addition, SCC is more likely to have chromosome 3p12-14 loss and is associated with aggressive tumour growth compared to precancerous lesions. Therefore, these eight genes may contribute to evaluating cancer aggressiveness in the early invasive stage. Based on the low intratumor heterogeneity of these genes, the gene expression level can be obtained by FISH for clinical diagnostic testing [43].

SLC25A26 expression is detected as low in HCC tissues, which is correlated with a high level of proliferation index Ki67 and low expression of senescence markers p16, p21 and HMGA1 (28). Therefore, we speculate that the low expression of SLC25A26 in HCC tissues may be related to the poor prognosis of patients.

For NSCLC, a total of 5 genes including SLC25A26 were selected and made as a risk assessment model. In the model, high expression of SLC25A26 in NSCLC patients is positively correlated with the risk score and predicts a poor 10-year survival rate [31].

In brief, these studies suggest that SLC25A26 expression level may be differently correlated with the prognosis in different cancers. However, the relationship between SLC25A26 expression and the prognosis of other cancers as well as the specific predictive indicators remain to be investigated. In addition, it should be explored whether SLC25A26 expression is relevant for predicting, detecting, or diagnosing certain cancers.

It has also been reported that SLC25A26 mutation may lead to mitochondrial defects and then induce a mitochondrial disease called combined oxidative phosphorylation deficiency 28 (COXPD28).

COXPD28 is an autosomal recessive genetic disease first identified by Kishita et al. in 2015 in three unrelated severe infant cases [69]. Subsequently, two new infants with COXPD28 were reported in 2022 [70, 71]. The five patients presented with varying degrees of clinical symptoms, ranging from mild muscle weakness, cardiopulmonary insufficiency, and developmental delay to respiratory and circulatory/multiple organ failure and death, accompanied by hyperlactatemia. Muscle biopsy revealed varying degrees of decrease in mitochondrial complexes I, III, and IV [69]. Further research on infants with COXPD28 indicated that the SLC25A26 mutation severely impairs the function of SAMC in transporting SAM into the mitochondria [69], which may lead to a more severe early-onset phenotype. This mutation results in a deficiency of mitochondrial SAM input, leading to a lack of methylation substrates and impaired mitochondrial biosynthesis. Specifically, mtRNA methylation is impaired, affecting rRNA stability and tRNA maturation, further impacting ribosomal assembly and de novo translation processes in mitochondria. The steady-state levels of COXII, a subunit of complex IV, was reduced, and the methylation of ADP/ATP translocase genes ANT1 and ANT2, as well as the electron transfer flavoprotein ETFβ, were found to be hypomethylated. The biosynthesis of LA [72], which relies on SAM for methylation, is impaired, leading to reduced levels of the pyruvate dehydrogenase complex E2 (PDHC-E2) and the α-ketoglutarate dehydrogenase E2 (α-KGDH-E2), of which LA is a subunit, and further affecting the activity of PDH and α-KDGH. The biosynthesis of CoQ10, an electron carrier in the mitochondrial oxidative respiratory chain, is also impaired, leading to a significant decrease in mitochondrial ATP production [69].

Additionally, three adult female patients with milder phenotypes of COXPD28 have been reported [73, 74]. The common symptoms of these three patients were muscle weakness, gastrointestinal discomfort, and hyperlactacidemia. Independent symptoms include respiratory and multi-organ failure, exercise intolerance with muscle pain and disability. Studies in adult cases of COXPD28 suggest that the SLC25A26 mutation primarily affects the function of SAMC in transporting SAH into the cytoplasm, which may result in a milder late-onset phenotype. In mouse embryonic fibroblast models, cells with the SLC25A26 mutation also showed reduced mitochondrial LA levels and PDH activity [73]. In Drosophila Melanogaster larvae with the SLC25A26 mutation, a decrease in the pentose phosphate pathway and bile acid synthesis was found, while iron-sulfur clusters and ubiquinone biosynthesis proteins were upregulated, and OXPHOS components UQCR-11 and COX7A proteins both showed increased expression, along with biomarkers of mitochondrial methylation defects [21], including the absence of glycine-N-methyltransferase (GNMT) and an increase in serine biosynthetic enzyme phosphoserine phosphatase (PSPH) [73].

In conclusion, SLC25A26 mutations impair mitochondrial RNA stability, protein synthesis, LA, and CoQ10 biosynthesis, which further affect TCA and the mitochondrial oxidative respiratory chain, resulting in the intractable mitochondrial disease COXPD28. This also emphasizes the importance of SLC25A26 for mitochondrial function. By the way, in patients with major depression disorder, the plasma SAMC level was found to be significantly increased [75].

In conclusion, we briefly reviewed the essential roles of SAMC and its encoding gene, further empathizes association of SLC25A26 aberrant expression and some cancers, as well as potential mechanisms for SLC25A26 regulating the occurrence and development of cancers including regulating the activity of methionine cycle metabolism, DNA methylation, senescence, apoptosis and immune cell infiltration. Next, we summarized its potential in cancer prognosis and finally emphasized its importance in mitochondria function by reviewing an intractable mitochondrial disease named COXPD28 caused by SLC25A26 mutation.

However, the role of SLC25A26 in cancer regulation remains to be fully elucidated. Key questions include how varying expression levels of SLC25A26 affect the methylation of genes in the nucleus or mitochondria, and how these changes regulate various aspects of cancer through specific pathways. Additionally, the impact of SLC25A26 expression on the infiltration of immune cell subsets adjacent to different cancer cells and the abundance of cancer cells, and its subsequent influence on cancer progression through immune modulation, is an area that needs further investigation. The potential of SLC25A26 as a target for cancer therapy is yet to be fully exploited, either. For instance, the discovery of potent inhibitors of the expression product of SLC25A26, SAMC, has been made [9], but their effects on cancer have not yet been studied. Moreover, the downregulation of SLC25A26 in invasive cervical SCC may enhance invasiveness and resistance to treatment [43]. This finding prompts a deeper exploration into the mechanisms linking SLC25A26 downregulation with cancer cell invasiveness and treatment resistance, potentially revealing new strategies to reduce cancer lethality and improve therapeutic efficacy. Furthermore, the novel copper complex CTB has been shown to inhibit tumorigenesis in vivo by up-regulating SLC25A26 expression [28], while MC38 cells with SLC25A26 knockout exhibited massive cell death [32], and SLC25A26 knockout mice were embryonically lethal [21]. These observations suggest that both extremely high and low levels of SLC25A26 expression could lead to the inhibition or death of cancer cells via distinct pathways, indicating that SLC25A26 inhibitors or activators may represent novel cancer gene therapies awaiting further research. Besides, further investigation is needed to determine the role of SLC25A26 in predicting, diagnosing, and prognosing cancer.

Overall, SLC25A26 may regulate the occurrence and development of cancers via many pathways, which suggests that SLC25A26 will be a potential new therapeutic target for cancers.