The metabolic hallmark of most cancer cells is the Warburg effect, the tendency to ferment glucose into lactate even when oxygen is abundant. Colorectal cancer cells exemplify this behavior, preferentially catabolizing glucose into lactate to fuel their accelerated proliferation. Yet the Warburg effect is only half the story. In parallel, colorectal cancer cells display a strong dependence on glutamine, which they use to replenish intermediates of the tricarboxylic acid cycle. This anaplerotic supply supports not just ATP production but also lipid biosynthesis and the maintenance of redox homeostasis, the delicate balance of oxidizing and reducing agents that keeps cells alive under stress. Mitochondria, far from being passive power plants, thus become central hubs of the biosynthetic and energetic demands that outstrip anything required for basal energy homeostasis in normal tissue.

Moving metabolites into and out of mitochondria requires dedicated transporter proteins, and the review concentrates on three of them: the mitochondrial pyruvate carrier, or MPC; the mitochondrial citrate carrier, known as CIC or SLC25A1; and a mitochondrial variant of the glutamine transporter SLC1A5, designated SLC1A5_var. Each of these sits in the inner mitochondrial membrane, the impermeable barrier that normally controls which carbon fuels enter the mitochondrial matrix. Their regulation determines whether pyruvate from glycolysis reaches the TCA cycle, whether citrate can be exported for fat synthesis, and whether glutamine can be funneled into mitochondrial metabolism. Strikingly, the three carriers appear to behave very differently in colorectal cancer.

The mitochondrial pyruvate carrier, composed of MPC1 and MPC2 subunits, is frequently lost or downregulated in colorectal cancer. This loss is not incidental. Work cited in the review showed that the MPC functions as a repressor of the Warburg effect and of colon cancer cell growth; when pyruvate entry into mitochondria is curtailed, cells shift more fully toward aerobic glycolysis. Decreased expression of MPC2 has been linked to activation of the mTOR pathway, a master growth regulator, promoting aerobic glycolysis and proliferation in colorectal cancer. Conversely, restoring mitochondrial pyruvate transport has been shown to elicit robust production of reactive oxygen species, sensitizing colon cancer cells to the antitumor effects of interferon-gamma. MPC1 expression has also been implicated in controlling epithelial-mesenchymal transition and radioresistance, processes that govern metastasis and treatment failure. In other words, the status of this single transporter can influence both the metabolic phenotype and the therapeutic responsiveness of tumor cells.

The citrate carrier presents a contrasting picture. Rather than being suppressed, CIC is upregulated in colorectal cancer and actively promotes tumor growth and survival. Citrate exported from mitochondria is the essential cytosolic precursor for acetyl-CoA, the building block of fatty acid synthesis, and for the acetylation reactions that modify proteins and chromatin. Recent work highlighted in the review shows that SLC25A1 and ATP-citrate lyase together maintain cytosolic acetyl-CoA pools and regulate ferroptosis susceptibility through acetylation of the ferroptosis suppressor protein FSP1. This connects the citrate carrier to one of the hottest topics in cancer biology: ferroptosis, an iron-dependent form of cell death that tumors work hard to evade. Earlier studies have also shown that SLC25A1 sustains redox homeostasis and supports radioresistance under cycling severe hypoxia, and that in other cancers it drives stemness and therapy resistance. In colorectal cancer specifically, SLC25A1 has been shown to reprogram energy metabolism in ways that directly promote tumor growth and survival.

The third transporter, SLC1A5_var, is a spliced variant of the well-known glutamine transporter SLC1A5 that localizes to the inner mitochondrial membrane. It has been reported to exhibit elevated expression in colon cancer cells, and recent evidence indicates that inhibiting it reduces colorectal cancer cell viability. However, the review is candid about the limits of current knowledge: the specific role of SLC1A5_var in colorectal cancer progression remains to be fully elucidated. Glutamine metabolism itself is a validated vulnerability in colorectal cancer, with oncogenic PIK3CA mutations known to reprogram glutamine utilization, and glutaminase expression upregulated in tumors and of clinical significance. But how glutamine crosses the inner mitochondrial membrane, and how that step could be therapeutically exploited, is still an open question that the authors identify as a priority for future research.

Perhaps the most provocative dimension of the review is its argument that these transporters shape not only metabolism but also the epigenetic landscape of colorectal cancer. Metabolites are the raw materials and cofactors of chromatin-modifying enzymes. Acetyl-CoA derived from citrate is the substrate for histone acetyltransferases, and its availability directly influences histone acetylation marks such as H3K9ac and H3K27ac. Alpha-ketoglutarate, a TCA cycle intermediate replenished by glutamine, is the obligatory cosubstrate for the TET family of DNA demethylating enzymes and the Jumonji-C domain histone demethylases. Lactate, produced in abundance by Warburg metabolism, has emerged as a source of histone lactylation, a modification that recent studies link to tumor progression, immunotherapy responses and chemoresistance in colorectal cancer stem cells. By controlling which metabolites reach which cellular compartments, the MPC, CIC and SLC1A5_var effectively tune the chemical state of chromatin and, with it, the transcriptional programs that drive malignancy.

The epigenetic consequences are concrete rather than abstract. Alpha-ketoglutarate has been shown to attenuate Wnt signaling and drive differentiation in colorectal cancer, suggesting that metabolic flux through glutamine-dependent transporters could suppress Wnt-driven stemness. Under hypoxia, cells produce L-2-hydroxyglutarate, an alpha-ketoglutarate analog that inhibits demethylases and can remodel gene expression. Epigenetic silencing of Wnt antagonists such as SFRP genes is a recognized feature of colorectal cancer progression, and the review situates transporter-dependent metabolite supply within this regulatory web. If transporter activity determines the balance of acetyl-CoA, alpha-ketoglutarate, lactate and their derivatives in the nucleus, then these inner membrane proteins are, in effect, metabolic conductors of gene expression.

Therapeutically, the implications are substantial but measured. Glutaminase inhibitors such as CB-839 have demonstrated antitumor activity in other cancers, and interference with glutamine utilization has been shown to synergize with immune checkpoint inhibitors and to promote antitumor immunity through ROS-induced degradation of the immune checkpoint molecule B7-H3. Extending this strategy to the mitochondrial glutamine entry point via SLC1A5_var is an appealing next step. For the citrate carrier, inhibitors of SLC25A1 could deprive tumors of the lipid synthesis and ferroptosis-escape machinery that depend on citrate export, potentially combining with radiotherapy, given the carrier’s role in radioresistance, or with ferroptosis-inducing agents. For the MPC, the therapeutic logic runs in the opposite direction: because loss of the carrier promotes the Warburg phenotype, pharmacological restoration of pyruvate flux, as demonstrated with ROS-sensitizing effects in colon cancer models, could resensitize tumors to oxidative stress and immune-mediated killing.

The review is careful to frame these possibilities as strategies requiring further validation rather than imminent clinical tools. Transporters of the mitochondrial carrier family are expressed in normal tissues, and systemic inhibition risks on-target toxicity in high-energy organs. Biomarkers that identify which tumors depend on which transporter, for example through immunohistochemical assessment of MPC1, SLC25A1 or SLC1A5_var expression, will be essential for patient selection. Nevertheless, by consolidating the evidence that three inner mitochondrial membrane carriers are differentially deregulated in colorectal cancer and that they jointly govern both metabolism and epigenetics, the authors make a compelling case that the next generation of metabolism-targeted therapies for colorectal cancer may need to look inward, to the membrane that separates the mitochondrial matrix from the rest of the cell.

Subject of Research: Mitochondrial metabolite transporters in the metabolic reprogramming and epigenetic regulation of colorectal cancer

Article Title: Mitochondrial metabolite transporters at the crossroads of metabolic reprogramming, epigenetic regulation and therapeutic vulnerabilities in colorectal cancer

Article References: S, K., Arockiasamy, S., Srinivas, K. S., & Shirley, S. (2026). Mitochondrial metabolite transporters at the crossroads of metabolic reprogramming, epigenetic regulation and therapeutic vulnerabilities in colorectal cancer. Molecular Biology Reports, 53(1), Article 1595. https://doi.org/10.1007/s11033-026-12769-9

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12769-9

Keywords: colorectal cancer, mitochondrial pyruvate carrier, citrate carrier SLC25A1, SLC1A5 variant, Warburg effect, glutamine metabolism, metabolic reprogramming, epigenetic regulation, histone acetylation, ferroptosis, tumor metabolism, therapeutic targets