In the relentless fight against colorectal cancer (CRC), researchers are unraveling intricate metabolic adaptations that tumors deploy to elude therapeutic destruction. Recent advances have spotlighted mitochondrial metabolic reprogramming as a pivotal driver of drug resistance, underpinning the tumor’s survival tactics against chemotherapy and targeted agents. This burgeoning field reveals how CRC cells remodel their bioenergetic and biosynthetic pathways, dynamically tuning mitochondrial function and exploiting cellular heterogeneity to sustain growth and foster metastasis. As the scientific community probes deeper, a triad of regulatory mechanisms emerges as core orchestrators of this metabolic plasticity, offering tantalizing prospects for precision therapies aimed at shutting down cancer’s metabolic lifelines.
Central to this metabolic pliability are multifunctional enzymes traditionally known for their catalytic roles but now recognized for moonlighting functions that influence signaling, gene expression, and redox balance. Pyruvate kinase M2 (PKM2) exemplifies this duality. In CRC cells, PKM2 shifts from its active tetrameric form into a less enzymatically proficient dimer that accumulates glycolytic intermediates, which are repurposed for anabolic processes critical to tumor expansion. Beyond metabolism, this dimeric PKM2 infiltrates the nucleus, regulating genes governing glycolysis and suppressing mitochondrial oxidative phosphorylation (OXPHOS), effectively erecting a metabolic firewall that buffers cells against therapeutic stresses. This nuanced control underscores how metabolic enzymes act as molecular nexus points, bridging metabolic flux and oncogenic signaling.
Fructose-1,6-bisphosphatase 1 (FBP1), a key gluconeogenic enzyme downregulated in CRC, further exemplifies the complex functionality of metabolic proteins. Its loss sustains intensified glycolysis, but more critically, it disrupts mitochondrial membrane potential and triggers reactive oxygen species (ROS) production, undermining mitochondrial integrity and antioxidant defenses. FBP1’s reach extends beyond metabolism, influencing mitotic control and modulating transcriptional pathways linked to oncogenic drivers like c-Myc. Such pleiotropic roles render FBP1 a linchpin in fostering a drug-resistant phenotype by intertwining metabolic and proliferative signaling axes.
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Intriguingly, these insights into multifunctional enzymes have paved the way for innovative therapeutic avenues, including biomimetic nanomaterials. Scientists have engineered copper-based metal-organic frameworks (MOFs) with enzyme-like activity capable of generating ROS and perturbing mitochondrial homeostasis in CRC cells. This nanozyme strategy not only hampers tumor growth but also primes cancer cells to regain sensitivity to chemotherapy agents like 5-fluorouracil (5-FU), spotlighting a futuristic approach that mimics endogenous enzymatic functions to disrupt cancer metabolism.
Aside from molecular regulators, the spatial and temporal heterogeneity within CRC profoundly shapes mitochondrial dynamics and therapeutic outcomes. Tumors arising on the right side of the colon predominantly adopt glycolytic metabolism, often associated with high microsatellite instability and heightened immune infiltration. Conversely, left-sided and rectal tumors lean heavily on mitochondrial respiration and OXPHOS. This metabolic dichotomy corresponds to variations in oxygen availability within the tumor microenvironment; hypoxic niches instigate HIF-1α–mediated glycolytic rewiring while well-oxygenated regions preserve mitochondrial oxidative pathways. These spatial metabolic niches foster divergent responses to treatment, complicating uniform therapeutic approaches.
Temporal evolution compounds this metabolic diversity. As CRC progresses from primary lesions to metastatic disease, a discernible shift occurs—glucose uptake declines, and the dependence on oxidative metabolites like glutamate and pyruvate intensifies. This metabolic transition underlies the emergence of a hybrid phenotype that harnesses mitochondrial respiration and fatty acid oxidation to buffer oxidative stress and sustain energy demands. Adaptations facilitating this switch enable subsets of tumor cells to withstand chemotherapeutic insults, enhancing survival and metastatic competence.
Metastatic dissemination itself introduces another layer of metabolic heterogeneity. Liver metastases often manifest heightened lipid metabolism and a fortified antioxidant arsenal, characterized by high mitochondrial density and robust electron transport chain (ETC) functionality. These traits equip metastatic cells to neutralize chemotherapy-induced oxidative damage efficiently. Additionally, nuclear–mitochondrial crosstalk, mediated by factors such as the exonuclease MYG1, fine-tunes metabolic flexibility by synchronizing glycolysis alongside mitochondrial activity, reinforcing the adaptive arsenal of CRC cells in hostile environments.
Integral to this metabolic reshaping are microRNAs (miRNAs), potent post-transcriptional regulators that influence key mitochondrial and metabolic processes. Oncogenic miRNAs such as miR-21 orchestrate chemoresistance by repressing PTEN, activating PI3K/AKT/mTOR signaling cascades that suppress mitochondrial respiration and augment glycolytic flux. This metabolic reprogramming confers adaptive advantages under drug-induced stress. Hypoxia-driven induction of the miR-23a/24 cluster further propels glycolytic dominance, expediting tumor progression under oxygen-limited conditions.
The regulatory complexity of miRNAs extends to modulation of amino acid metabolism; miR-23 family members downregulate glutaminase, thereby altering glutamine catabolism. Although their direct impact on drug resistance necessitates further elucidation, these findings hint at their multifaceted roles. Moreover, miRNAs such as miR-141-3p, governed by long non-coding RNAs like HIF1A-AS2, activate transcription factors (e.g., FOXC1), promoting metabolic reprogramming and CRC cell proliferation, especially in hypoxic microenvironments.
Extracellular miRNAs also sculpt tumor-microenvironment interactions by reprogramming immune cells. Exosomal miR-1246 from CRC cells can polarize tumor-associated macrophages towards a pro-tumoral phenotype, reshaping their metabolic state to favor immune evasion and tumor progression. This crosstalk underscores the systemic impact of miRNA-mediated metabolic shifts beyond cancer cells themselves.
Contrastingly, tumor-suppressive miRNAs impose constraints on metabolic plasticity. miR-137 impedes glutamine uptake by targeting the transporter SLC1A5, restricting substrate availability for the tricarboxylic acid (TCA) cycle. Its epigenetic silencing in CRC unleashes glutaminolytic pathways, bolstering therapeutic resistance. Similarly, miR-181d modulates circadian regulators and establishes oncogenic feedback loops with c-Myc, perpetuating metabolic reprogramming and disease progression.
Mitochondrial dynamics and quality control are likewise under miRNA governance. miR-155 suppresses Parkin-dependent mitophagy, leading to the accrual of damaged mitochondria and heightened resistance to apoptosis, while miR-27a enhances mitophagy, thereby increasing sensitivity to 5-FU, particularly in microsatellite instability-high CRC subtypes. Additionally, mitochondria-resident miRNAs (mito-miRs), such as miR-124, directly modulate mitochondrial gene expression and transcription, further influencing chemoresistance and metabolic adaptability at a sub-organelle level.
Collectively, these multifaceted miRNA networks intricately fine-tune energy production, redox equilibrium, and cellular responses to the tumor microenvironment, culminating in a highly adaptable metabolic state. This dynamic state empowers CRC cells to endure therapeutic assaults and drives metastatic progression, highlighting miRNAs as compelling targets for combinatorial interventions woven into precision oncology frameworks.
The convergence of multifunctional enzyme regulation, metabolic heterogeneity, and miRNA-mediated post-transcriptional modulation paints a complex portrait of mitochondrial metabolic reprogramming as a cornerstone of CRC pathobiology. The enhanced resolution offered by state-of-the-art metabolomics, single-cell multi-omics, and mitochondrial functional imaging technologies now permits dissection of this intricate landscape with unprecedented granularity. Understanding the spatial and temporal undercurrents of metabolic adaptation opens avenues to devise region-specific and temporally tuned therapeutic regimens aimed at dismantling mitochondrial resilience and overcoming drug resistance.
This paradigm shift towards metabolic precision medicine in colorectal cancer signals a promising horizon wherein targeted disruption of non-canonical metabolic enzyme functions, tailored interception of metabolic subtypes, and modulation of miRNA circuits can synergistically sensitize tumors to existing therapies. Nanozyme-based approaches and biomimetic materials harnessing enzymatic mimicry represent pioneering strategies poised to translate mechanistic insights into effective clinical tools. As the metabolic intricacies of CRC capitulate to molecular interrogation, the promise of eradicating resistance and improving patient outcomes draws nearer, heralding a new era in cancer treatment rooted in the nuanced mastery of mitochondrial metabolism.
Subject of Research: Mitochondrial metabolic reprogramming and its role in therapeutic resistance in colorectal cancer
Article Title: Mitochondrial metabolic reprogramming in colorectal cancer: mechanisms of resistance and future clinical interventions
Article References:
Qiu, X., Wang, A., Wang, J. et al. Mitochondrial metabolic reprogramming in colorectal cancer: mechanisms of resistance and future clinical interventions. Cell Death Discov. 11, 375 (2025). https://doi.org/10.1038/s41420-025-02670-y
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41420-025-02670-y
Tags: bioenergetic pathways in tumorschemotherapy resistance mechanismscolorectal cancer drug resistanceglycolytic intermediates in cancermetabolic plasticity in CRCmitochondrial metabolic reprogrammingmultifunctional enzymes in cancerPKM2 role in cancer metabolismprecision therapies for colorectal cancerredox balance and cancer resistancesignaling pathways in colorectal cancertumor bioenergetics adaptations