Natalie Danesova

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide, with surgery representing the cornerstone of curative treatment. Although surgical techniques and perioperative care have improved markedly, postoperative complications (POCs) still significantly affect early morbidity, prolong recovery and negatively influence long-term outcomes. These challenges have led to growing efforts to identify biological markers that could help predict adverse events and improve risk stratification. Inflammatory activation and mitochondrial dysfunction have emerged as interconnected contributors to postoperative vulnerability, and their measurable mediators represent attractive candidates for biomarker development. Cytokines, as central regulators of immune signalling, together with mitochondrial-derived danger signals (mtDAMPs) released during surgical trauma and ischemia–reperfusion injury, may enable earlier identification of patients at risk of POCs. In this review, we summarize current evidence linking key cytokines, including interleukin (IL)-6, tumour necrosis factor (TNF)-α, IL-1β and IL-10, to postoperative outcomes after CRC surgery and discuss mechanistic pathways through which cytokine signalling can modulate mitochondrial function, reactive oxygen species production and tissue integrity. We also highlight the translational potential of mitochondrial biomarkers such as circulating mitochondrial DNA, while acknowledging that CRC-specific clinical evidence remains limited and methodologically heterogeneous. Taken together, a deeper understanding of these interconnections, supported by standardized longitudinal perioperative profiling, could ultimately improve complication prediction and support more personalized strategies for POCs prevention, early detection and optimized recovery following CRC surgery.

Background: Telomere shortening and mitochondrial dysfunction are well-known independent contributors to many diseases, but emerging evidence suggests a reciprocal relationship between the two processes. The role of the so-called telomere-mitochondrial axis in colorectal cancer (CRC) remains largely unknown. Methods: This prospective cohort study screened CRC patients who underwent surgery, from whom peripheral blood, intestinal mucosa, and tumor samples were collected. Colonoscopically confirmed cancer- and adenoma-free healthy individuals were screened as controls, from whom peripheral blood and intestinal mucosa samples were obtained. Relative mitochondrial DNA copy number (mtDNA-CN) and relative telomere length (RTL) were measured in all samples by real-time quantitative polymerase chain reaction and were further compared and correlated considering clinical data. Relative mtDNA-CN was quantified using both TaqMan probes and SYBR Green to compare both methods. Finally, multivariable analyses were conducted to investigate the association between both biomarkers and the risk of tumor recurrence and mortality. Results: A total of 166 CRC patients and 61 healthy individuals were included in the study. In TNM stage I patients, relative mtDNA-CN and RTL were negatively correlated with each other in intestinal mucosa (ρ = -0.77, p < 0.0001), tumor tissue (ρ = -0.41, p = 0.032), and the tumor-to-intestinal mucosa ratio (ρ = -0.39, p = 0.046). However, these associations disappeared with increasing TNM stage, suggesting a dysregulation of the telomere-mitochondrial axis in advanced disease. Higher relative mtDNA-CN in blood was associated with a lower risk of disease recurrence even after adjusting for multiple covariates (HR = 0.43, 95% CI 0.20–0.97, p = 0.041), highlighting its potential use as a prognostic tool. The quantification of mtDNA-CN performed by both methods -TaqMan probes and SYBR Green- was shown to be positively correlated ( p < 0.01). Relative mtDNA-CN and RTL were found to be tissue-dependent in both CRC patients and healthy controls. Conclusions: This study provides a novel contribution to the understanding of the almost unexplored telomere-mitochondrial axis in CRC, highlighting its potential role in disease progression and prognosis. Graphical Created with https://www.BioRender.com .

Figure S4 from Mitochondrial Transfer Rescues Respiration to Support De Novo Pyrimidine Biosynthesis and Tumor Progression

Properties related to parental, rho0 and rho0 AOX cells

Figure S5 from Mitochondrial Transfer Rescues Respiration to Support De Novo Pyrimidine Biosynthesis and Tumor Progression

Gating strategy for flow cytometry

Figure S3 from Mitochondrial Transfer Rescues Respiration to Support De Novo Pyrimidine Biosynthesis and Tumor Progression

Gating strategy for flow cytometry

Cancer cells with severe defects in mitochondrial DNA (mtDNA) can import mitochondria via horizontal mitochondrial transfer to restore respiration. Mitochondrial respiration is necessary for the activity of dihydroorotate dehydrogenase (DHODH), an enzyme of the inner mitochondrial membrane that catalyzes the fourth step of de novo pyrimidine synthesis. In this study, we investigated the role of de novo synthesis of pyrimidines in driving tumor growth in mtDNA-deficient (ρ0) cells. Although ρ0 cells grafted in mice readily acquired mtDNA, this process was delayed in cells transfected with alternative oxidase (AOX), which combines the functions of mitochondrial respiratory complexes III and IV. The ρ0 AOX cells were glycolytic but maintained normal DHODH activity and pyrimidine production. Deletion of DHODH in a panel of tumor cells completely blocked or delayed tumor growth. The grafted ρ0 cells rapidly recruited tumor-promoting/stabilizing cells of the innate immune system, including protumor M2 macrophages, neutrophils, eosinophils, and mesenchymal stromal cells (MSC). The ρ0 cells recruited MSCs early after grafting, which were potential mitochondrial donors. Grafting MSCs together with ρ0 cancer cells into mice resulted in mitochondrial transfer from MSCs to cancer cells. Overall, these findings indicate that cancer cells with compromised mitochondrial function readily acquire mtDNA from other cells in the tumor microenvironment to restore DHODH-dependent respiration and de novo pyrimidine synthesis. The inhibition of tumor growth induced by blocking DHODH supports targeting pyrimidine synthesis as a potential widely applicable therapeutic approach.Significance:Mitochondrial complexes III and IV promote tumor progression by supporting de novo pyrimidine synthesis, requiring cancer cells devoid of mitochondrial DNA to recruit mitochondria from source cells to restore respiration in order to form tumors.