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INTERNATIONAL CONGRESS OF

CancerGenetics

• Nuclear–Mitochondrial Genome Crosstalk in Cancer: Linking Metabolic Reprogramming to Precision Oncology

• Kianaz Aminzare,^1,* Mohamad-Reza Aghanoori,²
  1. Department of Chemical and Biological Technologies, CT.C, Islamic Azad University, Tehran, Iran
  2. Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
  
  
  
• Introduction: Introduction: Mitochondria are major sites of cellular energy metabolism and also participate in a wide range of signaling processes. Their activity depends on close coordination between the nuclear genome and the mitochondrial genome. Although mitochondria retain their own DNA, most proteins required for mitochondrial function are encoded by nuclear genes, making coordination between the two genomes essential for maintaining mitochondrial homeostasis and oxidative phosphorylation. This coordination is supported by two-way communication between the nucleus and mitochondria, together with mitonuclear feedback and stress-response pathways that help adjust mitochondrial function to changing cellular conditions. In cancer, alterations affecting either the nuclear or mitochondrial genome can disturb oxidative phosphorylation, redox balance, tricarboxylic acid cycle activity, and intermediary metabolism. These changes can reshape tumor metabolism and influence tumor progression, heterogeneity, and therapeutic response. Differences in mitochondrial function and genomic state may also contribute to distinct metabolic phenotypes, providing a link between mitonuclear biology and precision oncology.
• Methods: Methods: A focused narrative review was conducted using selected peer-reviewed reviews covering mitonuclear communication, coordinated regulation of the nuclear and mitochondrial genomes, mitochondrial signaling, mitochondrial metabolism in cancer, and the integration of metabolic and genomic features into precision oncology. The literature was considered across four related areas: regulation between the nuclear and mitochondrial genomes, metabolic reprogramming in cancer, mitochondrial contributions to tumor heterogeneity and adaptation to treatment, and the potential use of mitochondrial features in biomarker development and patient stratification.
• Results: Results: Across the reviewed literature, the nuclear and mitochondrial genomes emerge as closely interconnected regulatory systems. Their coordination occurs at several levels, including transcription and translation, as well as post-transcriptional and post-translational regulation of mitochondrial proteins involved in oxidative phosphorylation. Mitochondria also communicate changes in their functional state to the nucleus through retrograde signaling, with metabolic intermediates, redox signals, and stress-responsive pathways contributing to this process. In malignant cells, these interactions are closely tied to metabolic remodeling. Alterations in nuclear or mitochondrial genomes can affect oxidative phosphorylation, tricarboxylic acid cycle activity, glutamine utilization, lipid metabolism, and redox homeostasis. Tumor cells can shift their use of these metabolic pathways as nutrient availability, cellular conditions, or therapeutic pressure change, helping them maintain growth and survival. This metabolic plasticity is relevant to tumor heterogeneity and may contribute to differences in treatment response. Findings from breast cancer further illustrate this connection: alterations in nuclear genes such as BRCA1 and TP53 have been associated with changes in mitochondrial bioenergetics and tumor metabolism. Mitochondrial features are also being investigated as potential clinical biomarkers. mtDNA alterations, mitochondrial heterogeneity, and metabolic gene-expression signatures may provide information relevant to diagnosis, prognosis, and treatment response. Their potential utility may increase when mitochondrial data are combined with circulating mtDNA, transcriptomic or proteomic profiles, and computational analyses. Machine-learning-derived metabolic signatures and genome-scale metabolic models represent additional approaches for relating mitochondrial phenotypes to tumor classification and individualized treatment selection.
• Conclusion: Conclusion: Mitonuclear genome crosstalk provides an important connection between cancer genomics and metabolic regulation. Changes in the nuclear genome can influence mitochondrial function, while mitochondrial metabolic and stress signals can, in turn, affect nuclear responses. This reciprocal relationship offers a framework for understanding metabolic plasticity, tumor heterogeneity, and variation in therapeutic response. Integrating mitonuclear genomic information with metabolic profiling and computational analysis may strengthen biomarker discovery and improve the identification of metabolically distinct tumor states. At the same time, mitochondrial heterogeneity and the ability of tumor cells to adapt metabolically remain important challenges for mitochondria-directed treatment. A clearer understanding of these interactions could support biomarker-guided patient stratification and more precise, metabolism-informed approaches to cancer therapy.
• Keywords: Keywords: Mitonuclear Crosstalk; Mitochondrial Genomics; Mitochondrial Metabolism; Cancer Metabolism