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  • The Mitochondrial Transfer Paradox: A Comparative Transcriptomic and Connectivity Map Profiling of Divergent Fates in Tumor and Immune Cells

  • Melika Shomal Zadeh,1,* Fatemeh Zabihi,2 Rutba Arjumand Khan,3 Maryam Zahedinasab,4 Aria Rezaian Jahromi,5 Hiva Bahramimoghadam,6
    1. 1. Department of Hematology and Transfusion Medicine, School of Allied Medical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran 2. Student Research Committee, Shiraz University of Medical Sciences, Shiraz. Iran
    2. Student Research Committee, Shiraz University of Medical Sciences, Shiraz. Iran
    3. Student Research Committee, Shiraz University of Medical Sciences, Shiraz. Iran
    4. Student Research Committee, Shiraz University of Medical Sciences, Shiraz. Iran
    5. Student Research Committee, Shiraz University of Medical Sciences, Shiraz. Iran
    6. Student Research Committee, Shiraz University of Medical Sciences, Shiraz. Iran


  • Introduction: Intercellular mitochondria transfer has emerged as a critical regulator of tissue homeostasis and disease progression, yet it remains unknown whether this process uniformly benefits recipient cells or is associated with context-dependent transcriptional responses.
  • Methods: A comparative transcriptomic and network topology analysis was conducted on two publicly available human datasets. The first dataset (GSE292157) represented a pathological model of breast cancer cells acquiring mitochondria from tumor-infiltrating nerves, and the second (GSE224187) represented a beneficial model of NK cells receiving allogeneic mitochondria. The workflow integrated differential expression analysis, Gene Ontology (GO) enrichment, protein-protein interaction (PPI) network mapping, and Connectivity Map (CMap) analysis.
  • Results: Mitochondria acquisition in cancer cells was associated with 295 differentially expressed genes (232 upregulated) enriched by cell cycle progression, telomerase activity, and chaperone-mediated stress tolerance, with STAT3 emerging as the dominant network hub (degree = 11, betweenness = 0.42). In contrast, NK cells exhibited 186 differentially expressed genes (176 upregulated) enriched for neurodevelopmental pathways, junctional structures, and surface receptor signaling, with IL1B as the preeminent hub (degree = 11, betweenness = 0.70). Connectivity Map analysis identified proteasome inhibitors (MG-132, bortezomib) and CDK inhibitors (R-547, AZD-5438) as agents capable of reversing the pathological cancer signature, while HDAC inhibitors (vorinostat, belinostat) mimicked the beneficial immune-enhancing transcriptional program.
  • Conclusion: Intercellular mitochondrial transfer is not a uniform metabolic gift but a context-dependent transcriptional switch. The same organelle that correlates with STAT3-driven proliferation and stress resilience in cancer cells can, in an NK cell, correlate with reinforcement of IL1B-centered inflammatory and cytotoxic circuits. This mitochondrial transfer paradox suggests candidate pharmacological perturbations with an innovative insight: the ability to block "bad" transfer while promoting "good" transfer, simultaneously disarming tumors and arming the immune system.
  • Keywords: Mitochondrial transfer, Transcriptional reprogramming, TME, PPI, Cancer

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