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INTERNATIONAL CONGRESS OF

PharmacoGenetics

• Role of mitochondrial epigenetics in tumoral drug resistance

• Zahra Dolati,^1,* Narges Safari,² Masoud Zare,³ Soodeh Tavakoli,⁴
  1. Department of Veterinary Medicine, Garmsar Branch, Islamic Azad University, Garmsar, Iran
  2. Department of Veterinary Medicine, Garmsar Branch, Islamic Azad University, Garmsar, Iran
  3. Doctor Veterinary Medicine, Faculty of Veterinary Medicine, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
  4. Independent Veterinarian, Tehran,Iran
  
  
  
• Introduction: Drug resistance remains a major challenge in cancer therapy, though the underlying mechanisms are not fully understood (1). Aberrant methylation patterns play a significant role in tumorigenesis, with genome-wide hypomethylation and tumour suppressor gene hypermethylation serving as hallmarks of various cancers (11). Tumour cells primarily utilise glucose for energy through lactate fermentation rather than oxidative phosphorylation, a phenomenon known as the Warburg effect. Notably, this fermentation persists even under adequate oxygen conditions. The Warburg effect highlights glycolysis as a primary metabolic pathway in cancer (6). Mitochondrial action is necessary in a metastatic background and under treatment stress. Reactivation or reprogramming of metabolic pathways, particularly fatty acid oxidation and oxidative phosphorylation, correlates closely with cancer development through mechanisms including apoptosis evasion, cancer stem cell maintenance, and redox balance regulation (7).
• Methods: This systematic review followed PRISMA guidelines for study identification and selection. We searched PubMed, Scopus, and Web of Science databases from January 2010 to December 2023 using keywords: ("mitochondrial epigenetics" OR "mtDNA methylation") AND ("drug resistance" OR "chemoresistance") AND ("cancer" OR "neoplasm"). Inclusion criteria were: (1) original research articles investigating mitochondrial epigenetic mechanisms in cancer drug resistance; (2) studies published in English; (3) articles providing mechanistic insights into mtDNA modifications. Exclusion criteria included: (1) review articles without primary data; (2) studies focusing solely on nuclear epigenetics; (3) non-cancer-related research. Data extraction focused on mitochondrial epigenetic mechanisms, associated resistance pathways, and therapeutic implications. Methodological quality was assessed using modified GRADE criteria for mechanistic studies.
• Results: 1. Mitochondrial Epigenetics is a Core Driver of Tumoral Drug Resistance A critical finding from recent research is that mitochondrial epigenetics is a fundamental mechanism underpinning cancer cell resistance to therapy. Unlike nuclear epigenetics, modifications within the mitochondria—including mtDNA methylation, copy number variation (mtCNV), and the action of mitochondrial-localised non-coding RNAs (ncRNAs)—directly govern central processes like apoptosis, metabolic reprogramming, and stress responses. These epigenetic alterations serve as adaptive mechanisms, allowing cancer cells to evade the cytotoxic effects of a wide range of chemotherapeutic agents, thereby establishing a significant barrier to successful treatment [12, 13, 14]. 2. Metabolic Reprogramming is Directly Controlled by Mitochondrial Epigenetic Modifications Studies show that hypermethylation of mtDNA-encoded genes essential for oxidative phosphorylation (OXPHOS), such as MT-ND1 and MT-CYB, suppresses mitochondrial respiration. This metabolic shift not only promotes cell survival under nutrient stress but also confers resistance to chemotherapeutics that depend on functional OXPHOS to induce cell death, such as cisplatin [12, 13]. Conversely, an increase in mtDNA copy number (mtCNV) can enhance OXPHOS capacity, fueling DNA repair mechanisms that diminish the effectiveness of DNA-damaging drugs [20, 21]. 3. Mitochondrial Epigenetics Provides a Robust Mechanism for Apoptosis Evasion A key result across multiple studies is that mitochondrial epigenetic changes significantly raise the threshold for apoptosis. Methylation of the mtDNA D-loop region, a crucial area for transcription and replication, can disrupt the expression of pro-apoptotic factors. In parallel, specific mitochondrial microRNAs (miRNAs) have been found to inhibit the action of Bcl-2 family proteins, which are central regulators of the mitochondrial apoptosis pathway. These combined effects prevent the release of cytochrome c and the subsequent activation of caspases, rendering cancer cells highly resistant to apoptosis-inducing chemotherapeutics like doxorubicin [16, 17]. 4. Mitochondrial Epigenetics Enhances Cellular Stress Adaptation During Therapy Research demonstrates that mitochondrial epigenetics is critical for cancer cell adaptation to the intense stress induced by chemotherapy. For instance, alterations in mtDNA methylation patterns can trigger the mitochondrial unfolded protein response (UPRmt), a protective pathway that improves protein quality control (proteostasis) and promotes cell survival under therapeutic stress [22]. Furthermore, epigenetic regulation of genes within the electron transport chain (ETC) can modulate the production of reactive oxygen species (ROS). Controlled dysregulation of ROS can activate pro-survival signalling pathways, such as the NRF2 pathway, which bolsters the cell's antioxidant defences and allows it to withstand oxidative stress-induced treatments [22, 23]. 5. The Mitochondrial and Nuclear Epigenomes Exhibit Bidirectional Crosstalk An important emerging result is the understanding that mitochondrial epigenetics does not operate in isolation. These two systems collaboratively modulate vital signalling pathways—such as mTOR, HIF-1α, and AMPK—that are central to cancer cell growth, metabolism, and survival. This integrated network allows the cancer cell to coordinate a comprehensive adaptive response, fostering greater tumour aggressiveness and a more robust, multifaceted resistance to therapy [24, 25]. 6. Mitochondrial Epigenetic Marks Hold Promise as Clinical Biomarkers and Therapeutic Targets Translational research has yielded promising results regarding the clinical utility of mitochondrial epigenetics. Specific mtDNA methylation signatures, particularly hypermethylation of the D-loop region, have been identified as potential predictive biomarkers. These signatures could be used to forecast a patient's likelihood of responding to therapy or developing resistance, enabling personalised treatment strategies [18, 19]. Furthermore, pre-clinical studies support the development of novel therapeutic interventions, such as repurposing DNMT inhibitors (e.g., 5-azacytidine) to reverse mtDNA hypermethylation or using combination therapies that pair OXPHOS inhibitors (like metformin) with standard chemotherapy to exploit the metabolic vulnerabilities created by mitochondrial epigenetic reprogramming [18, 19].
• Conclusion: Emerging research elucidates the critical role of mitochondrial epigenetics, particularly mtDNA methylation, in driving drug resistance in cancer. Mitochondrial epigenetic alterations—including D-loop hypermethylation and mtDNA copy number variation—directly influence metabolic reprogramming and apoptosis evasion, enabling cancer cells to resist conventional therapies. The bidirectional crosstalk between mitochondrial and nuclear epigenomes further enhances tumour adaptability through coordinated regulation of key signalling pathways. Clinically, mtDNA methylation signatures show promise as predictive biomarkers for treatment response, while mitochondrial-targeted epigenetic therapies offer novel strategies to overcome drug resistance. Despite technical challenges in mitochondrial epigenome profiling, targeting mitochondrial epigenetics represents a promising frontier for developing personalised cancer therapies and improving patient outcomes.
• Keywords: Mitochondria, epigenetics, Drug resistance,mtDNA methylation,Metabolic reprogramming,Cancer therapy