Breast cancer, particularly triple-negative breast cancer (TNBC), remains a leading cause of cancer-related mortality due to its aggressive nature and limited therapeutic targets. Metabolic reprogramming, a hallmark of cancer, enables tumor cells to adapt to environmental stresses and fuel rapid proliferation. While the Warburg effect initially emphasized glycolysis, recent research highlights the critical role of mitochondrial oxidative metabolism in cancer progression. Mitochondria, dynamic organelles regulated by fission, fusion, and mitophagy, are central to metabolic plasticity, supporting tumor growth, metastasis, and therapy resistance. This review explores the molecular mechanisms of mitochondrial dynamics in breast cancer metastasis, their diagnostic and prognostic potential, and emerging therapeutic strategies targeting these pathways.
Mitochondrial Metabolism and Breast Cancer Plasticity
Metabolic heterogeneity is a defining feature of breast cancer, with TNBC exhibiting heightened reliance on fatty acid oxidation (FAO) and mitochondrial respiration to meet its energetic and biosynthetic demands. Key adaptations include:
Lipid Metabolism: Elevated FASN (fatty acid synthase) and ATP citrate lyase drive de novo lipogenesis, supporting membrane biogenesis and signaling.
Oxidative Phosphorylation (OXPHOS): Despite glycolytic dominance in primary tumors, metastatic lesions show increased TCA cycle flux and ATP production, underscoring mitochondrial metabolic flexibility.
Metabolic Shifts: Hypoxia and nutrient scarcity further rewire mitochondrial function, promoting survival and chemoresistance.
These adaptations highlight mitochondria as central hubs of metabolic reprogramming, offering vulnerabilities for therapeutic intervention.
Mitochondrial Fission, Fusion, and Mitophagy in Breast Cancer
Mitochondrial dynamics—governed by fission (Drp1, Fis1) and fusion (MFN1/2, OPA1) proteins—regulate cellular homeostasis and are dysregulated in cancer:
Fission: Promotes proliferation, stemness, and metastasis. Drp1 overexpression correlates with poor prognosis and is linked to Notch1-mediated chemoresistance in TNBC.
Fusion: Enhances OXPHOS and mitigates ROS. MFN2-PKM2 interactions suppress glycolysis, while OPA1 inhibition reduces tumor aggressiveness.
Mitophagy: Balances quality control and survival. PINK1/Parkin-mediated mitophagy eliminates damaged mitochondria, but its dual role—suppressing ROS or enabling stress adaptation—depends on context.
For example, BRCA1 deficiency disrupts mitophagy, elevating ROS and NLRP3 inflammasome activation, which drives metastasis. Conversely, mitophagy induction by compounds like polyphyllin I or silibinin triggers apoptosis in TNBC.
Mitochondrial Dynamics as Therapeutic Targets
Targeting mitochondrial dynamics shows promise in preclinical models:
Fission Inhibition: Mdivi-1 (Drp1 inhibitor) and P110 peptide reduce metastasis and restore chemosensitivity.
Fusion Promotion: Enhancing MFN2 activity suppresses glycolytic flux and tumor growth.
Mitophagy Modulation: Compounds like warangalone and kaempferol induce lethal mitophagy, while others (e.g., cepharanthine) block pro-survival pathways.
Table 1 summarizes key therapeutics, including cisplatin and flubendazole, which exploit mitochondrial vulnerabilities in TNBC.
Clinical Significance and Future Directions
Despite progress, challenges remain:
Heterogeneity: Mitochondrial adaptations vary by tumor subtype and stage, necessitating personalized approaches.
Drug Resistance: Metabolic plasticity may undermine targeted therapies, requiring combinatorial strategies.
Translational Gaps: Standardizing mitochondrial biomarkers (e.g., Drp1 levels) and improving drug delivery (e.g., nanoparticle carriers) are critical for clinical adoption.
Future research should integrate multi-omics to unravel metabolic-immune crosstalk and explore mitochondrial transplantation as a novel therapy.
Conclusion
Mitochondrial dynamics are pivotal in breast cancer metastasis, influencing metabolic flexibility, stemness, and therapy resistance. Targeting fission, fusion, and mitophagy offers a transformative approach to disrupt tumor adaptability. While challenges persist, advancing mitochondrial-directed therapies—combined with precision medicine tools—holds immense potential to improve outcomes for aggressive breast cancer subtypes.
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The study was recently published in the Oncology Advances .
Oncology Advances is dedicated to improving the diagnosis and treatment of human malignancies, advancing the understanding of molecular mechanisms underlying oncogenesis, and promoting translation from bench to bedside of oncological sciences. The aim of Oncology Advances is to publish peer-reviewed, high-quality articles in all aspects of translational and clinical studies on human cancers, as well as cutting-edge preclinical and clinical research of novel cancer therapies.
