A recent review published in the Genes & Diseases journal by researchers from Sichuan University provides insights into the role of mitochondria in various aspects of tumorigenesis and the underlying molecular mechanisms, and discusses the therapeutic implications of mitochondria-targeting in tumor therapy.
The review begins with an introduction to the structure and functions of mitochondria, detailing their origins, the molecular composition of mitochondrial membranes, and their role in cellular respiration. In addition to oxidative phosphorylation, mitochondria are also involved in signal transduction, the urea cycle, apoptosis, regulation of cytoplasmic calcium concentration, and biogenesis of iron–sulfur clusters—highlighting that any perturbations in mitochondrial function (mitochondrial dysfunction) may lead to various diseases, including cancer.
The review then proceeds to describe the role of mitochondria in various cell death pathways, including apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis. The authors emphasize the need to investigate the molecular mechanisms underlying these processes and their role in diseases associated with mitochondrial dysfunction, which may aid in the development of targeted therapeutics.
It then elucidates how mitochondrial DNA (mtDNA) heterogeneity influences the initiation and progression of tumors. Previous research has indicated that tumor cells exhibit higher mtDNA heterogeneity, particularly in the RNA-coding region, and also show a greater frequency of missense mutations, nonsense mutations, deletions, and insertions compared to normal cells. Mutations in the mtDNA genes encoding proteins involved in oxidative phosphorylation (OXPHOS) impair OXPHOS, resulting in the excessive generation of mitochondrial-derived ROS. Such mutations have been reported in various tumors, including colorectal cancer, bladder cancer, thyroid cancer, melanoma, breast cancer, pancreatic cancer, and osteosarcoma.
Similarly, a decrease in mitochondrial copy number (mtDNA CN) is associated with decreased mitochondrial transcription, downregulation of OXPHOS-related proteins, and impaired mitochondrial respiratory function and fusion. mtDNA CN is closely associated with many tumors and, therefore, is a good diagnostic and prognostic tool.
Metabolic reprogramming, one of the major metabolic characteristics of tumor cells, is primarily manifested as hyperactive glycolysis and impaired aerobic metabolism (aerobic glycolysis), which is also known as the Warburg effect. Shifts in these metabolic pathways are associated with changes in cancer cell metabolism, an increase in oxidative stress, and a decrease in antioxidant status.
Various mitochondrial adaptations—including fusion and division, altered metabolism, and autophagy—as well as mitochondria-associated endoplasmic reticulum membranes (MAMs), contribute to drug resistance in tumors. Targeting mitochondria represents an ideal anti-tumor therapeutic approach. The review then lists the different mitochondria-targeting chemotherapeutic drugs and chemical compounds, alongside nanoparticle- and nanomaterial-based mitochondria-targeted drugs.
In conclusion, the complex interplay between mitochondrial dynamics and tumorigenesis presents a critical area for understanding tumor biology and developing innovative diagnostic, prognostic, and therapeutic approaches.
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