Imbalances of mitochondrial dynamics in solid tumors

ABTRACT: In cancer, mitochondrial fission and fusion dynamics are often imbalanced due to altered transcriptional and post-transcriptional control of their key regulators, resulting in either excessive fission or fusion. Despite being opposing processes, these imbalances in mitochondrial dynamics play a critical role in tumorigenic processes. Excessive fission drives metabolic reprogramming by promoting a shift toward aerobic glycolysis and regulating fatty acid metabolism, whereas excessive fusion supports oxidative phosphorylation and glutaminolysis. Both processes, in their own specific way, enable rapid growth and enhance survival in heterogeneous and unfavorable tumor microenvironments. Beyond metabolic regulation, excessive fission plays a key role in invasion and metastasis by promoting cytoskeletal remodeling for single-cell migration and inducing epithelial-to-mesenchymal transition. Moreover, both excessive fission and fusion can inhibit apoptosis and enhance therapy resistance by modulation of the intrinsic apoptosis pathway, upregulation of antioxidant defenses, and/or activation of autophagy. This review examines how both dysregulated fission and fusion contribute to tumorigenic processes in solid tumors and highlights mitochondrial dynamics as a promising therapeutic target.