MAPK-driven remodeling of mitochondrial dynamics in melanoma: implications for metabolic plasticity and response to targeted therapy.

Melanoma is the most aggressive form of skin cancer due to its high metastatic potential and resistance to therapy. Current treatment strategies include surgical resection for localized disease, as well as targeted therapy with MAPK inhibitors and immunotherapy for advanced stages. However, therapeutic resistance and disease relapse remain major clinical challenges. Activating mutations in components of the mitogen-activated protein kinase (MAPK) pathway, particularly in BRAF and NRAS, are among the most frequent oncogenic events in melanoma, driving tumor initiation and progression through sustained ERK signaling. Mitochondria are dynamic organelles whose morphology is regulated by the balance between fission and fusion. In melanoma cells, MAPK-dependent signaling has been implicated in the regulation of key components of the mitochondrial dynamics machinery, thereby reshaping the mitochondrial network. These structural alterations have functional consequences for cellular metabolism, contributing to metabolic plasticity and enabling tumor cells to switch between glycolytic and oxidative metabolic states in response to environmental stimuli and therapeutic pressures. In this review, we discuss current evidence linking oncogenic MAPK signaling to the control of mitochondrial dynamics in melanoma and examine how these processes contribute to metabolic reprogramming. We further explore how mitochondrial remodeling influences therapeutic response and resistance, particularly in the context of MAPK pathway inhibition. Finally, we highlight mitochondrial dynamics as key regulators of metabolic plasticity and as promising therapeutic targets to improve treatment response in melanoma.