Dysregulated mitochondrial dynamics in cancer: Unlocking new strategies to combat drug resistance

Mitochondria continuously alternate between fragmented and fused states, a process known as mitochondrial dynamics, which plays a pivotal role in essential cellular functions, including metabolism, apoptosis, reactive oxygen species production, and signal transduction. Disruptions in this dynamic equilibrium, frequently observed in aggressive cancers, can promote malignant transformation and tumor progression. A growing body of evidence indicates that dysregulated mitochondrial dynamics contribute to resistance against both conventional and targeted anticancer therapies. In this review, we explore the regulatory mechanisms governing mitochondrial dynamics, with a focus on the genetic and epigenetic modulation of key drivers such as DRP1, MFN1/2 and OPA1. We also discuss how altered mitochondrial dynamics converge into diverse mechanisms of drug resistance in cancer. Overall, these insights underscore aberrant mitochondrial dynamics as a potential biomarker of therapeutic resistance, and position mitochondrial dynamics-related GTPases, particularly DRP1 and Mitofusins, as exploitable targets for novel treatments in advanced solid and hematologic malignancies.