Mitochondrial fission and fusion in inflammatory diseases: mechanisms and therapeutic implications

Mitochondrial fission and fusion are dynamic and highly regulated processes that are essential for maintaining cellular homeostasis. These processes are regulated by core proteins, including dynamin-related protein 1 (DRP1), fission 1 protein (FIS1), mitochondrial fission factor (MFF), mitofusin 1 (MFN1), mitofusin 2 (MFN2), and optic atrophy 1 (OPA1), which ensure proper mitochondrial function and integrity. An imbalance in fission and fusion can lead to excessive production of ROS, mtDNA release, and alterations in immune cell phenotypes. These disruptions compromise mitochondrial integrity, redox balance, and metabolic adaptability, ultimately activating inflammatory signaling pathways and triggering immune dysregulation. Restoring mitochondrial dynamics has emerged as a promising therapeutic strategy to mitigate these disruptions. A growing number of evidence indicates that small-molecule modulators, natural compounds, genetic interventions, chemical drugs, and mitochondria-targeted nanoformulations hold great potential for re-establishing mitochondrial homeostasis and suppressing inflammation. This review systematically elucidates the molecular mechanisms by which mitochondrial fission and fusion regulate inflammation, summarizes current therapeutic advances, and discusses translational perspectives and future challenges in this rapidly evolving field. Modulating mitochondrial dynamics is a promising therapeutic strategy for inflammation, but its clinical translation still faces many challenges. Future research should focus on optimizing mitochondrial dynamic modulation strategies and evaluating their long-term efficacy and safety.