Effect of SUMOylation on Maintaining Mitochondrial Dynamics Balance by DRP1

Mitochondria, as the center of energy metabolism within the cell, play a crucial role in maintaining cell homeostasis. The regulation of its morphology and function is essential for the normal functioning of cells. In this complex regulatory network, the small ubiquitin-like modifier (SUMO) and dynamin-related protein 1 (DRP1) have become the focus of research, especially their close association with mitochondrial dynamics. SUMOylation is an important form of protein modification that regulates the function of target proteins by binding them to SUMO. This modification also plays a significant role in mitochondrial dynamics. The complex network of interactions between SUMOylation and DRP1 plays a key role in mitochondrial division, fusion and autophagy. DRP1, as a mitochondrial fission protein, regulates the morphology and function of mitochondria with the participation of the endoplasmic reticulum (ER). Recent studies have revealed the complex relationship between DRP1 and SUMOylation. DRP1 completes SUMOylation under the action of mitochondrial-anchored protein ligase (MAPL). SUMOylation mainly occurs in the variable domain of DRP1, and eight lysine residues have been identified as its targets. DRP1 serves as the target protein of SUMO1 and SUMO2/3, which play different regulatory roles in mitochondrial fission. SUMO1 modification can enrich DRP1 into mitochondria, thus promoting mitochondrial fission. However, SUMO2/3 modification can transfer DRP1 to cytoplasm and reduce mitochondrial fission. This dynamic regulatory mechanism allows the cell to flexibly adjust the state of the mitochondria according to energy requirements. Correspondingly, there is also deSUMOylation. SUMO-specific proteases (SENPs) is responsible for the deSUMOylation of proteins, with seven subtypes identified so far. Among them, SENP3/5 is a SUMO2/3 specific deSUMOylation protease. In actual cellular processes, the SUMO1 and SUMO2/3 modifications of DRP1 occur simultaneously, which can be regarded as a competitive relationship between the them. So, the SUMOylation of DRP1 in cells is often determined by SENPs. By increasing the level of SENP3/5, the SUMO2/3 modification level of DRP1 can be reduced, and the SUMO1 modification level can be indirectly increased, thus promoting the division of mitochondria. This dual regulatory mechanism enables cells to more finely control the state of mitochondria and adapt to different cellular environments and physiological needs. In addition, as an important energy supply organelle in the cell, the abnormal dynamic level of mitochondria often leads to the occurrence of a variety of diseases. In some diseases, the increase of the SUMO1 modification level of DRP1 leads to the increase of DRP1 activity, which leads to the increase of mitochondrial fission and mitophagy. For example, it can cause myocardial ischemia-reperfusion injury, ischemic stroke and retinopathy. According to current research progress, the interaction between SUMOylation and DRP1 plays a key role in the regulation of mitochondrial dynamics. The in-depth study of this regulatory mechanism not only helps to reveal the basic principle of cell regulation, but also provides an important reference for the treatment strategy of related diseases. In addition, it also could help identify new therapeutic targets and provide additional tools for disease prevention and treatment. In this review, we review the advances in the study of the interaction between SUMOylation and DRP1 on the regulation of mitochondrial dynamics, and further explore the potential of inhibiting DRP1-SUMOylation as a target for the treatment of related diseases in the future.