Controlling lipid droplet dynamics via tether condensates

Lipid droplets (LDs) are dynamic cellular organelles that regulate lipid metabolism and various cellular processes. Their functionality relies on a dynamic proteome and precise spatiotemporal interactions with other organelles, making LD biology highly complex. Tools that enable the sequestration and release of LDs within their intracellular environment could synchronize their behavior, providing deeper insights into their functions. To address this need, we developed Controlled Trapping of LDs (ControLD), a new method for manipulating LD dynamics. This approach uses engineered condensates to reversibly sequester LDs, temporarily halting their activity. Upon release, the LDs resume their normal functions. ControLD effectively disrupts LD remobilization during metabolic demands and prevents the formation of LD–mitochondria contact sites, which are re-established upon condensate dissociation. ControLD represents a powerful tool for advancing the study of LD biology and opens avenues for investigating and manipulating other cellular organelles. (Figure presented.)