Lipid Droplet–Mitochondria Interactions: From Molecular Components to Spatial Aggregation Manipulation

ABSTRACT The aggregate form of interorganelle interaction is essential for the stable operation of cellular energy metabolism, signal transduction, as well as growth and development. Among these, the discovery of lipid droplet–mitochondria interactions (LDMIs) mediated by their aggregation has reshaped the understanding of how intracellular lipid metabolic networks operate within cells. Complex spatiotemporal interactions between lipid droplets and mitochondrial aggregates are commonly observed at the subcellular level, supporting the stable and efficient cycling of lipids and energy within the cell. Advanced techniques enabling organelle aggregation manipulation with high spatiotemporal precision have emerged as critical tools for investigating LDMIs and addressing diseases associated with LDMI dysregulation. This study aimed to summarize and update the distinctive characteristics of LDMIs and highlight the increasing understanding of their operational mechanisms, while also examining diseases caused by their dysfunction. Special emphasis was placed on the current challenges and prospects of strategies for the spatial aggregation manipulation of LDMIs, particularly the remarkable potential of optogenetic tools. With the continuous advancement of subcellular imaging and organelle aggregation manipulation technologies, LDMIs are poised to transform our understanding of cellular lipid metabolism networks and facilitate the effective manipulation of these complex networks at the organelle level.