Mechanisms of Lipid Droplet-Mitochondria Interactions and Their Roles in Diseases

Lipid droplets (LDs) coordinate cellular lipid utilization, energy homeostasis, redox balance, and autophagy through dynamic inter-organelle communication with mitochondria. This review summarized recent advances in the molecular mechanisms regulating LD-mitochondria interactions and discusses how their dysregulation contributes to disease progression. Accumulating evidence has indicated that the contacts between LD and mitochondria are dynamically regulated through specialized membrane contact sites and protein complexes, such as Perilipin (PLIN) family of proteins, Mitofusin2 (Mfn2), and Rab GTPases. Rather than being a passive structural association, this interaction serves as a regulatory hub that integrates fatty acid (FA) transport, metabolic adaptation, and stress responses. It enables bidirectional regulation of lipid metabolism, allowing cells to flexibly and efficiently switch between lipid storage and FA oxidation in response to metabolic signals. Disruption of this inter-organelle communication impairs intracellular lipid utilization, compromises mitochondrial function, and exacerbates oxidative stress and ferroptosis. Such dysfunction is increasingly recognized as a core mechanism underlying metabolic disorders, cardiovascular diseases and neurodegenerative diseases. In the future, integration of protein regulation, gene editing technologies, and precision therapeutic approaches may enable specific targeting of LD-mitochondria communication, thereby offering new avenues for the treatment of relevant diseases.