Abstract
Metabolic diseases, a major challenge in global public health, are commonly characterized by insulin resistance, lipid metabolism disorders, and mitochondrial dysfunction, and their pathological processes are often accompanied by the abnormal accumulation of lipids in metabolically active tissues such as the liver, heart, and skeletal muscle. Recently, lipid droplets and mitochondria have been shown to interact with each other through membrane contact sites and play a central role in maintaining cellular metabolic homeostasis. The unique monolayer phospholipid membrane structure and formation process of lipid droplets, along with the double-membrane structure and diverse functions of mitochondria, together form the basis for their interaction. There are two modes of interaction, namely dynamic contact and stable anchoring, which are mediated by a variety of proteins to achieve efficient exchange and metabolic regulation of metabolites such as fatty acids. However, dysregulation of lipid droplet-mitochondria interactions initiates a pathogenic cascade involving fatty acid overload, increased reactive oxygen species generation, and mitochondrial dysfunction. These perturbations drive the pathogenesis of metabolic disorders. This review systematically summarizes the key pathological roles of dysregulated lipid droplet-mitochondrial interactions in globally prevalent metabolic diseases such as diabetes mellitus, metabolic dysfunction-associated fatty liver disease, and obesity. This in-depth analysis of molecular mechanisms clarifies the physiological basis of the regulation of lipid homeostasis in the body and provides a theoretical basis for developing novel therapeutic strategies for these diseases to alleviate the related growing global health burden.