Lipid Droplets and Mitochondria: From Static Depots to Dynamic Metabolic Dialogue as a Therapeutic Target

The essay critically analyzes the role of physical and functional contacts between lipid droplets and mitochondria (MLCs) in maintaining cellular lipid and redox homeostasis and in the pathogenesis of metabolic and neurodegenerative diseases. The molecular architecture of MLCs, including the involvement of PLIN5, Mfn2, FATP4, Rab8a, SNAP23, CIDE proteins, and seipin, as well as the mechanisms of fatty acid transport into mitochondria for β-oxidation, are reviewed. Based on data from cellular and animal models, it has been shown that dysregulation of MLCs accompanies obesity, type 2 diabetes, MASLD, cardiovascular, and neurodegenerative disorders. The central thesis is that MLC disruption is not only a marker of lipotoxicity, but also a causally significant early driver of metabolic dysfunction; accordingly, stabilization or restoration of these contacts may be a promising therapeutic strategy. At the same time, the counterargument about the adaptive nature of MLC and the tissue specificity of their regulation is critically reviewed. The need for clinical validation of MLC modulators, improvement of contact imaging methods, and longitudinal studies to establish cause-and-effect relationships is emphasized.