Lipid regulation of mitochondrial function in metabolic Diseases: Lipotoxic mediators and therapeutic targeting.

Lipid dysregulation is a key driver of chronic metabolic and degenerative diseases. However, lipid abnormalities and mitochondrial dysfunction are often examined separately, with limited attention given to their mechanistic links. As the central hub of energy metabolism, mitochondria continuously adapt their structure, substrate utilization, and quality control in response to the surrounding lipid environment and lipid-derived regulatory signals. This review examines mitochondrial function from the perspective of lipid regulation, focusing on how membrane lipid remodeling, lipid droplet-mitochondria coupling, substrate flux, bioactive lipid signaling, and mitochondrial turnover collectively determine mitochondrial function during lipid stress. In obesity, metabolic dysfunction-associated steatotic liver disease, type 2 diabetes, cardiovascular disease, and neurodegenerative disorders, disruption of lipid-dependent mitochondrial regulation manifests in tissue-specific patterns but consistently involves excessive lipid supply, aberrant membrane remodeling, and impaired mitochondrial quality control. These alterations do not arise from a single pathway but reflect the combined disruption of multiple lipid-related processes. This lipid-centered perspective identifies lipid imbalance as a central determinant of mitochondrial fate in disease and supports the critical evaluation of both the therapeutic potential and pharmacological limitations of targeting the lipid-mitochondria axis, with particular attention to target engagement, structural tractability, and translational feasibility.