Impact of mitochondrial lipid alterations on liver disease mechanisms and progression

Lipids are intricate biomolecules responsible for the building up of biological membranes. Besides this structural function, they also display crucial roles in signaling, acting as second messengers that activate specific pathways. Mitochondria are fundamental for cells as they participate in several pivotal functions, such as ATP synthesis, cell survival, metabolic pathways, and calcium homeostasis. Thus, the lipid composition of mitochondrial membranes can affect specific proteins and impact vital functions of mitochondria, such as oxidative phosphorylation and dynamics. The liver possesses a critical function in lipid homeostasis, involving the generation, oxidation, and trafficking of free fatty acids (FFA), triglycerides (TG), cholesterol, and bile acids (BAs). Mitochondria play a key role in lipid storage regulation in hepatocytes, which can control liver function. Their diverse tasks are affected by the lipid composition of mitochondrial membranes, characterized by low cholesterol content and enrichment of specific lipids such as cardiolipin. As mitochondria determine the bioenergetic status of cells and are key regulators of cell viability, alterations of mitochondrial lipid composition can contribute to the induction and progression of chronic diseases, including alcohol-related liver disease (ARLD) and metabolic dysfunction-associated steatotic liver disease (MASLD), two of the most common forms of liver diseases characterized by steatosis, necroinflammation, and fibrosis, which can progress to hepatocellular carcinoma (HCC). Thus, the disruption of lipid metabolism and membrane composition of mitochondria are characteristic features of cancer cells, and altered mitochondrial lipid composition may be a critical player in the progression of chronic liver diseases toward HCC. This review will address the mechanisms whereby alterations of mitochondrial lipid composition lead to the onset and progression of chronic liver diseases. Thus, a better characterization of the alterations of lipid composition in mitochondria may be a crucial step to design strategies and novel therapeutic opportunities for the treatment of MASLD and ARLD.