Mitochondrial MFN2 integrates the function of multiple organelles to regulate metabolic dysfunction-associated steatotic liver disease: mechanisms and therapeutic insights.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a wide spectrum of liver diseases with increasing global prevalence. Its hallmarks include aberrant lipid accumulation and inflammation, which lead to liver fibrosis. The efficacious therapies for treating MASLD are limited, and the response rates to antifibrotic drugs are moderate. Understanding the novel mechanisms that regulate the progression of MASLD enables the discovery of drugs with higher response rates and safety. Besides the canonical pathogenic pathways, the dysfunctions in the contacts and communication between mitochondria, endoplasmic reticulum (ER) and lipid droplet (LD) causatively drive and promote MASLD. Mitofusin-2 (MFN2) is a mitochondria-bound GTPase that stimulates mitochondrial fusion and is an emerging key factor that suppresses the progression of MASLD and liver fibrosis by maintaining the contact between mitochondria, ER and LD. MFN2 interacts with distinct binding proteins in the ER to facilitate the ER-to-mitochondria transfer of Ca2+ and phosphatidylserine. Moreover, MFN2 is essential for mitochondria-LD contact, which facilitates the lipid transfer and maintains homeostasis. Our analyses indicate that MFN2 is a validated therapeutic target, and exercise elevates the expression of mitochondrial MFN2 to enhance fatty acid oxidation. Regarding translational potential, the advantages and limitations of small-molecule- and peptide-based MFN2 agonists are critically discussed. They effectively induce conformational change and activation of MFN2. We demonstrate that echinacoside and compound 5 are the most promising lead compounds for future development. Evaluation of their anti-MASLD and antifibrotic activities and the combination with current therapies and exercise to combat MASLD is warranted in the future.