Alcohol-related liver disease (ALD) is a condition caused by excessive and prolonged alcohol consumption, posing a significant global health issue as it can lead to severe liver damage, liver cirrhosis, and even liver failure. The condition is prevalent worldwide, current treatment approaches remain unsuccessful due to a lack of complete understanding of its underlying mechanisms. Korean researchers have identified mitochondrial damage in liver cells as a critical mechanism in ALD.

The research team led by Professor In-Kyu Lee (Kyungpook National University, School of medicine) has laid the groundwork for developing new treatments by elucidating the mechanism related to the formation of mitochondrial and cellular organelle complexes and mitochondrial calcium accumulation. 

The research team found that alcohol consumption increases PDK4 levels in liver cells, promoting the formation of the mitochondria-associated ER membrane (MAM) and accelerating calcium transport to the mitochondria. The study confirmed these findings in liver tissue analysis of ALD patients. In an ALD mouse model, the team demonstrated that increased PDK4 levels led to the formation of MAM calcium-channeling complexes, causing mitochondrial dysfunction.

Professor Lee emphasized the need for further research targeting PDK4 for treatment strategies and drug development, focusing on the development of effective and safe ALD treatments using PDK4 inhibitors. This multidisciplinary research was supported by the Ministry of Science and ICT and the Korea Research Foundation and was published in the international journal Nature Communications on March 27.

PDK4-mediated Ca2+-channeling complex formation at the ER-mitochondria contact site promotes mitochondrial dysfunction in alcohol-associated liver disease. 

[Reference] 

T. Thoudam et al. Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease. Nature Communications 14, 1703 (2023). https://doi.org/10.1038/s41467-023-37214-4

[Main Author] 

Themis Thoudam(Kyungpook National University/1st author), Suthat Liangpunsakul(Indiana University/corresponding author), In-Kyu Lee(Kyungpook National University/corresponding author)

* Contact : Professor In-Kyu Lee (leei@knu.ac.kr)