Thoudam, ThemisChanda, DipanjanLee, Jung YiJung, Min-KyoSinam, Ibotombi SinghKim, Byung-GyuPark, Bo-YoonKwon, Woong HeeKim, Hyo-JeongKim, MyeongjinLim, Chae WonLee, HoyulHuh, Yang HoonMiller, Caroline A.Saxena, RomilSkill, Nicholas J.Huda, NazmulKusumanchi, PraveenMa, JingYang, ZhihongKim, Min-JiMun, Ji YoungHarris, Robert A.Jeon, Jae-HanLiangpunsakul, SuthatLee, In-Kyu2023-11-032023-11-032023-03-27Thoudam T, Chanda D, Lee JY, et al. Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease. Nat Commun. 2023;14(1):1703. Published 2023 Mar 27. doi:10.1038/s41467-023-37214-4https://hdl.handle.net/1805/36941Ca2+ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca2+ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca2+-channeling (MCC) complex formation promotes mitochondrial dysfunction in vitro and in male mouse model of ALD. Unbiased transcriptomic analysis reveals PDK4 as a prominently inducible MAM kinase in ALD. Analysis of human ALD cohorts further corroborate these findings. Additional mass spectrometry analysis unveils GRP75 as a downstream phosphorylation target of PDK4. Conversely, non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced MCC complex formation and subsequent mitochondrial Ca2+ accumulation and dysfunction. Finally, ectopic induction of MAM formation reverses the protective effect of PDK4 deficiency in alcohol-induced liver injury. Together, our study defines a mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD.en-USAttribution 4.0 InternationalPhosphorylationAlcoholic liver diseaseEndoplasmic reticulumMitochondriaArticle