Enhanced Ca²⁺-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease

• Type of Material: Article
• Authors: Themis Thoudam, Kyungpook National University; Dipanjan Chanda, Kyungpook National University; Jung Yi Lee, Kyungpook National University Hospital; Min-Kyo Jung, Korea Brain Research Institute; Ibotombi S Sinam, Kyungpook National University Hospital; Byung-Gyu Kim, Institute for Basic Science, Daejeon; Bo-Yoon Park, Kyungpook National University; Woong-Hee Kwon, Kyungpook National University Hospital; Hyo-Jeong Kim, Korea Basic Science Institute; Myeongjin Kim, Kyungpook National University; Chae Won Lim, Kyungpook National University Hospital; Hoyul Lee, Kyungpook National University; Yang Hoon Huh, Korea Basic Science Institute; Caroline A Miller, Indiana University School of Medicine; Romil Saxena, Emory University; Nicholas J Skill, LSU Health Sciences Center - New Orleans; Nazmul Huda, Indiana University School of Medicine; Praveen Kusumanchi, Indiana University School of Medicine; Jing Ma, Indiana University School of Medicine; Zhijong Yang, Indiana University School of Medicine; Min-Ji Kim, Kyungpook National University Chilgok Hospital; Ji-Young Mun, Korea Brain Research Institute; Robert A Harris, Indiana University School of Medicine; Jae-Han Jeon, Kyungpook National University Chilgok Hospital; Suthat Liangpunsakul, Indiana University School of Medicine; In-Kyu Lee, Kyungpook National University
• Language: English
• Date: 2023-12-01
• Publisher: Springer Nature Limited
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-023-37214-4
• Title of Journal or Parent Work: Nature Communications
• Volume: 14
• Issue: 1
• Start Page: 1703
• End Page: 1703
• Keywords: Animals; Mitochondria; Liver Diseases; Mice; Male; Endoplasmic Reticulum; Humans
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

Ca2+ 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.