Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease
dc.contributor.author | Thoudam, Themis | |
dc.contributor.author | Chanda, Dipanjan | |
dc.contributor.author | Lee, Jung Yi | |
dc.contributor.author | Jung, Min-Kyo | |
dc.contributor.author | Sinam, Ibotombi Singh | |
dc.contributor.author | Kim, Byung-Gyu | |
dc.contributor.author | Park, Bo-Yoon | |
dc.contributor.author | Kwon, Woong Hee | |
dc.contributor.author | Kim, Hyo-Jeong | |
dc.contributor.author | Kim, Myeongjin | |
dc.contributor.author | Lim, Chae Won | |
dc.contributor.author | Lee, Hoyul | |
dc.contributor.author | Huh, Yang Hoon | |
dc.contributor.author | Miller, Caroline A. | |
dc.contributor.author | Saxena, Romil | |
dc.contributor.author | Skill, Nicholas J. | |
dc.contributor.author | Huda, Nazmul | |
dc.contributor.author | Kusumanchi, Praveen | |
dc.contributor.author | Ma, Jing | |
dc.contributor.author | Yang, Zhihong | |
dc.contributor.author | Kim, Min-Ji | |
dc.contributor.author | Mun, Ji Young | |
dc.contributor.author | Harris, Robert A. | |
dc.contributor.author | Jeon, Jae-Han | |
dc.contributor.author | Liangpunsakul, Suthat | |
dc.contributor.author | Lee, In-Kyu | |
dc.contributor.department | Pathology and Laboratory Medicine, School of Medicine | |
dc.date.accessioned | 2023-11-03T11:43:33Z | |
dc.date.available | 2023-11-03T11:43:33Z | |
dc.date.issued | 2023-03-27 | |
dc.description.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. | |
dc.eprint.version | Final published version | |
dc.identifier.citation | Thoudam 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/s41467-023-37214-4 | |
dc.identifier.uri | https://hdl.handle.net/1805/36941 | |
dc.language.iso | en_US | |
dc.publisher | Springer Nature | |
dc.relation.isversionof | 10.1038/s41467-023-37214-4 | |
dc.relation.journal | Nature Communications | |
dc.rights | Attribution 4.0 International | en |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.source | PMC | |
dc.subject | Phosphorylation | |
dc.subject | Alcoholic liver disease | |
dc.subject | Endoplasmic reticulum | |
dc.subject | Mitochondria | |
dc.title | Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease | |
dc.type | Article |