Enhanced Ca 2+ -channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease
In: School of Medicine Faculty Publications, 2023
Online
academicJournal
Zugriff:
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.
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Enhanced Ca 2+ -channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease
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Autor/in / Beteiligte Person: | Thoudam, Themis ; Chanda, Dipanjan ; Lee, Jung Yi ; Jung, Min Kyo ; Sinam, Ibotombi Singh ; Kim, Byung Gyu ; Park, Bo Yoon ; Kwon, Woong Hee ; Kim, Hyo Jeong ; Kim, Myeongjin ; Lim, Chae Won ; Lee, Hoyul ; Huh, Yang Hoon ; Miller, Caroline A. ; Saxena, Romil ; Skill, Nicholas J. ; Huda, Nazmul ; Kusumanchi, Praveen ; Ma, Jing ; Yang, Zhihong ; Kim, Min Ji ; Mun, Ji Young ; Harris, Robert A. ; Jeon, Jae Han ; Liangpunsakul, Suthat ; Lee, In Kyu |
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Zeitschrift: | School of Medicine Faculty Publications, 2023 |
Veröffentlichung: | LSU Health Digital Scholar, 2023 |
Medientyp: | academicJournal |
DOI: | 10.1038/s41467-023-37214-4 |
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