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

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Title
Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease
Author(s)
Thoudam, T.; Chanda, D.; Lee, J.Y.; Jung, M.-K.; Sinam, I.S.; Byung Gyu Kim; Park, B.-Y.; Kwon, W.H.; Kim, H.-J.; Kim, M.; Lim, C.W.; Lee, H.; Huh, Y.H.; Miller, C.A.; Saxena, R.; Skill, N.J.; Huda, N.; Kusumanchi, P.; Ma, J.; Yang, Z.; Kim, M.-J.; Mun, J.Y.; Harris, R.A.; Jeon, J.-H.; Liangpunsakul, S.; Lee, I.-K.
Publication Date
2023-03
Journal
Nature communications, v.14, no.1, pp.1703
Publisher
NLM (Medline)
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. © 2023. The Author(s).
URI
https://pr.ibs.re.kr/handle/8788114/13376
DOI
10.1038/s41467-023-37214-4
ISSN
2041-1723
Appears in Collections:
HiddenCommunity > 1. Journal Papers (저널논문)
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