1. Enhanced Ca 2+ -channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease.
- Author
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Thoudam T, Chanda D, Lee JY, Jung MK, Sinam IS, Kim BG, Park BY, Kwon WH, Kim HJ, Kim M, Lim CW, Lee H, Huh YH, Miller CA, Saxena R, Skill NJ, Huda N, Kusumanchi P, Ma J, Yang Z, Kim MJ, Mun JY, Harris RA, Jeon JH, Liangpunsakul S, and Lee IK
- Subjects
- Mice, Animals, Male, Humans, Mitochondria, Endoplasmic Reticulum metabolism, Liver Diseases metabolism
- Abstract
Ca
2+ 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).)- Published
- 2023
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