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Enhanced Ca 2+ -channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease.
- Source :
-
Nature communications [Nat Commun] 2023 Mar 27; Vol. 14 (1), pp. 1703. Date of Electronic Publication: 2023 Mar 27. - Publication Year :
- 2023
-
Abstract
- Ca <superscript>2+</superscript> 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 Ca <superscript>2+</superscript> accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca <superscript>2+</superscript> -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 Ca <superscript>2+</superscript> 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.<br /> (© 2023. The Author(s).)
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 36973273
- Full Text :
- https://doi.org/10.1038/s41467-023-37214-4