Enhanced Ca 2+ -channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease

Ca 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 accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in...

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Published inNature communications Vol. 14; no. 1; p. 1703
Main Authors 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
Format Journal Article
LanguageEnglish
Published England 27.03.2023
Subjects
Animals
Endoplasmic Reticulum - metabolism
Humans
Liver Diseases - metabolism
Male
Mice
Mitochondria
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Summary:Ca 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 accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca -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 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.
ISSN:2041-1723