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

Authors

Themis Thoudam, Kyungpook National University
Dipanjan Chanda, Kyungpook National University
Jung Yi Lee, Kyungpook National University Hospital
Min Kyo Jung, Korea Brain Research Institute
Ibotombi Singh Sinam, Kyungpook National University Hospital
Byung Gyu Kim, Institute for Basic Science, Daejeon
Bo Yoon Park, Kyungpook National University
Woong Hee Kwon, Kyungpook National University Hospital
Hyo Jeong Kim, Korea Basic Science Institute
Myeongjin Kim, Kyungpook National University
Chae Won Lim, Kyungpook National University Hospital
Hoyul Lee, Kyungpook National University
Yang Hoon Huh, Korea Basic Science Institute
Caroline A. Miller, Indiana University School of Medicine
Romil Saxena, Indiana University School of Medicine
Nicholas J. Skill, LSU Health Sciences Center - New OrleansFollow
Nazmul Huda, Indiana University School of Medicine
Praveen Kusumanchi, Indiana University School of Medicine
Jing Ma, Indiana University School of Medicine
Zhihong Yang, Indiana University School of Medicine
Min Ji Kim, Kyungpook National University Chilgok Hospital
Ji Young Mun, Korea Brain Research Institute
Robert A. Harris, Indiana University School of Medicine
Jae Han Jeon, Kyungpook National University Chilgok Hospital
Suthat Liangpunsakul, Indiana University School of Medicine
In Kyu Lee, Kyungpook National University

Document Type

Article

Publication Date

3-27-2023

Publication Title

Nature Communications

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.

PubMed ID

36973273

Volume

14

Issue

1

Creative Commons License

This work is licensed under a Creative Commons Attribution-No Derivative Works 4.0 International License.

Recommended Citation

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; and Lee, In Kyu, "Enhanced Ca²⁺-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease" (2023). School of Medicine Faculty Publications. 834.
https://digitalscholar.lsuhsc.edu/som_facpubs/834
10.1038/s41467-023-37214-4

File Format

pdf

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