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경북대학교 의과대학

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Nat. Commun., 2023 Mar 27;14(1):1703 | https://doi.org/10.1038/s41467-023-37214-4 Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease

Themis Thoudam ¹, Dipanjan Chanda ^1,2, Jung Yi Lee ², Min-Kyo Jung³, Ibotombi Singh Sinam ⁴, Byung-Gyu Kim ⁵, Bo-Yoon Park ¹, Woong Hee Kwon ², Hyo-Jeong Kim ⁶, Myeongjin Kim^1,7, Chae Won Lim^4,7, Hoyul Lee¹, Yang Hoon Huh⁶, Caroline A. Miller⁸, Romil Saxena^9,10, Nicholas J. Skill¹¹, Nazmul Huda¹², Praveen Kusumanchi¹², Jing Ma¹², Zhihong Yang¹², Min-Ji Kim¹³, Ji Young Mun³, Robert A. Harris¹⁴, Jae-Han Jeon¹⁵, Suthat Liangpunsakul ^12,14,16,18 & In-Kyu Lee ^1,17,18

¹Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea.
²Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea.
³Neural Circuit Research Group, Korea Brain Research Institute, Daegu, Republic of Korea.
⁴Bio-Medical Research Institute, Kyungpook National University Hospital, Daegu, Republic of Korea.
⁵Center for Genomic Integrity, Institute for Basic Science (IBS), Ulsan, Republic of Korea.
⁶Electron Microscopy Research Center, Korea Basic Science Institute, Ochang, Chungbuk, Republic of Korea.
⁷Department of Medicine, Daegu Catholic University, Daegu, Republic of Korea.
⁸Electron Microscopy Core, Indiana University School of Medicine, Indianapolis, IN, USA.
⁹Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁰Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
¹¹Department of Surgery, Louisiana State University Health Science Center, New Orleans, LA, USA.
¹²Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹³Department of Internal Medicine, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea.
¹⁴Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁵Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea.
¹⁶Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.
¹⁷Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
¹⁸These authors jointly supervised this work: Suthat Liangpunsakul, In-Kyu Lee.

Corresponding authors : Correspondence to Suthat Liangpunsakul or In-Kyu Lee.

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.

논문정보

형식Research article
게재일2023년 03월 (BRIC 등록일 2023-04-07)
연구진국내(교신)+국외 연구진
분야 의약학 > 응용의학

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