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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.
Ca2+ overload-induced mitochondrial dysfunction is considered a contributing factor alcohol-associated liver disease pathogenesis. Here the authors report that PDK4 promotes Ca2 + -channelling complex formation at the endoplasmic reticulum-mitochondria contact sites, which contributes to the pathogenesis of alcohol-associated liver disease in studies with male mouse and hepatocyte models.
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1 Kyungpook National University, Research Institute of Aging and Metabolism, Daegu, Republic of Korea (GRID:grid.258803.4) (ISNI:0000 0001 0661 1556)
2 Kyungpook National University, Research Institute of Aging and Metabolism, Daegu, Republic of Korea (GRID:grid.258803.4) (ISNI:0000 0001 0661 1556); Kyungpook National University Hospital, Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Daegu, Republic of Korea (GRID:grid.411235.0) (ISNI:0000 0004 0647 192X)
3 Kyungpook National University Hospital, Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Daegu, Republic of Korea (GRID:grid.411235.0) (ISNI:0000 0004 0647 192X)
4 Korea Brain Research Institute, Neural Circuit Research Group, Daegu, Republic of Korea (GRID:grid.452628.f) (ISNI:0000 0004 5905 0571)
5 Kyungpook National University Hospital, Bio-Medical Research Institute, Daegu, Republic of Korea (GRID:grid.411235.0) (ISNI:0000 0004 0647 192X)
6 Institute for Basic Science (IBS), Center for Genomic Integrity, Ulsan, Republic of Korea (GRID:grid.410720.0) (ISNI:0000 0004 1784 4496)
7 Korea Basic Science Institute, Electron Microscopy Research Center, Ochang, Republic of Korea (GRID:grid.410885.0) (ISNI:0000 0000 9149 5707)
8 Kyungpook National University, Research Institute of Aging and Metabolism, Daegu, Republic of Korea (GRID:grid.258803.4) (ISNI:0000 0001 0661 1556); Daegu Catholic University, Department of Medicine, Daegu, Republic of Korea (GRID:grid.412072.2) (ISNI:0000 0004 0621 4958)
9 Kyungpook National University Hospital, Bio-Medical Research Institute, Daegu, Republic of Korea (GRID:grid.411235.0) (ISNI:0000 0004 0647 192X); Daegu Catholic University, Department of Medicine, Daegu, Republic of Korea (GRID:grid.412072.2) (ISNI:0000 0004 0621 4958)
10 Indiana University School of Medicine, Electron Microscopy Core, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919)
11 Indiana University School of Medicine, Department of Pathology and Laboratory Medicine, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919); Emory University School of Medicine, Department of Pathology and Laboratory Medicine, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502)
12 Louisiana State University Health Science Center, Department of Surgery, New Orleans, USA (GRID:grid.279863.1) (ISNI:0000 0000 8954 1233)
13 Indiana University School of Medicine, Division of Gastroenterology and Hepatology, Department of Medicine, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919)
14 Kyungpook National University Chilgok Hospital, Department of Internal Medicine, Daegu, Republic of Korea (GRID:grid.258803.4) (ISNI:0000 0001 0661 1556)
15 Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919)
16 Kyungpook National University Chilgok Hospital, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea (GRID:grid.258803.4) (ISNI:0000 0001 0661 1556)
17 Indiana University School of Medicine, Division of Gastroenterology and Hepatology, Department of Medicine, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919); Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919); Richard L. Roudebush VA Medical Center, Indianapolis, USA (GRID:grid.280828.8) (ISNI:0000 0000 9681 3540)
18 Kyungpook National University, Research Institute of Aging and Metabolism, Daegu, Republic of Korea (GRID:grid.258803.4) (ISNI:0000 0001 0661 1556); Kyungpook National University Hospital, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea (GRID:grid.411235.0) (ISNI:0000 0004 0647 192X)